Search

Background: This study aimed to investigate the association between sugammadex use and the occurrence of delayed passage of first flatus and oral intake tolerance following open pancreaticoduodenectomy (PD)., Methods: We reviewed consecutive patients who underwent open PD between 2015 and 2019; subsequently, they were divided into the sugammadex (group S) and neostigmine with anticholinergics (group N) groups based on the reversal agent used. We performed stabilized inverse probability of treatment weighting (IPTW) analysis to adjust for baseline differences between the groups. We compared the delayed passage of first flatus, oral intake tolerance, and other postoperative outcomes between the groups before and after IPTW., Results: Of the 736 included patients, 309 (42.0%) received sugammadex. Stabilized IPTW revealed a significantly lower occurrence of delayed passage of first flatus in group S (19.3%) compared to group N (28.3%) (OR 0.61, 95% CI: 0.43-0.86, P=0.005). Further, there was a significantly lower occurrence of delayed oral intake tolerance in group S (19.9%) than in group N (27.7%) (OR 0.65, 95% CI: 0.46-0.92, P=0.016)., Conclusions: Compared to previous reversal agents, sugammadex use was significantly associated with a decrease in the occurrence of prolonged time to first flatus and oral intake tolerance following open PD.

Background: The antitumor efficacy of human epidermal growth factor receptor 2 (HER2)-targeted therapies, such as humanized monoclonal antibody trastuzumab (Herceptin®, Roche), in patients with breast-to-brain cancer metastasis is hindered by the low permeability of the blood-brain barrier (BBB). NEO100 is a high-purity version of the natural monoterpene perillyl alcohol, produced under current good manufacturing practice (cGMP) regulations, that was shown previously to reversibly open the BBB in rodent models. Here we investigated whether NEO100 could enable brain entry of trastuzumab to achieve greater therapeutic activity., Methods: An in vitro BBB, consisting of human astrocytes and brain endothelial cells, was used to determine trastuzumab penetration in the presence or absence of NEO100. For in vivo studies, we administered intravenous (IV) trastuzumab or the trastuzumab-drug conjugate ado-trastuzumab emtansine (T-DM1; Kadcyla®, Roche), to mouse models harboring intracranial HER2+ breast cancer, with or without BBB opening via IA NEO100. Brain and tumor tissues were examined for the presence of trastuzumab and infiltration of immune cells. Therapeutic impact was evaluated based on overall survival., Results: NEO100 greatly increased trastuzumab penetration across an in vitro BBB. In vivo, IA NEO100-mediated BBB opening resulted in brain tumor-selective accumulation of trastuzumab, without detectable presence in normal brain tissue, along with increased presence of immune cell populations. IV delivery of trastuzumab or T-DM1 achieved significantly greater overall survival of tumor-bearing mice when combined with IA NEO100., Conclusion: IA NEO100 facilitates brain tumor entry of trastuzumab and T-DM1 and significantly enhances their therapeutic efficacy, along with increased antibody-dependent immune cell recruitment., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

SM-102 (1-octylnonyl 8-[(2-hydroxyethyl)[6-oxo-6-(undecyloxy)hexyl]amino]-octanoate) is an amino cationic lipid that has been tailored for the formation of lipid nanoparticles and it is one of the essential ingredients present in the Moderna TM COVID-19 vaccine. However, to what extent it may modify varying types of plasmalemmal ionic currents remains largely uncertain. In this study, we investigate the effects of SM-102 on ionic currents either in two types of endocrine cells (e.g., rat pituitary tumor (GH 3 ) cells and mouse Leydig tumor (MA-10) cells) or in microglial (BV2) cells. Hyperpolarization-activated K + currents in these cells bathed in high-K + , Ca 2+ -free extracellular solution were examined to assess the effects of SM-102 on the amplitude and hysteresis of the erg-mediated K + current (I K(erg) ). The SM-102 addition was effective at blocking I K(erg) in a concentration-dependent fashion with a half-maximal concentration (IC 50 ) of 108 μM, a value which is similar to the K D value (i.e., 134 μM) required for its accentuation of deactivation time constant of the current. The hysteretic strength of I K(erg) in response to the long-lasting isosceles-triangular ramp pulse was effectively decreased in the presence of SM-102. Cell exposure to TurboFectin TM 8.0 (0.1%, v / v ), a transfection reagent, was able to inhibit hyperpolarization-activated I K(erg) effectively with an increase in the deactivation time course of the current. Additionally, in GH 3 cells dialyzed with spermine (30 μM), the I K(erg) amplitude progressively decreased; moreover, a further bath application of SM-102 (100 μM) or TurboFectin (0.1%) diminished the current magnitude further. In MA-10 Leydig cells, the I K(erg) was also blocked by the presence of SM-102 or TurboFectin. The IC 50 value for SM-102-induced inhibition of I K(erg) in MA-10 cells was 98 μM. In BV2 microglial cells, the amplitude of the inwardly rectifying K + current was inhibited by SM-102. Taken together, the presence of SM-102 concentration-dependently inhibited I K(erg) in endocrine cells (e.g., GH 3 or MA-10 cells), and such action may contribute to their functional activities, assuming that similar in vivo findings exist.

Inferring phenotypic outcomes from genomic features is both a promise and challenge for systems biology. Using gene expression data to predict phenotypic outcomes, and functionally validating the genes with predictive powers are two challenges we address in this study. We applied an evolutionarily informed machine learning approach to predict phenotypes based on transcriptome responses shared both within and across species. Specifically, we exploited the phenotypic diversity in nitrogen use efficiency and evolutionarily conserved transcriptome responses to nitrogen treatments across Arabidopsis accessions and maize varieties. We demonstrate that using evolutionarily conserved nitrogen responsive genes is a biologically principled approach to reduce the feature dimensionality in machine learning that ultimately improved the predictive power of our gene-to-trait models. Further, we functionally validated seven candidate transcription factors with predictive power for NUE outcomes in Arabidopsis and one in maize. Moreover, application of our evolutionarily informed pipeline to other species including rice and mice models underscores its potential to uncover genes affecting any physiological or clinical traits of interest across biology, agriculture, or medicine., (© 2021. The Author(s).)

Oxidative stress is caused by an imbalance between the production of reactive oxygen species (ROS) in cells and tissues and the ability of a biological system to detoxify them. During a normal pregnancy, oxidative stress increases the normal systemic inflammatory response and is usually well-controlled by the balanced body mechanism of the detoxification of anti-oxidative products. However, pregnancy is also a condition in which this adaptation and balance can be easily disrupted. Excessive ROS is detrimental and associated with many pregnancy complications, such as preeclampsia (PE), fetal growth restriction (FGR), gestational diabetes mellitus (GDM), and preterm birth (PTB), by damaging placentation. The placenta is a tissue rich in mitochondria that produces the majority of ROS, so it is important to maintain normal placental function and properly develop its vascular network to ensure a safe and healthy pregnancy. Antioxidants may ameliorate these diseases, and related research is progressing. This review aimed to determine the association between oxidative stress and adverse pregnancy outcomes, especially PE, FGR, GDM, and PTB, and explore how to overcome this oxidative stress in these unfavorable conditions.

Ozone (O 3 ) is the predominant oxidant air pollutant associated with airway inflammation, lung dysfunction, and the worsening of preexisting respiratory diseases. We previously demonstrated the injurious roles of pulmonary immune receptors, tumor necrosis factor receptor (TNFR), and toll-like receptor 4, as well as a transcription factor NF-κB, in response to O 3 in mice. In the current study, we profiled time-dependent and TNFR- and NF-κB-regulated lung transcriptome changes by subacute O 3 to illuminate the underlying molecular events and downstream targets. Mice lacking Tnfr1 / Tnfr2 ( Tnfr -/- ) or Nfkb1 ( Nfkb1 -/- ) were exposed to air or O 3 . Lung RNAs were prepared for cDNA microarray analyses, and downstream and upstream mechanisms were predicted by pathway analyses of the enriched genes. O 3 significantly altered the genes involved in inflammation and redox (24 h), cholesterol biosynthesis and vaso-occlusion (48 h), and cell cycle and DNA repair (48-72 h). Transforming growth factor-β1 was a predicted upstream regulator. Lack of Tnfr suppressed the immune cell proliferation and lipid-related processes and heightened epithelial cell integrity, and Nfkb1 deficiency markedly suppressed lung cell cycle progress during O 3 exposure. Common differentially regulated genes by TNFR and NF-κB1 (e.g., Casp8 , Il6 , and Edn1 ) were predicted to protect the lungs from cell death, connective tissue injury, and inflammation. Il6 -deficient mice were susceptible to O 3 -induced protein hyperpermeability, indicating its defensive role, while Tnf -deficient mice were resistant to overall lung injury caused by O 3 . The results elucidated transcriptome dynamics and provided new insights into the molecular mechanisms regulated by TNFR and NF-κB1 in pulmonary subacute O 3 pathogenesis.

