Sugammadex, a selective antagonist of steroidal non‐depolarizing neuromuscular blocking agents, has been used in children in limited circumstances. However, neither pharmacokinetics (PKs) nor ...recovery profile of sugammadex for intense neuromuscular blockade reversal in children have been reported. This prospective study aimed to obtain a PK model of sugammadex and evaluate its efficacy and safety for intense neuromuscular blockade reversal in children. Forty children (age, 2–17 years) who underwent surgery that required early neuromuscular blockade reversal were enrolled. After neuromuscular blockade with 1 mg∙kg−1 of rocuronium, sugammadex (2, 4, and 8 mg∙kg−1) or a conventional dose of neostigmine (0.03 mg∙kg−1) was administered randomly after confirmation of zero post‐tetanic count. The plasma concentrations of rocuronium and sugammadex were measured 2 min after rocuronium injection; immediately before, 2, 5, 15, 60, 120, 240, and 480 min after the study drug injection. Response to train‐of‐four stimulation was continuously recorded. Noncompartmental analysis and population PK modeling were performed. For pharmacodynamics, the recovery profile was measured. Three‐compartment PK model was established for sugammadex. The median (interquartile range IQR) time from injection of 8 mg∙kg−1 of sugammadex to recovery of T4/T1greater than or equal to 0.9 at train‐of‐four stimulation was 1.1 (IQR: 0.88–1.8) min. No adverse events related to sugammadex were observed. We present a PK analysis of sugammadex for rocuronium‐induced intense neuromuscular blockade reversal in children with its recovery profile. The time to recover T4/T1 greater than or equal to 0.9 at train‐of‐four stimulation with 8 mg∙kg−1 of sugammadex was less than 3 min and comparable to that in adults.
PyK2 is a member of the proline-rich tyrosine kinase and focal adhesion kinase families and is ubiquitously expressed. PyK2 is mainly activated by stimuli, such as activated Src kinases and ...intracellular acidic pH. The mechanism of PyK2 activation in cancer cells has been addressed extensively. The up-regulation of PyK2 through overexpression and enhanced phosphorylation is a key feature of tumorigenesis and cancer migration. In this review, we summarized the cancer milieu, including acidification and cancer-associated molecules, such as chemical reagents, interactive proteins, chemokine-related molecules, calcium channels/transporters, and oxidative molecules that affect the fate of PyK2. The inhibition of PyK2 leads to a beneficial strategy to attenuate cancer cell development, including metastasis. Thus, we highlighted the effect of PyK2 on various cancer cell types and the distribution of molecules that affect PyK2 activation. In particular, we underlined the relationship between PyK2 and cancer metastasis and its potential to treat cancer cells.
To overcome the lithium storage barriers of current lithium‐ion batteries, it is imperative that conventional low capacity graphite anodes be replaced with other higher capacity anode materials. ...Silicon is a promising alternative anode material due to its huge energy densities; however, its lithium‐concentration‐dependent volumetric changes can induce severely adverse effects that lead to drastic degradations in capacity during cycling. The dealloying of Si–metal alloys is recently suggested as a scalable approach to fabricate high‐performance porous Si anode materials. Herein, a microstructure controlled porous Si is developed by the dealloying in conjunction with wet alkaline chemical etching. The resulting 3D networked structure enables enhancement in lithium storage properties when the Si‐based material is applied not only as a single active material but also in a graphite‐blended electrode.
A microstructure‐controlled 3D porous Si material is fabricated by dual chemical etching of a designed Si‐alloy in which Si and the metal‐alloy are entangled. Benefiting from the enlarged pore volume and reduced Si domain size, the resulting 3D porous Si anode shows improvement in lithium‐storage properties in terms of cyclability and energy density.
To evaluate a fully deep learning mask region-based convolutional neural network (R-CNN) method for automated tooth segmentation using individual annotation of panoramic radiographs.
In total, 846 ...images with tooth annotations from 30 panoramic radiographs were used for training, and 20 panoramic images as the validation and test sets. An oral radiologist manually performed individual tooth annotation on the panoramic radiographs to generate the ground truth of each tooth structure. We used the augmentation technique to reduce overfitting and obtained 1024 training samples from 846 original data points. A fully deep learning method using the mask R-CNN model was implemented through a fine-tuning process to detect and localize the tooth structures. For performance evaluation, the F1 score, mean intersection over union (IoU), and visual analysis were utilized.
The proposed method produced an F1 score of 0.875 (precision: 0.858, recall: 0.893) and a mean IoU of 0.877. A visual evaluation of the segmentation method showed a close resemblance to the ground truth.
The method achieved high performance for automation of tooth segmentation on dental panoramic images. The proposed method might be applied in the first step of diagnosis automation and in forensic identification, which involves similar segmentation tasks.