Automatic three-dimensional (3-D) reconstruction of the coronary arteries (CA) from medical imaging modalities is still a challenging task. In this study, we present a deep learning-based method of automatic identification of the two ends of the vessel from X-ray coronary angiography (XCA). We also present a method of using template models of CA in matching the two-dimensional segmented vessels from two different angles of XCA. For the deep learning network, we used a U-net consisting of an encoder (Resnet) and a decoder. The two ends of the vessel were manually labeled to generate training images. The network was trained with 2,342, 1,907, and 1,523 labeled images for the left anterior descending (LAD), left circumflex (LCX), and right coronary artery (RCA), respectively. For template models of CA, ten reconstructed 3-D models were averaged for each artery. The accuracy of correspondence using template models was compared with that of manual matching. The deep learning network pointed the proximal region (20% of the total length) in 97.7, 97.5, and 96.4% of 315, 201, and 167 test images for LAD, LCX, and RCA, respectively. The success rates in pointing the distal region were 94.9, 89.8, and 94.6%, respectively. The average distances between the projected points from the reconstructed 3-D model to the detector and the points on the segmented vessels were not statistically different between the template and manual matchings. The computed FFR was not significantly different between the two matchings either. Deep learning methodology is feasible in identifying the two ends of the vessel in XCA, and the accuracy of using template models is comparable to that of manual correspondence in matching the segmented vessels from two angles., Competing Interests: MH, S-BH, HY, JK, DK, WH, A-JR, HC, and ES were employed by the company AI Medic, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hwang, Hwang, Yu, Kim, Kim, Hong, Ryu, Cho, Zhang, Koo and Shim.)

Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a free radical scavenger approved for the treatment of amyotrophic lateral sclerosis, a fatal neuromuscular disease. Edaravone is administered as an intravenous infusion over 60 min for several treatment cycles. To ease the burden of patients and caregivers, the oral formulation of edaravone has been developed. The purpose of this study was to evaluate pharmacokinetics and tissue distribution of TEJ-1704, an edaravone oral prodrug, in male Sprague Dawley rats and beagle dogs. Animal experiments were conducted using Sprague Dawley rats and beagle dogs to evaluate pharmacokinetics, tissue distribution, and excretion of TEJ-1704. Blood, tissues, cerebrospinal fluid, urine, and feces samples were collected at designated sampling time after intravenous (IV) or oral (PO) administration of edaravone or TEJ-1704. A modified bioanalysis method was developed to quantify edaravone in samples including plasma, tissues, cerebrospinal fluid, urine, and feces. The bioanalysis method was validated and successfully applied to pharmacokinetics, tissue distribution, and excretion studies of the novel edaravone prodrug. Although plasma C max of TEJ-1704 was low, groups administered with TEJ-1704 had high AUC inf , suggesting continuous metabolism of TEJ-1704 into edaravone. Groups treated with TEJ-1704 also showed lower CSF distribution than the control groups. After the administration of TEJ-1704, the majority of edaravone was distributed to the heart, lung, and kidney. It was excreted equally via urine and feces. The pharmacokinetics, tissue distribution, and excretion of TEJ-1704, a novel edaravone oral prodrug, were successfully characterized. Additional studies are needed to fully understand the difference between TEJ-1704 and edaravone and determine the potency of TEJ-1704.

Apocynin ( aPO , 4'-Hydroxy-3'-methoxyacetophenone) is a cell-permeable, anti-inflammatory phenolic compound that acts as an inhibitor of NADPH-dependent oxidase (NOX). However, the mechanisms through which aPO can interact directly with plasmalemmal ionic channels to perturb the amplitude or gating of ionic currents in excitable cells remain incompletely understood. Herein, we aimed to investigate any modifications of aPO on ionic currents in pituitary GH 3 cells or murine HL-1 cardiomyocytes. In whole-cell current recordings, GH 3 -cell exposure to aPO effectively stimulated the peak and late components of voltage-gated Na+ current (I Na ) with different potencies. The EC 50 value of aPO required for its differential increase in peak or late I Na in GH 3 cells was estimated to be 13.2 or 2.8 μM, respectively, whereas the K D value required for its retardation in the slow component of current inactivation was 3.4 μM. The current-voltage relation of I Na was shifted slightly to more negative potential during cell exposure to aPO (10 μM); however, the steady-state inactivation curve of the current was shifted in a rightward direction in its presence. Recovery of peak I Na inactivation was increased in the presence of 10 μM aPO . In continued presence of aPO , further application of rufinamide or ranolazine attenuated aPO -stimulated I Na . In methylglyoxal- or superoxide dismutase-treated cells, the stimulatory effect of aPO on peak I Na remained effective. By using upright isosceles-triangular ramp pulse of varying duration, the amplitude of persistent I Na measured at low or high threshold was enhanced by the aPO presence, along with increased hysteretic strength appearing at low or high threshold. The addition of aPO (10 μM) mildly inhibited the amplitude of erg-mediated K+ current. Likewise, in HL-1 murine cardiomyocytes, the aPO presence increased the peak amplitude of I Na as well as decreased the inactivation or deactivation rate of the current, and further addition of ranolazine or esaxerenone attenuated aPO -accentuated I Na . Altogether, this study provides a distinctive yet unidentified finding that, despite its effectiveness in suppressing NOX activity, aPO may directly and concertedly perturb the amplitude, gating and voltage-dependent hysteresis of I Na in electrically excitable cells. The interaction of aPO with ionic currents may, at least in part, contribute to the underlying mechanisms through which it affects neuroendocrine, endocrine or cardiac function.

Background: Spasticity is a factor that impairs the independent functional ability of stroke patients, and noninvasive methods such as electrical stimulation or taping have been reported to have antispastic effects. The purpose of this study was to investigate the effects of transcutaneous electrical nerve stimulation (TENS) combined with taping on spasticity, muscle strength, and gait ability in stroke patients., Methods: From July to October 2020, 46 stroke patients with moderate spasticity in the plantar flexors participated and were randomly assigned to the TENS group ( n = 23) and the TENS+taping group ( n = 23). All subjects performed a total of 30 sessions of functional training for 30 min/session, 5 days/week, for 6 weeks. For therapeutic exercise, sit-to-standing, indoor walking, and stair walking were performed for 10 min each. In addition, all participants in both groups received TENS stimulation around the peroneal nerve for 30 min before performing functional training. In the TENS+taping group, taping was additionally applied to the feet, ankles, and shin area after TENS, and the taping was replaced once a day. The composite spasticity score and handheld dynamometer measurements were used to assess the intensity of spasticity and muscle strength, respectively. Gait ability was measured using a 10 m walk test., Results: The spasticity score and muscle strength were significantly improved in the TENS+taping group compared to those in the TENS group ( p < 0.05). A significant improvement in gait speed was observed in the TENS+taping group relative to that in the TENS group ( p < 0.05)., Conclusions: Thus, TENS combined with taping may be useful in improving spasticity, muscle strength, and gait ability in stroke patients. Based on these results, an additional application of taping could be used to enhance the antispastic effect of TENS or other electrical stimulation treatments in the clinic. A long-term follow-up study is needed to determine whether the spasticity relieving effect persists after taping is removed., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021 Tae-Sung In et al.)

This study aimed to assess the association between smartphone use in the sitting posture and changes in thoracolumbar kyphosis, lumbar lordosis, and pelvic asymmetry in adolescents with low back pain (LBP). Twenty-five adolescents with LBP and 25 healthy adolescents participated in this study. They were instructed to sit on a height-adjustable chair with their hips and knees bent at 90° for 30 min in their usual sitting postures. Thoracolumbar kyphosis, lumbar lordosis, and pelvic asymmetry were measured using a three-dimensional motion capture system. Thoracolumbar kyphosis and lumbar lordosis increased after 30 min of sitting compared to the baseline. In both groups, thoracic kyphosis and lumbar lordosis angle increased with increasing sitting time. Compared to healthy adolescents, adolescents with LBP presented greater thoracolumbar kyphosis and lumbar lordosis after prolonged sitting. Pelvic asymmetry showed no significant difference between the sitting time and groups. Using a smartphone during prolonged sitting may lead to a slumped posture; these associations were more pronounced in adolescents with LBP.

A variety of robotic exoskeletons have been developed for patients with spinal cord injuries. However, the optimal training method and period for using a robotic exoskeleton have been uncertain until now. The purpose of this study is to determine the minimum training period for using a robotic exoskeleton with minimal muscle activity by investigating the changes in muscle activity and muscle characteristics of healthy adults during robotic exoskeleton training. A total of 16 people participated in the study. The robotic exoskeleton locomotion training consisted of three 50-min sessions a week for 7 weeks. The assessment consisted of sitting, standing, wide standing, sit-to-stand, and stand-to-sit where muscle activity and muscle characteristics were measured during each motion. All measurements were performed in the first session and every five sessions. Participants showed decreased muscle activity up to 10 sessions of training in the standing position, and 15 sessions in sit-to-stand and stand-to-sit motions. Upper extremity muscles showed decreased muscle activity, tone, stiffness, and logarithmic decrement up to the 15th session. The study results show that at least 15 training sessions are required to use the robotic exoskeleton with minimal load on the musculoskeletal system, and longer training is required for patients with spinal cord injury.

The effects of electrotherapy with task-oriented training on upper limb function in subacute stroke patients are unclear. This study investigated the influence of transcutaneous electrical nerve stimulation (TENS) with task-oriented training on spasticity, hand function, upper limb function, and activities of daily living in patients with subacute stroke. Forty-eight patients with subacute stroke were randomly assigned to either the TENS group (n = 22) or the placebo-TENS group (n = 21). High-frequency (100 Hz) TENS with below-motor threshold intensity or placebo-TENS was applied for 30 min/day, five times a week, for 4 weeks. The two groups also received task-oriented training after TENS. The Modified Ashworth Scale (MAS), Jebsen-Taylor Hand Function Test (JTHFT), Manual Function Test (MFT), and Modified Barthel Index (MBI) were used to assess spasticity, hand function, upper limb function, and activities of daily living, respectively. There was a significant time-group interaction with the MFT ( p = 0.003). The TENS group showed significantly improved MAS ( p = 0.003), JTHFT ( p < 0.001), MFT ( p < 0.001), and MBI ( p < 0.001) scores after the intervention. The placebo-TENS group showed significantly improved JTHFT ( p < 0.001), MFT ( p = 0.001), and MBI scores ( p < 0.001). There was a significant correlation between the MFT and MBI scores ( p = 0.025). These results suggest that electrotherapy with task-oriented training can be used to improve upper limb function in patients with subacute stroke.

Gumiganghwal-tang is a traditional herbal medicine widely used for its anti-inflammatory, analgesic, and antipyretic effects. However, the safety and efficacy of its active ingredients based on an in vivo pharmacokinetic (PK) study have yet been investigated. We have established a sensitive and accurate UPLC-ESI-MS/MS method and conducted a PK study on 14 constituents of Gumiganghwal-tang through human plasma analysis. Analytical conditions were optimized according to the physicochemical properties of the 14 compounds to facilitate efficient separation and eliminate overlap or interference between peaks. KINETEX-C 18 and Inertsil-C 8 columns were used as UPLC stationary phases, and acetonitrile and aqueous formic acid were used as mobile phases. All the analytes were quantified with a triple quadrupole mass spectrometer using electrospray ionization in multiple reaction monitoring mode. The chromatograms of 14 bioactive compounds showed excellent elution and sensitivity, and each peak was selectively separated and quantified without interference with each other or impurities. The established analytical method was based on international guidelines and was successfully used to perform PK studies of 14 herbal ingredients in humans after oral administration with Gumiganghwal-tang tablets. The oral absorption of most active components of Gumiganghwal-tang was relatively rapid and remained considerably long in the body to be quantified in plasma up to 48 h after administration., Competing Interests: The authors declare that there are no conflicts of interest., (© 2020 Xi'an Jiaotong University. Production and hosting by Elsevier B.V.)

Driver drowsiness is a major cause of fatal accidents throughout the world. Recently, some studies have investigated steering wheel grip force-based alternative methods for detecting driver drowsiness. In this study, a driver drowsiness detection system was developed by investigating the electromyography (EMG) signal of the muscles involved in steering wheel grip during driving. The EMG signal was measured from the forearm position of the driver during a one-hour interactive driving task. Additionally, the participant's drowsiness level was also measured to investigate the relationship between muscle activity and driver's drowsiness level. Frequency domain analysis was performed using the short-time Fourier transform (STFT) and spectrogram to assess the frequency response of the resultant signal. An EMG signal magnitude-based driver drowsiness detection and alertness algorithm is also proposed. The algorithm detects weak muscle activity by detecting the fall in EMG signal magnitude due to an increase in driver drowsiness. The previously presented microneedle electrode (MNE) was used to acquire the EMG signal and compared with the signal obtained using silver-silver chloride (Ag/AgCl) wet electrodes. The results indicated that during the driving task, participants' drowsiness level increased while the activity of the muscles involved in steering wheel grip decreased concurrently over time. Frequency domain analysis showed that the frequency components shifted from the high to low-frequency spectrum during the one-hour driving task. The proposed algorithm showed good performance for the detection of low muscle activity in real time. MNE showed highly comparable results with dry Ag/AgCl electrodes, which confirm its use for EMG signal monitoring. The overall results indicate that the presented method has good potential to be used as a driver's drowsiness detection and alertness system.

The aim of this study was to evaluate the effect of core stability exercise combined with Kinesio taping on pain, endurance, and balance in patients with lower back pain (LBP). 46 patients with LBP were recruited and randomly allocated into the core stability exercise with taping (CSET) group and the core stability exercise (CSE) group. All participants performed core stability exercises for 40 min/day, 5 times/week for 8 weeks, and additional Kinesio taping was applied to the lower backs in the CSET group. The primary outcome measure was the pain intensity using the visual analog scale, and secondary outcome measures were trunk endurance and balance using the Biering-Sorensen test and force plate, respectively. After the intervention, the CSET group showed significant improvements in pain and postural balance compared to the CSE group ( p < 0.05). However, there was no significant difference in trunk endurance between two groups ( p > 0.05). This study found that core stability exercise was effective in reducing pain and enhancing balance in patients with LBP, and demonstrated that the application of additional Kinesio taping further increased these effects. Therefore, we recommend that core exercise combined with Kinesio taping may be used to improve the pain and postural balance of patients with LBP in clinics.

This prospective study aimed to investigate the impact of laparoscopic hysterectomy (LH) and laparoscopic myomectomy (LM) on ovarian reserve by comparing serum anti-Mullerian hormone (AMH) changes following surgery. Serum AMH levels were measured preoperatively (AMH0), and 7 days (AMH1), 2 months (AMH2), and 6 months (AMH3) after LH and LM in 79 premenopausal women (LH = 59; LM = 20). AMH0, AMH1, AMH2, and AMH3 were significantly higher in the LM group than in the LH group ( p = 0.012, 0.001, 0.001, and 0.015, respectively). Since there are differences in indications between myomectomy and hysterectomy, logically, women who underwent myomectomy were younger and had higher AMH baseline levels. In addition, AMH changes at 7 days postoperatively from the baseline level were significantly decreased in the LH group compared to those in the LM group ( p = 0.042). However, AMH changes at 2 months and 6 months postoperatively, compared to the baseline level, were not different between the two groups ( p = 0.053 and 0.752, respectively). Moreover, the significant decrease in AMH (more than 60% decrease from the baseline level) was not different at 7 days, 2 months, and 6 months postoperatively between the two groups ( p = 0.415, 487, and 0.364, respectively). Our data suggest that serum AMH levels were significantly decreased directly after LH, which suggests that LH may have adverse effects on ovarian reserve. However, mid-term follow-up showed that the damaged ovarian reserve in women who underwent LH may be partially restored in 6 months.