Although several novel resistant breast cancer cell lines have been established, only a few resistant breast cancer cell lines overexpress breast cancer resistance proteins (BCRP). The aim of this ...study was to establish new resistant breast cancer cell lines overexpressing BCRP using SN38 (7-ethyl-10-hydroxycamptothecin), an active metabolite of irinotecan and was to discover genes and mechanisms associated with multidrug resistance.
SN38-resistant T47D breast cancer cell sublines were selected from the wild-type T47D cells by gradually increasing SN38 concentration. The sensitivity of the cells to anti-cancer drugs was assessed by 3-(4,5-methylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. Expression profiles of the resistance-related transporters were examined using RT-qPCR, and western blot analysis. Intracellular fluorescent dye accumulation in the resistant cells was determined using flow cytometry.
The SN38-resistant T47D breast cancer cell sublines T47D/SN120 and T47D/SN150 were established after long-term exposure (more than 16 months) of wild-type T47D cells to 120 nM and 150 nM SN38, respectively. T47D/SN120 and T47D/SN150 cells were more resistant to SN38 (14.5 and 59.1 times, respectively), irinotecan (1.5 and 3.7 times, respectively), and topotecan (4.9 and 12 times, respectively), than the wild-type parental cells. Both T47D/SN120 and T47D/SN150 sublines were cross-resistant to various anti-cancer drugs. These resistant sublines overexpressed mRNAs of MRP1, MRP2, MRP3, MRP4, and BCRP. The DNA methylase inhibitor 5-aza-2'-deoxycytidine and the histone deacetylase inhibitor trichostatin A increased the expression levels of BCRP, MRP1, MRP2, MRP3, and MRP4 transcripts in T47D/WT cells. Fluorescent dye accumulation was found to be lower in T47D/SN120 and T47D/SN150 cells, compared to that in T47D/WT cells. However, treatment with known chemosensitizers increased the intracellular fluorescent dye accumulation and sensitivity of anti-tumor agents.
T47D/SN120 and T47D/SN150 cells overexpressed MRP1, MRP2, MRP3, MRP4, and BCRP, which might be due to the suppression of epigenetic gene silencing via DNA hypermethylation and histone deacetylation. Although these resistant cells present a higher resistance to various anti-cancer drugs than their parental wild-type cells, multidrug resistance was overcome by treatment with chemosensitizers. These SN38 resistant T47D breast cancer cell sublines expressing resistance proteins can be useful for the development of new chemosensitizers.
Rheumatoid arthritis (RA) is a systemic inflammatory disease that mainly affects the synovial joints. Although involvement of the fibroblast growth factor (FGF) signaling pathway has been suggested ...as an important modulator in RA development, no clear evidence has been provided. In this study, we found that synovial fluid basic FGF (bFGF) concentration was significantly higher in RA than in osteoarthritis (OA) patients. bFGF stimulates proliferation and migration of human fibroblast-like synoviocytes (FLSs) by activation of the bFGF-FGF receptor 3 (FGFR3)-ribosomal S6 kinase 2 (RSK2) signaling axis. Moreover, a molecular docking study revealed that kaempferol inhibited FGFR3 activity by binding to the active pocket of the FGFR3 kinase domain. Kaempferol forms hydrogen bonds with the FGFR3 backbone oxygen of Glu555 and Ala558 and the side chain of Lys508. Notably, the inhibition of bFGF-FGFR3-RSK2 signaling by kaempferol suppresses the proliferation and migration of RA FLSs and the release of activated T-cell-mediated inflammatory cytokines, such as IL-17, IL-21, and TNF-α. We further found that activated phospho-FGFR3 and -RSK2 were more highly observed in RA than in OA synovium. The hyperplastic lining and sublining lymphoid aggregate layers of RA synovium showed p-RSK2-expressing CD68
macrophages with high frequency, while pRSK2-expressing CD4
T-cells was observed at a lower frequency. Notably, kaempferol administration in collagen-induced arthritis mice relieved the frequency and severity of arthritis. Kaempferol reduced osteoclast differentiation in vitro and in vivo relative to the controls and was associated with the inhibition of osteoclast markers, such as tartrate-resistant acid phosphatase, integrin β3, and MMP9. Conclusively, our data suggest that bFGF-induced FGFR3-RSK2 signaling may play a critical role during the initiation and progression of RA in terms of FLS proliferation and enhanced osteoclastogenesis, and that kaempferol may be effective as a new treatment for RA.
Vaccines and therapeutics are urgently needed for the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we screen human monoclonal antibodies (mAb) targeting the ...receptor binding domain (RBD) of the viral spike protein via antibody library constructed from peripheral blood mononuclear cells of a convalescent patient. The CT-P59 mAb potently neutralizes SARS-CoV-2 isolates including the D614G variant without antibody-dependent enhancement effect. Complex crystal structure of CT-P59 Fab/RBD shows that CT-P59 blocks interaction regions of RBD for angiotensin converting enzyme 2 (ACE2) receptor with an orientation that is notably different from previously reported RBD-targeting mAbs. Furthermore, therapeutic effects of CT-P59 are evaluated in three animal models (ferret, hamster, and rhesus monkey), demonstrating a substantial reduction in viral titer along with alleviation of clinical symptoms. Therefore, CT-P59 may be a promising therapeutic candidate for COVID-19.