Di-isobutyl phthalate (DiBP) is a substance used in the production of objects frequently used in human life. Mono-isobutyl phthalate (MiBP), a major in vivo metabolite of DiBP, is a biomarker for DiBP exposure assessment. Therefore, risk assessment studies on DiBP and MiBP, which have not yet been reported in detail, are needed. The aim of this study was to develop and evaluate a physiologically based pharmacokinetic (PBPK) model for DiBP and MiBP in rats and extend this to human risk assessment based on human exposure. Pharmacokinetic studies were performed in male rats following the administration of 5-100 mg/kg DiBP, and these results were used for the development and validation of the PBPK model. In addition, the previous pharmacokinetic results in female rats following DiBP administration and the pharmacokinetic results in both males and females according to multiple exposures to DiBP were used to develop and validate the PBPK model. The metabolism of DiBP to MiBP in the body was very significant and rapid, and the biodistribution of MiBP was broad and major. Furthermore, the amount of MiBP in the body showed a correlation with DiBP exposure, and from this, a PBPK model was developed to evaluate the external exposure of DiBP from the internal exposure of MiBP. The predicted rat plasma, urine, fecal, and tissue concentrations using the developed PBPK model fitted well with the observed values. The established PBPK model for rats was extrapolated to a human PBPK model of DiBP and MiBP based on human physiological parameters and allometric scaling. The reference dose of 0.512 mg/kg/day of DiBP and external doses of 6.14-280.90 μg/kg/day DiBP for human risk assessment were estimated using Korean biomonitoring values. Valuable insight and approaches to assessing human health risks associated with DiBP exposure were provided by this study.

Mucin-5AC (MUC5AC) is a major secreted mucin in pathogenic airways. To determine its role in mucus-related airway disorders, Muc5ac -deficient ( Muc5ac -/- ) and wild-type ( Muc5ac +/+ ) mice were compared in bleomycin-induced pulmonary fibrosis, respiratory syncytial virus (RSV) disease, and ozone toxicity. Significantly greater inflammation and fibrosis by bleomycin were developed in Muc5ac -/- lungs compared to Muc5ac +/+ lungs. More severe mucous cell metaplasia in fibrotic Muc5ac -/- lungs coincided with bronchial Muc2 , Muc4 , and Muc5b overexpression. Airway RSV replication was higher in Muc5ac -/- than in Muc5ac +/+ during early infection. RSV-caused pulmonary epithelial death, bronchial smooth muscle thickening, and syncytia formation were more severe in Muc5ac -/- compared to Muc5ac +/+ . Nasal septal damage and subepithelial mucoserous gland enrichment by RSV were greater in Muc5ac -/- than in Muc5ac +/+ . Ozone exposure developed more severe nasal airway injury accompanying submucosal gland hyperplasia and pulmonary proliferation in Muc5ac -/- than in Muc5ac +/+ . Ozone caused periodic acid-Schiff-positive secretion only in Muc5ac -/- nasal airways. Lung E-cadherin level was relatively lower in Muc5ac -/- than in Muc5ac +/+ basally and after bleomycin, RSV, and ozone exposure. Results indicate that MUC5AC is an essential mucosal component in acute phase airway injury protection. Subepithelial gland hyperplasia and adaptive increase of other epithelial mucins may compensate airway defense in Muc5ac -/- mice.

Purpose: This study aimed to evaluate anticancer effects of combination treatment with poly(ADP-ribose) polymerase (PARP) and checkpoint kinase 1 (Chk1) inhibitors in BRCA wild-type ovarian cancer. PARP inhibitors can function as DNA-damaging agents in BRCA wild-type cancer, even if clinical activity is limited. Most epithelial ovarian cancers are characterized by a TP53 mutation causing dysfunction at the G1/S checkpoint, which makes tumor cells highly dependent on Chk1-mediated G/M phase cell-cycle arrest for DNA repair., Materials and Methods: We investigated the anticancer effects of combination treatment with prexasertib (LY2606368), a selective ATP competitive small molecule inhibitor of Chk1 and Chk2, and rucaparib, a PARP inhibitor, in BRCA wild-type ovarian cancer cell lines (OVCAR3 and SKOV3)., Results: We found that combined treatment significantly decreased cell viability in all cell lines and induced greater DNA damage and apoptosis than in the control and/or using monotherapies. Moreover, we found that prexasertib significantly inhibited homologous recombination-mediated DNA repair and thus showed a marked anticancer effect in combination treatment with rucaparib. The anticancer mechanism of prexasertib and rucaparib was considered to be caused by an impaired G2/M checkpoint due to prexasertib treatment, which forced mitotic catastrophe in the presence of rucaparib., Conclusion: Our results suggest a novel effective therapeutic strategy for BRCA wild-type epithelial ovarian cancer using a combination of Chk1 and PARP inhibitors.

The purpose of this study was to investigate the effects of multidimensional approach model on the pain, disability, and sitting posture in patients with nonspecific low back pain (LBP). Sixty LBP patients were recruited and were randomly divided into two groups: multidimensional treatment (MT) group ( n  = 30) and unimodal treatment (UT) group ( n  = 30). All participants underwent 48 sessions of treatment (40 min/session, two sessions per day, 2 days per week) for 12 weeks. The MT group conducted a core stability exercise twice a day and additionally provided training on pain principles and management methods. The UT group only performed a core stability exercise twice a day. The visual analog scale (VAS) and Oswestry Disability index (ODI) were used to measure pain intensity and disability. Thoracolumbar kyphosis and lumbar lordosis in the sitting position were measured using a motion capture system. After training, the pain and disability in the MT group improved significantly greater than the UT group ( p < 0.05). In the MT group, the pain relief effect persisted 3 months after the end of training. Thoracolumbar kyphosis and lumbar lordosis in the MT group were significantly improved compared to the UT group ( p < 0.05). Thus, MT combined with core stability exercise may be used to improve the pain, disability, and sitting posture in patients with LBP., Competing Interests: The authors have declared that no conflicts of interest exist., (Copyright © 2021 Tae-Sung In et al.)

The most common type of spinal cord injury is the contusion of the spinal cord, which causes progressive secondary tissue degeneration. In this study, we applied genetically modified human neural stem cells overexpressing BDNF (brain-derived neurotrophic factor) (F3.BDNF) to determine whether they can promote functional recovery in the spinal cord injury (SCI) model in rats. We transplanted F3.BDNF cells via intrathecal catheter delivery after a contusion of the thoracic spinal cord and found that they were migrated toward the injured spinal cord area by MR imaging. Transplanted F3.BDNF cells expressed neural lineage markers, such as NeuN, MBP, and GFAP and were functionally connected to the host neurons. The F3.BDNF-transplanted rats exhibited significantly improved locomotor functions compared with the sham group. This functional recovery was accompanied by an increased volume of spared myelination and decreased area of cystic cavity in the F3.BDNF group. We also observed that the F3.BDNF-transplanted rats showed reduced numbers of Iba1- and iNOS-positive inflammatory cells as well as GFAP-positive astrocytes. These results strongly suggest the transplantation of F3.BDNF cells can modulate inflammatory cells and glia activation and also improve the hyperalgesia following SCI.

Memory is supported by a specific collection of neurons distributed in broad brain areas, an engram. Despite recent advances in identifying an engram, how the engram is created during memory formation remains elusive. To explore the relation between a specific pattern of input activity and memory allocation, here we target a sparse subset of neurons in the auditory cortex and thalamus. The synaptic inputs from these neurons to the lateral amygdala (LA) are not potentiated by fear conditioning. Using an optogenetic priming stimulus, we manipulate these synapses to be potentiated by the learning. In this condition, fear memory is preferentially encoded in the manipulated cell ensembles. This change, however, is abolished with optical long-term depression (LTD) delivered shortly after training. Conversely, delivering optical long-term potentiation (LTP) alone shortly after fear conditioning is sufficient to induce the preferential memory encoding. These results suggest a synaptic plasticity-dependent competition rule underlying memory formation.

In mammals, eight aminoacyl-tRNA synthetases (AARSs) and three AARS-interacting multifunctional proteins (AIMPs) form a multi-tRNA synthetase complex (MSC). MSC components possess extension peptides for MSC assembly and specific functions. Human cytosolic methionyl-tRNA synthetase (MRS) has appended peptides at both termini of the catalytic main body. The N-terminal extension includes a glutathione transferase (GST) domain responsible for interacting with AIMP3, and a long linker peptide between the GST and catalytic domains. Herein, we determined crystal structures of the human MRS catalytic main body, and the complex of the GST domain and AIMP3. The structures reveal human-specific structural details of the MRS, and provide a dynamic model for MRS at the level of domain orientation. A movement of zinc knuckles inserted in the catalytic domain is required for MRS catalytic activity. Depending on the position of the GST domain relative to the catalytic main body, MRS can either block or present its tRNA binding site. Since MRS is part of a huge MSC, we propose a dynamic switching between two possible MRS conformations; a closed conformation in which the catalytic domain is compactly attached to the MSC, and an open conformation with a free catalytic domain dissociated from other MSC components., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

We investigated the role of nuclear factor of activated T cells 5 (NFAT5) under hyperosmotic conditions in human lens epithelial cells (HLECs). Hyperosmotic stress decreased the viability of human lens epithelial B-3 cells and significantly increased NFAT5 expression. Hyperosmotic stress-induced cell death occurred to a greater extent in NFAT5-knockout (KO) cells than in NFAT5 wild-type (NFAT5 WT) cells. Bcl-2 and Bcl-xl expression was down-regulated in NFAT5 WT cells and NFAT5 KO cells under hyperosmotic stress. Pre-treatment with a necroptosis inhibitor (necrostatin-1) significantly blocked hyperosmotic stress-induced death of NFAT5 KO cells, but not of NFAT5 WT cells. The phosphorylation levels of receptor-interacting protein kinase 1 (RIP1) and RIP3, which indicate the occurrence of necroptosis, were up-regulated in NFAT5 KO cells, suggesting that death of these cells is predominantly related to the necroptosis pathway. This finding is the first to report that necroptosis occurs when lens epithelial cells are exposed to hyperosmolar conditions, and that NFAT5 is involved in this process.

Background: Dysphonia influences the quality of life by interfering with communication. However, a laryngoscopic examination is expensive and not readily accessible in primary care units. Experienced laryngologists are required to achieve an accurate diagnosis., Objective: This study sought to detect various vocal fold diseases through pathological voice recognition using artificial intelligence., Methods: We collected 189 normal voice samples and 552 samples of individuals with voice disorders, including vocal atrophy (n=224), unilateral vocal paralysis (n=50), organic vocal fold lesions (n=248), and adductor spasmodic dysphonia (n=30). The 741 samples were divided into 2 sets: 593 samples as the training set and 148 samples as the testing set. A convolutional neural network approach was applied to train the model, and findings were compared with those of human specialists., Results: The convolutional neural network model achieved a sensitivity of 0.66, a specificity of 0.91, and an overall accuracy of 66.9% for distinguishing normal voice, vocal atrophy, unilateral vocal paralysis, organic vocal fold lesions, and adductor spasmodic dysphonia. Compared with the accuracy of human specialists, the overall accuracy rates were 60.1% and 56.1% for the 2 laryngologists and 51.4% and 43.2% for the 2 general ear, nose, and throat doctors., Conclusions: Voice alone could be used for common vocal fold disease recognition through a deep learning approach after training with our Mandarin pathological voice database. This approach involving artificial intelligence could be clinically useful for screening general vocal fold disease using the voice. The approach includes a quick survey and a general health examination. It can be applied during telemedicine in areas with primary care units lacking laryngoscopic abilities. It could support physicians when prescreening cases by allowing for invasive examinations to be performed only for cases involving problems with automatic recognition or listening and for professional analyses of other clinical examination results that reveal doubts about the presence of pathologies., (©Hao-Chun Hu, Shyue-Yih Chang, Chuen-Heng Wang, Kai-Jun Li, Hsiao-Yun Cho, Yi-Ting Chen, Chang-Jung Lu, Tzu-Pei Tsai, Oscar Kuang-Sheng Lee. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 08.06.2021.)

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 (EC 50  = 81 nM against the mutant KRS-overexpressed MDA-MB-231 cells) and was superior to the previously reported KRS inhibitor (migration inhibitory EC 50  = 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

The purpose of this study was to compare pharmacokinetic (PK) parameters obtained using two newly developed assays, HPLC-UV and UPLC-ESI-MS/MS. Selection of assay and results obtained therefrom are very important in PK studies and can have a major impact on the PK-based clinical dose and usage settings. For this study, we developed two new methods that are most commonly used in biosample analysis and focused on PK parameters obtained from them. By HPLC-UV equipped with a Luna-C 8 column using UV detector, cefprozil diastereomers were separated using water containing 2% ( V/V ) acetic acid and acetonitrile as a mobile phase. By UPLC-ESI-MS/MS equipped with a HALO-C 18 column, cefprozil diastereomers were separated using 0.5% ( V/V) aqueous formic acid containing 5 mM ammonium-formate buffer and methanol as a mobile phase. Chromatograms showed high resolution, sensitivity, and selectivity without interference by plasma constituents. Both intra- and inter-day precisions (CV, %) were within 8.88% for HPLC-UV and UPLC-ESI-MS/MS. Accuracy of both methods was 95.67%-107.50%. These two analytical methods satisfied the criteria of international guidance and could be successfully applied to PK study. Comparison of PK parameters between two assays confirmed that there is a difference in the predicted minimum plasma concentrations at steady state, which may affect clinical dose and usage settings. Furthermore, we confirmed possible correlation between PK parameters and various biochemical parameters after oral administration of 1000 mg cefprozil to humans., Competing Interests: The authors declare that there are no conflicts of interest., (© 2020 Xi'an Jiaotong University. Production and hosting by Elsevier B.V.)

Background and Objectives: Spasticity is one of the factors that make it more difficult to control posture in stroke patients. Taping has been used to manage muscle stiffness in various musculoskeletal disorders. Recently, it has been used to decrease spasticity in stroke patients, but the effect of taping combined with therapeutic exercise is still unclear. The purpose of the present study was to determine whether the sit-to-stand (STS) training combined with taping improves the ankle spasticity, muscle strength, gait speed, and quality of life in stroke patients., Material and Methods: The study recruited 40 stroke patients, who were randomly divided into two groups: the taping and STS training (TSTS) group (n = 20) and the STS group (n = 20). The subjects in the TSTS group underwent STS training with Kinesio taping on the tibialis anterior, calf and ankle joint, whereas the subjects in the STS group underwent only STS training. All participants underwent 30 sessions of STS training (30 minutes, 5 days per week for 6 weeks). The present study evaluated the spasticity of ankle plantar flexors by the mean of the composite spasticity score; the muscle strength and gait speed were evaluated using the handheld dynamometer and the 10-meter walk test, respectively, and the quality of life was assessed using the stroke-specific quality of life scale., Result: The TSTS group and the STS group showed significant improvements in spasticity, muscle strength, walking speed, and quality of life after the intervention (p < 0.05). The level of improvement in the TSTS group was significantly higher in spasticity, muscle strength, and walking speed compared to the STS group (p < 0.05)., Conclusions: The present study demonstrated that STS training is effective for decreasing spasticity in stroke patients and suggested that additional taping intervention further improved this effect. In addition, improvement of muscle strength and gait function was observed with a significant decrease of ankle spasticity., Competing Interests: The authors declare no conflict of interest.

Objective: Pelvic alignment asymmetry in stroke patients negatively affects postural control ability. This study aimed to investigate the effect of posterior pelvic tilt taping on pelvic inclination, muscle strength, and gait ability in stroke patients., Methods: Forty stroke patients were recruited and randomly divided into the following two groups: the posterior pelvic tilt taping (PPTT) group ( n = 20) and the control group ( n = 20). All participants underwent sitting-to-standing, indoor walking, and stair walking training (30 min per day, 5 days per week, for 6 weeks). The PPTT group applied posterior pelvic tilt taping during the training period, while the control group did not receive a tape intervention. Pelvic inclination was measured using a palpation meter (PALM). A hand-held dynamometer and the 10-meter walk test were used to measure muscle strength and gait ability., Results: Significantly greater improvements in the pelvic anterior tilt were observed in the PPTT group than in the control group ( p < 0.05). Muscle strength in the PPTT group was significantly increased compared to the control group ( p < 0.05). Significantly greater improvements in gait speed were observed in the PPTT group than the control group., Conclusions: According to our results, posterior pelvic tilt taping may be used to improve the anterior pelvic inclination, muscle strength, and gait ability in stroke patients.