The aim of this study was to investigate heavy metal removal using waste biomass adsorbent, persimmon leaves, in an aqueous solution. Persimmon leaves, which are biomaterials, have a large number of ...hydroxyl groups and are highly suitable for removal of heavy metals. Therefore, in this study, we investigated the possibility of removal of Cu, Pb, and Cd in aqueous solution by using raw persimmon leaves (RPL) and dried persimmon leaves (DPL). Removal of heavy metals by RPL and DPL showed that DPL had a 10%–15% higher removal than RPL, and the order of removal efficiency was found to be Pb > Cu > Cd. The pseudo-second order model was a better fit to the heavy metal adsorption experiments using RPL and DPL than the pseudo-first order model. The adsorption of Cu, Pb, and Cd by DPL was more suitable with the Freundlich isothermal adsorption and showed an ion exchange reaction which occurred in the uneven adsorption surface layer. The maximum adsorption capacity of Cu, Pb, and Cd was determined to be 19.42 mg/g, 22.59 mg/g, and 18.26 mg/g, respectively. The result of the adsorption experiments showed that the n value was higher than 2 regardless of the dose, indicating that the heavy metal adsorption on DPL was easy. In the thermodynamic experiment, ΔG° was a negative value, and ΔH° and ΔS° were positive values. It can be seen that the heavy metal adsorption process using DPL was spontaneous in nature and was an endothermic process. Moreover, as the temperature increased, the adsorption increased, and the affinity of heavy metal adsorption to DPL was very good. This experiment, in which heavy metals are removed using the waste biomass of persimmon leaves is an eco-friendly new bioadsorbent method because it can remove heavy metals without using chemicals while utilizing waste recycling.
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•Raw persimmon leaves and dried persimmon leaves for heavy metal removal was evaluated.•Dried persimmon leaves (DPL) could supply more adsorbing power for heavy metal ions.•Adsorption process of DPL fitted Langmuir isotherm and pseudo-second-order model.•Maximum adsorption capacities were 19.42, 22.59 and 18.26 mg/g for Cu, Pb and Cd, respectively•Recommendation to use DPL as green and cost effective bioadsorbent.
The aim of this study is to investigate the effect of the N/P ratio on biomass growth with the simultaneous removal of nutrients from municipal wastewaters. An optical panel photobioreactor is ...employed for this investigation because it provides a uniform light distribution within the reactor, which enhances the efficiency of the reactor in the cultivation of microalgae. The N/P ratio is varied over a wide range, i.e., from 5 to 30, for the assessment of its effect on biomass productivity. There is not a strong correlation between biomass productivity and TN removal, and these factors do not seem to be proportional in the wastewater using the microalgae we employed. In contrast, the TP removal depends greatly on both the N/P ratio and biomass productivity. The optimum value of the N/P ratio for biomass productivity in and nutrient removal from municipal wastewater treatment using microalgae varies from 5 to 30, depending on the ecological conditions in the wastewater.
This study was conducted to evaluate the outcomes of multi-channel switching RFA using a separable cluster electrode in patients with HCC.
From November 2011 to July 2013, 79 patients with 98 HCCs < ...5 cm were enrolled and treated with RFA using a multi-channel switching radiofrequency system and a separable cluster electrode under the guidance of a real-time fusion imaging system. The primary and secondary endpoints were the 3-year local tumor progression (LTP) rate and recurrence-free survival (RFS) rate, respectively. For post hoc analyses, LTP, RFS, and major complication rates were retrospectively compared with a historical control group treated with RFA using the same radiofrequency system but with multiple internally-cooled electrodes.
The technique success rate of the 98 tumors was 100%. Cumulative 1-year, 2-year, and 3-year LTP rates were 3.4%, 6.9%, and 12.4%, respectively. For patient-level data, cumulative 1-year, 2-year, and 3-year RFS rates were 83.9%, 68.6%, and 45.4%, respectively. On post hoc analyses, none of the baseline characteristics showed a significant difference between the separable cluster electrode and multiple internally-cooled electrodes group. Cumulative LTP and RFS rates of the two groups also showed no significant difference (p = 0.401 and p = 0.881, respectively). Finally, major complication rates of the separable cluster electrode group (5.0%, 4/79) and multiple internally-cooled electrodes group (5.9%, 4/74) were also comparable (p = 1.000).
Switching monopolar RFA using a separable cluster electrode is a feasible and efficient technique for the treatment of HCCs smaller than 5 cm, providing comparable local tumor control to multiple internally-cooled electrodes.
ClinicalTrials.gov NCT02745483.
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