Triple-negative breast cancer (TNBC) is an aggressive breast-cancer subtype associated with poor prognosis and high relapse rates. Monopolar spindle 1 kinase (MPS1) is an apical dual-specificity protein kinase that is over-expressed in TNBC. We herein report a highly selective MPS1 inhibitor based on a 7 H -pyrrolo[2,3- d ]pyrimidine-5-carbonitrile scaffold. Our lead optimization was guided by key X-ray crystal structure analysis. In vivo evaluation of candidate ( 9 ) is shown to effectively mitigate human TNBC cell proliferation.

Thymic atrophy in sepsis is a critical disadvantage because it induces immunosuppression and increases the mortality rate as the disease progresses. However, the exact mechanism of thymic atrophy has not been fully elucidated. In this study, we discovered a novel role for VSIG4-positive peritoneal macrophages (V4(+) cells) as the principal cells that induce thymic atrophy and thymocyte apoptosis. In CLP-induced mice, V4(+) cells were activated after ingestion of invading microbes, and the majority of these cells migrated into the thymus. Furthermore, these cells underwent a phenotypic shift from V4(+) to V4(-) and from MHC II(low) to MHC II(+). In coculture with thymocytes, V4(+) cells mainly induced apoptosis in DP thymocytes via the secretion of TNF-α. However, there was little effect on CD4 or CD8 SP and DN thymocytes. V4(-) cells showed low levels of activity compared to V4(+) cells. Thymic atrophy in CLP-induced V4(KO) mice was much less severe than that in CLP-induced wild-type mice. In addition, V4(KO) peritoneal macrophages also showed similar activity to V4(-) cells. Taken together, the current study demonstrates that V4(+) cells play important roles in inducing immunosuppression via thymic atrophy in the context of severe infection. These data also suggest that controlling the function of V4(+) cells may play a crucial role in the development of new therapies to prevent thymocyte apoptosis in sepsis.

The aims of this study were: (1) to perform population pharmacokinetic analysis of cefaclor in healthy Korean subjects, and (2) to investigate possible effects of various covariates on pharmacokinetic parameters of cefaclor. Although cefaclor belongs to the cephalosporin family antibiotic that has been used in various indications, there have been very few population studies on factors affecting its pharmacokinetics. Therefore, this study is very important in that effective therapy could be possible through a population pharmacokinetic study that explores effective covariates related to cefaclor pharmacokinetic diversity between individuals. Pharmacokinetic results of 48 subjects with physical and biochemical parameters were used for the population pharmacokinetic analysis of cefaclor. A one-compartment with lag-time and first-order absorption/elimination was constructed as a base model and extended to include covariates that could influence between-subject variability. Creatinine clearance and body weight significantly influenced systemic clearance and distribution volume of cefaclor. Cefaclor's final population pharmacokinetic model was validated and some of the population's pharmacokinetic diversity could be explained. Herein, we first describe the establishment of a population pharmacokinetic model of cefaclor for healthy Koreans that might be useful for customizing cefaclor or exploring additional covariates in patients.

A controlled drug release formulation based on the subcutaneous injection of poly (lactic-co-glycolic acid) (PLGA) microspheres loaded with finasteride was prepared and evaluated for monthly delivery. After selection of biodegradable polymer and polymer-to-finasteride ratio, the formulation was characterized. Scanning electron microscopy (SEM) and laser-light particle size analysis were used to examine the morphology, surface structure, and particle size. High‑performance liquid chromatography (HPLC) was used to determine the drug loading, while liquid chromatography with tandem mass spectrometry (LC-MS/MS) was employed to analyze plasma finasteride concentrations. Results showed that the PLGA microspheres were spherical and of an appropriate size. The formulation stably releases the drug from the microspheres and the release sustained for a month without burst release, which was the desired duration. In vivo pharmacokinetic-pharmacodynamic (PK-PD) studies were conducted in beagle dogs through the administration of PROPECIA® (as a reference drug) per oral and subcutaneous injection of the long-acting injectable microsphere formulation (LAIF) loaded with five different doses of finasteride. From the acquired plasma data, PK-PD models for both PROPECIA®-administered group and LAIFs-injected groups were developed and validated. PK-PD profiles of both groups were predicted for up to one month. The predicted PK-PD profile of all LAIFs showed the achievability of monthly delivery and pharmacological effects without burst release, compared to the simulated PK-PD profile of PROPECIA®. According to the predicted PK-PD profiles, the formulation loaded with 16.8 mg of finasteride was determined to be the optimal dose. The data obtained from the PK-PD model could be used as the basis for the estimation of a first-in-human dose of the formulation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Blended hydrogels play an important role in enhancing the properties (e.g., mechanical properties and conductivity) of hydrogels. In this study, we generated a conductive blended hydrogel, which was achieved by mixing gelatin methacrylate (GelMA) with collagen, and silver nanowire (AgNW). The ratio of GelMA, collagen and AgNW was optimized and was subsequently gelated by ultraviolet light (UV) and heat. The scanning electron microscope (SEM) image of the conductive blended hydrogels showed that collagen and AgNW were present in the GelMA hydrogel. Additionally, rheological analysis indicated that the mechanical properties of the conductive GelMA-collagen-AgNW blended hydrogels improved. Biocompatibility analysis confirmed that the human umbilical vein endothelial cells (HUVECs) encapsulated within the three-dimensional (3D), conductive blended hydrogels were highly viable. Furthermore, we confirmed that the molecule in the conductive blended hydrogel was released by electrical stimuli-mediated structural deformation. Therefore, this conductive GelMA-collagen-AgNW blended hydrogel could be potentially used as a smart actuator for drug delivery applications.

Asarinin, β-eudesmol, and wogonin have common antiangiogenic activities and have the potential for use in chemotherapy. Besides, they are multivalent substances that are combined in various herbal medicines. The purpose of this study was to develop a method for simultaneous analysis of asarinin, β-eudesmol, and wogonin, which are representative pharmacological components of Asarum heterotropoides, Atractylodes lancea, and Scutellaria baicalensis, respectively, in rat biosamples using ultraperformance liquid chromatography-tandem mass spectrometry. The three components were separated using 5 mm aqueous ammonium acetate containing 0.1% formic acid and acetonitrile as a mobile phase, equipped with a KINETEX core-shell C 18 column. The analysis was quantitated on a triple-quadrupole mass-spectrometer employing electrospray ionization, and operated in the multiple reaction monitoring mode. The chromatograms showed high resolution, sensitivity, and selectivity with no interference with plasma, urine, and feces constituents. The developed analytical method satisfied international guidance criteria and could be successfully applied to the pharmacokinetic (PK) studies evaluating oral bioavailability of asarinin, β-eudesmol, and wogonin after oral and intravenous administration and their urinary and fecal excretion ratios after oral administration to rats. Furthermore, the analysis was extended to PK studies following oral administration of Gumiganghwal-tang. This study was the first simultaneous analysis of the aforesaid three constituents in rat plasma, urine, and feces that also determined their PK parameters., (© 2020 John Wiley & Sons, Ltd.)

Different types of polymer chains generated during the nitroxide-mediated polymerization of styrene are separated for the first time, and their molecular weight distribution (MWD) is investigated. Living and dead chains are monitored during the reaction; specifically, two types of living chains derived from the initiation of the alkoxyamine (RT) and the self-initiation of styrene and dead chains present in the as-prepared polystyrene (PS). To distinguish between each polymer species, different numbers of hydroxyl groups are introduced onto the T and R groups of the alkoxyamine (one and two groups, respectively). Each living and dead chains is resolved according to the distinct number of hydroxyl groups on its chain-end using high-performance liquid chromatography. Molecular structures of the fractionated PS are characterized using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and 1 H nuclear magnetic resonance spectroscopy, and the results of which show two distinct initiation paths: one originating from RT and the other from the self-initiation of styrene. Molecular weight and MWD are measured using size-exclusion chromatography and reveal a narrow MWD for the living chains derived from RT. Contrastingly, a broad and skewed MWD is observed for the other living chains derived from the self-initiation of styrene and the dead chains., (© 2021 Wiley-VCH GmbH.)

Objective: The purpose of this study was to evaluate the strategy of screening for preeclampsia (PE) in the first trimester based on maternal characteristics, and estimated placental volume (EPV)., Methods: A prospective cohort study was performed with 351 women enrolled, of which 13 women developed PE. This study analyzed the risk of PE according to ultrasonography findings of the placenta, maternal characteristics, and serum markers. The placental ultrasound exam and maternal serum pregnancy-associated plasma protein A (PAPP-A) was determined at 11 +0 to 13 +6  weeks and the serum alpha-fetoprotein (MSAFP), human chorionic gonadotropin (hCG), unconjugated estriol (uE 3 ), and inhibin A were assayed at 14 +0 to 22 +0  weeks. We reviewed all antenatal medical screening records and assessed the relationships of EPV of ultrasound examination, maternal characteristics, and serum markers by using multiple logistic regression analysis., Results: Thirteen of the 351 women (3.7%) developed PE in singleton pregnancy. The gestational age at delivery was significantly different between the normal and PE group ( p  < .001). In the PE group, the placental weight at delivery was not statistically different between the normal and the PE group. The EPV at the first trimester was significantly lower in women with PE compared to those without PE ( p  = .002). In addition, we predicted PE using combined maternal age, BMI, and EPV, which were achieving an area under the curve of 0.83 overall., Conclusion: A risk prediction model of PE, which combined maternal age, BMI, and EPV can be adopted for the screening of PE at the first trimester in singleton pregnancy.

The purpose of this study was to evaluate the effects of wrist stabilization exercise combined with taping on wrist pain, disability, and quality of life in postpartum women with wrist pain. Forty-five patients with wrist pain were recruited and randomly divided into three groups: wrist stabilization exercise + taping therapy (WSE + TT) group (n = 15), wrist stabilization exercise (WSE) group (n = 15), and control group (n = 15). The WSE + TT and WSE groups performed wrist stabilization exercises for 40 min (once a day, five times a week for eight weeks), and the control group performed passive range of motion (P-ROM) exercise for the same amount of time. Additionally, the WSE + TT group attached taping to the wrist and forearm during the training period. The visual analogue scale (VAS) was used to assess pain level of the wrist. The Disabilities of the Arm, Shoulder and Hand (DASH) and the Short Form-36 (SF-36) were used to evaluate the degree of wrist disability and quality of life, respectively. The WSE + TT group showed a significant decrease in wrist pain and functional disability compared to two groups ( p < 0.05). Significant improvement in the SF-36 score was observed in the WSE + TT and WSE groups compared to that in the control group ( p < 0.05). However, there was no significant difference between the WSE + TT and WSE groups in the SF-36. Our findings indicate that wrist stabilization exercise combined with taping is beneficial and effective in managing wrist pain and disability in postpartum women with wrist pain.

Osteoporosis is a common skeletal disease in post-menopausal women. Palmul -tang, an herbal medicine, has been treated for gynecological disease such as anemia, anorexia, anti-fatigue, unspecified menstruation and female infertility in East Asia. In this study, ameliorative effects of Palmul -tang soft extracts (PMT), a Korean Medicine, on osteoporosis were investigated. Ovariectomized (OVX) osteoporotic ICR mice were intragastrically administrated PMT for 4 weeks. The level of bone mineral density (BMD) was analyzed in bone tissues by dual X-ray absorptiometry. The bone medullary cavity and deposition of collagen were investigated by histological analysis. In addition, the BMP-2 signaling-related molecules, osteoblastic differentiation and formation markers, were determined in femoral tissues. The levels of BMD and bone mineral content were significantly increased in tibia, femurs and LV by treatment of PMT. PMT replenished bone marrow cavity and increased collagen deposition in bone marrow cells of femur. In addition, administration of PMT recovered serum ALP, bALP, osteocalcin and calcium levels in osteoporotic mice. Moreover, PMT treatment up-regulated the expressions of BMP-2, RUNX2 and OSX with its downstream factors, ALP, OPN and BSP-1, in the femoral tissues. Taken together, PMT restored the bone minerals and improvement of bone integrity by bone-forming BMP-2 signaling pathway. These results demonstrate that PMT could be an ameliorative agent for osteoporosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Choi, Kim, Nam, Kim, Cho and Yang.)

Banhahoobak-tang is the most prescribed herbal drug in East Asia when individuals experience sudden symptoms such as sore throat or neurological symptoms. The low toxicity and high in-vivo safety of this herbal medicine has made it more attractive to patients, and it has recently been formulated as tablets. In addition, Banhahoobak-tang tablets are registered as health insurance drugs in South Korea, and clinical prescriptions and demand are increasing. However, there are very few clinical trial data as well as very little accurate content analysis and results for Banhahoobak-tang tablets. The purpose of this study was to perform in-vitro and in-vivo studies on Banhahoobak-tang tablets, including content analysis, pharmacokinetics in humans, and plasma protein binding. For this study, a UPLC-ESI-MS/MS method with polarity switching was developed for simultaneous analysis of 18 components of Banhahoobak-tang. To separate the analytes, a C 8 reverse-phase column was used as the stationary phase, 0.1 % aqueous formic acid and acetonitrile as the mobile phase, and ionization and multiple reaction monitoring for quantification. The developed method was able to isolate and quantify the 18 components with good sensitivity and selectivity and was fully validated according to international analytical standards. Stability tests were also conducted on the analytes. Finally, the method was applied to in-vitro and in-vivo studies of Banhahoobak-tang tablets, and the tablet components were 52.49 ng/g to 91.00 μg/g on average. The detected components showed rapid oral absorption in humans as well as high plasma protein binding ratio overall. These results and methods can be useful not only for effectiveness and safety evaluation but also for quality control of Banhahoobak-tang tablets., Competing Interests: Declaration of Competing Interest All authors declare that they have no conflicts of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Detecting circulating tumor cells (CTCs) has been considered one of the best biomarkers in liquid biopsy for early diagnosis and prognosis monitoring in cancer. A major challenge of using CTCs is detecting extremely low-concentrated targets in the presence of high noise factors such as serum and hematopoietic cells. This review provides a selective overview of the recent progress in the design of microfluidic devices with optical sensing tools and their application in the detection and analysis of CTCs and their small malignant subset, circulating cancer stem cells (CCSCs). Moreover, discussion of novel strategies to analyze the differentiation of circulating cancer stem cells will contribute to an understanding of metastatic cancer, which can help clinicians to make a better assessment. We believe that the topic discussed in this review can provide brief guideline for the development of microfluidic-based optical biosensors in cancer prognosis monitoring and clinical applications.

Many natural products have demonstrated functionality as novel, green sorbents for organic compounds. However, only limited reports exist on the use of such green materials as solid-phase extraction (SPE) sorbents for select organic acids. In this study, we employed pollen grains as a hydrophilic sorbent and investigated the influence of various extraction parameters using a series of experimental designs. The chemical structure and surface properties of the prepared sorbent were investigated by Fourier-transform infrared spectroscopy and scanning electron microscopy. The Plackett-Burman design was used to experimentally screen for parameters that significantly influenced the extraction performance. Three selected parameters were then statistically optimized by applying a central composite design combined with a response surface methodology. Phenolic acid residues were determined and quantified using high performance liquid chromatography with ultraviolet detection; a mass spectrometric detector in the selected ion monitoring mode was also used for identification. As a practical example, phenolic acids in the soil were successfully separated by the developed pollen sorbent. These results therefore indicate that pollen grains can be considered as a sustainable, green, and safe alternative to bare silica for extraction and separation applications.

The amniotic fluid (AF) is a complex biofluid that reflects fetal well-being during development. AF con be divided into two fractions, the supernatant and amniocytes. The supernatant contains cell-free components, including placenta-derived microparticles, protein, cell-free fetal DNA, and cell-free fetal RNA from the fetus. Cell-free mRNA (cfRNA) analysis holds a special position among high-throughput analyses, such as transcriptomics, proteomics, and metabolomics, owing to its ease of profiling. The AF cell-free transcriptome differs from the amniocyte transcriptome and alters with the progression of pregnancy and is often associated with the development of various organ systems including the fetal lung, skin, brain, pancreas, adrenal gland, gastrointestinal system, etc. The AF cell-free transcriptome is affected not only by normal physiologies, such as fetal sex, gestational age, and fetal maturity, but also by pathologic mechanisms such as maternal obesity, and genetic syndromes (Down, Edward, Turner, etc.), as well as pregnancy complications (preeclampsia, intrauterine growth restriction, preterm birth, etc.). cfRNA in the amniotic fluid originates from the placenta and fetal organs directly contacting the amniotic fluid as well as from the fetal plasma across the placenta. The AF transcriptome may reflect the fetal and placental development and therefore aid in the monitoring of normal and abnormal development.

Background: To motivate people to adopt medical chatbots, the establishment of a specialized medical knowledge database that fits their personal interests is of great importance in developing a chatbot for perinatal care, particularly with the help of health professionals., Objective: The objectives of this study are to develop and evaluate a user-friendly question-and-answer (Q&A) knowledge database-based chatbot (Dr. Joy) for perinatal women's and their partners' obstetric and mental health care by applying a text-mining technique and implementing contextual usability testing (UT), respectively, thus determining whether this medical chatbot built on mobile instant messenger (KakaoTalk) can provide its male and female users with good user experience., Methods: Two men aged 38 and 40 years and 13 women aged 27 to 43 years in pregnancy preparation or different pregnancy stages were enrolled. All participants completed the 7-day-long UT, during which they were given the daily tasks of asking Dr. Joy at least 3 questions at any time and place and then giving the chatbot either positive or negative feedback with emoji, using at least one feature of the chatbot, and finally, sending a facilitator all screenshots for the history of the day's use via KakaoTalk before midnight. One day after the UT completion, all participants were asked to fill out a questionnaire on the evaluation of usability, perceived benefits and risks, intention to seek and share health information on the chatbot, and strengths and weaknesses of its use, as well as demographic characteristics., Results: Despite the relatively higher score of ease of learning (EOL), the results of the Spearman correlation indicated that EOL was not significantly associated with usefulness (ρ=0.26; P=.36), ease of use (ρ=0.19; P=.51), satisfaction (ρ=0.21; P=.46), or total usability scores (ρ=0.32; P=.24). Unlike EOL, all 3 subfactors and the total usability had significant positive associations with each other (all ρ>0.80; P<.001). Furthermore, perceived risks exhibited no significant negative associations with perceived benefits (ρ=-0.29; P=.30) or intention to seek (SEE; ρ=-0.28; P=.32) or share (SHA; ρ=-0.24; P=.40) health information on the chatbot via KakaoTalk, whereas perceived benefits exhibited significant positive associations with both SEE and SHA. Perceived benefits were more strongly associated with SEE (ρ=0.94; P<.001) than with SHA (ρ=0.70; P=.004)., Conclusions: This study provides the potential for the uptake of this newly developed Q&A knowledge database-based KakaoTalk chatbot for obstetric and mental health care. As Dr. Joy had quality contents with both utilitarian and hedonic value, its male and female users could be encouraged to use medical chatbots in a convenient, easy-to-use, and enjoyable manner. To boost their continued usage intention for Dr. Joy, its Q&A sets need to be periodically updated to satisfy user intent by monitoring both male and female user utterances., (©Kyungmi Chung, Hee Young Cho, Jin Young Park. Originally published in JMIR Medical Informatics (http://medinform.jmir.org), 03.03.2021.)

Background and Overview: 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., Case Description: 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., Conclusions and Practical Implications: 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., (Copyright © 2021 American Dental Association. Published by Elsevier Inc. All rights reserved.)

Metastasis is the primary cause of a large number of cancer-associated deaths. By portraying the precise environment of the metastasis process in vitro , the microfluidic system provides useful insights on the mechanisms underlying cancer cell migration, invasion, colonization, and the procurement of supplemental nutrients. However, current in vitro metastasis models are biased in studying blood vessel-based metastasis pathways and thus the understanding of lymphatic metastasis is limited which is also closely related to the inflammatory system. To understand the effects of inflammatory cytokines in lymphatic metastasis, we developed a three-channel microfluidic system by mimicking the lymph vessel-tissue-blood vessel (LTB) structure. Based on the LTB chip, we successfully confirmed the inflammatory cytokine, interleukin 6 (IL-6), -mediated intercellular communication in the tumor microenvironment during lymphatic metastasis. The IL-6 exposure to different subtypes of breast cancer cells was induced epithelial-mesenchymal transition (EMT) and improved tissue invasion property (8-fold). And the growth of human vein endothelial cells toward the lymph vessel channel was observed by VEGF secretion from human lymphatic endothelial cells with IL-6 treatment. The proposed LTB chip can be applied to analyze the intercellular communication during the lymphatic metastasis process and be a unique tool to understand the intercellular communication in the cancer microenvironment under various extracellular stimuli such as inflammatory cytokines, stromal reactions, hypoxia, and nutrient deficiency., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cho, Choi, Kim, Shin and Choi.)

The significance of glutamine in cancer metabolism has been extensively studied. Cancer cells consume an excessive amount of glutamine to facilitate rapid proliferation. Thus, glutamine depletion occurs in various cancer types, especially in poorly vascularized cancers. This makes glutamine synthetase (GS), the only enzyme responsible for de novo synthesizing glutamine, essential in cancer metabolism. In cancer, GS exhibits pro-tumoral features by synthesizing glutamine, supporting nucleotide synthesis. Furthermore, GS is highly expressed in the tumor microenvironment (TME) and provides glutamine to cancer cells, allowing cancer cells to maintain sufficient glutamine level for glutamine catabolism. Glutamine catabolism, the opposite reaction of glutamine synthesis by GS, is well known for supporting cancer cell proliferation via contributing biosynthesis of various essential molecules and energy production. Either glutamine anabolism or catabolism has a critical function in cancer metabolism depending on the complex nature and microenvironment of cancers. In this review, we focus on the role of GS in a variety of cancer types and microenvironments and highlight the mechanism of GS at the transcriptional and post-translational levels. Lastly, we discuss the therapeutic implications of targeting GS in cancer.

Lidocaine-incorporated hyaluronic acid injection (LHA) is considered a promising way to increase patient compliance. Various reviews and analyses have been conducted to verify that the addition of lidocaine had no effect on the product quality of hyaluronic acid injections. However, possible pharmacokinetic (PK) alterations of lidocaine and its active metabolites, monoethylglycylxylidide (MEGX) and glycylxylidide (GX), in hyaluronic acid injection have not been studied so far. Thus, the objective of this study was to evaluate lidocaine and its metabolite PK after 0.3% lidocaine solution or LHA injection and to investigate any changes in PK profiles of lidocaine and its active metabolites. To do this, a novel bio-analytical method for simultaneous determination of lidocaine, MEGX, and GX in rat plasma was developed and validated. Then, plasma concentrations of lidocaine and its active metabolites MEGX and GX following subcutaneous (SC) injection of 0.3% lidocaine solution or LHA with 0.3-1% lidocaine in male Sprague-Dawley rats were successfully determined. The obtained data were used to develop a parent-metabolite pharmacokinetic (PK) model for LHA injection. The half-life, dose-normalized C max , and AUC inf of lidocaine after SC injection of lidocaine solution and LHA did not show statistically significant difference. The PK characteristics of lidocaine after LHA administration were best captured using a two-compartment model with combined first-order and transit absorption and its clearance described with Michaelis-Menten and first-order elimination kinetics. Two one-compartment models were consecutively added to the parent model for the metabolites. In conclusion, the incorporation of lidocaine in hyaluronic acid filler injection did not alter the chemical's pharmacokinetic characteristics.

Background: Intracarotid injection of mannitol has been applied for decades to support brain entry of therapeutics that otherwise do not effectively cross the blood-brain barrier (BBB). However, the elaborate and high-risk nature of this procedure has kept its use restricted to well-equipped medical centers. We are developing a more straightforward approach to safely open the BBB, based on the intra-arterial (IA) injection of NEO100, a highly purified version of the natural monoterpene perillyl alcohol., Methods: In vitro barrier permeability with NEO100 was evaluated by transepithelial/transendothelial electrical resistance and antibody diffusion assays. Its mechanism of action was studied by western blot, microarray analysis, and electron microscopy. In mouse models, we performed ultrasound-guided intracardiac administration of NEO100, followed by intravenous application of Evan's blue, methotrexate, checkpoint-inhibitory antibodies, or chimeric antigen receptor (CAR) T cells., Results: NEO100 opened the BBB in a reversible and nontoxic fashion in vitro and in vivo. It enabled greatly increased brain entry of all tested therapeutics and was well tolerated by animals. Mechanistic studies revealed effects of NEO100 on different BBB transport pathways, along with translocation of tight junction proteins from the membrane to the cytoplasm in brain endothelial cells., Conclusion: We envision that this procedure can be translated to patients in the form of transfemoral arterial catheterization and cannulation to the cerebral arteries, which represents a low-risk procedure commonly used in a variety of clinical settings. Combined with NEO100, it is expected to provide a safe, widely available approach to enhance brain entry of any therapeutic., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)