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Topology optimization (TO) is an optimal design method to obtain an efficient structure with minimal usage of material by satisfying two conflicting objectives of weight reduction and structural safety. Owing to the recent advances in additive manufacturing technology, TO has been developed in connection with the use of microscale lattices, of which complicated geometries require considerable computational loads to verify their structural performance. This study aims to develop an efficient computational method to analyze a complex TO model. Computational homogenization was then developed for efficient computation of the TO model that contains a number of microscale lattices. The proposed homogenization scheme was then applied to perform three-dimensional (3D) finite element analysis (FEA) on various TO models with three scales (i.e., macroscale, microscale, and multiscale TOs). The homogenized FEAs were conducted to verify the static and dynamic deformation behaviors of three optimized meta-sandwich beams, and their results and computational efficiency were compared with those from full solid FEAs. Experimental verification revealed that the proposed homogenized FEA provided more reliable results and better computational efficiency for the microscale and multiscale TO models, whereas the conventional solid FEA was advantageous for the macroscale TO model. To apply the proposed simulation strategy to a more complex 3D geometry, three TO models were calculated for a 3D block under a compression load. The simulation strategy combining the full solid and homogenized FEAs was then applied to analyze the static and dynamic deformation behaviors of various TO models, which provided reliable predictions of the experimentally observed behaviors within an acceptable computational time.

Purpose This research aims to examine the role of perceived threat (i.e. COVID-19) on people’s preferences for destination logo designs. In addition, it investigates the influence of childhood socioeconomic status (SES) and sensation seeking on the aforementioned effect. Design/methodology/approach Five experiments are used. Studies 1 A and 1B examine the impact of the threat of COVID-19 on visiting intentions as influenced by different destination logos. Study 2 replicates the previous studies and tests for evidence of mediation by the perceived risk. Studies 3 and 4 investigate the moderating role of childhood SES and sensation seeking. Findings The results show that a salient threat of COVID-19 leads people to display higher visiting intentions when presented with simpler (vs complex) destination logo designs. The perceived risk mediates this effect as well. This preference is evident only for people with low (vs high) childhood SES and only for relatively low sensation seekers. Research limitations/implications This study contributes to the branding literature by investigating how situational factors can influence affective reactions to brand logos and to the tourism literature by further investigating the impact of logos on visiting intentions. Practical implications This study provides actionable insights for tourism marketers and logo designers, allowing them to select or create positively perceived destination logos during a potential global crisis. Originality/value This research offers the first evidence that pandemic-related threat perceptions influence people’s visiting intentions when presented with different destination logos, and that these effects are influenced by individual characteristics such as childhood SES or sensation seeking. In doing so, the current study offers a more sophisticated understanding of the potential boundary conditions driving people’s brand logo evaluation.

An unstable shock-induced combustion (SIC) case around a hemispherical projectile has been numerically studied which experimentally produced a regular oscillation. Comparison of detailed H2/O2 reaction mechanisms is made for the numerical simulation of SIC with higher-order numerical schemes intended for the use of the code for the hypersonic propulsion and supersonic combustion applications. The simulations show that specific reaction mechanisms are grid-sensitive and produce spurious reactions in the high-temperature region, which trigger artificial instability in the oscillating flow field. The simulations also show that specific reaction mechanisms develop such spurious oscillations only at very fine grid resolutions. The instability mechanism is investigated using the dynamic mode decomposition (DMD) technique and the spatial structure of the decomposed modes are further analyzed. It is found that the instability triggered by the high-temperature reactions strengthens the reflecting compression wave and pushes the shock wave further and disrupts the regularly oscillating mechanism. The spatial coherent structure from the DMD analysis shows the effect of this instability in different regions in the regularly oscillating flow field.

This article investigates the role of diverse nudging communication strategies on perceived threat and stockpiling intention. Across three studies, the authors examined the various effects of “nudging” on consumer behavior. Study 1 demonstrates that a commonly used picture has a stronger impact on perceived threat than a less frequently exposed picture regardless of its accuracy. Study 2 shows that the perceived threat of COVID-19, in terms of severe health consequences, is lower when using an indirect (vs. direct) explanation of the virus, as well as when reducing the amount of information about the virus. Study 3 investigates the impact of salient negative information and childhood socioeconomic status (SES). Findings reveal that negative information about deaths associated with the virus increases the level of perceived threat and stockpiling intention, especially among people of low childhood SES.

This study examined human flavor perception and discrimination of powdered milk samples with various fat contents using two different sensory discrimination methods, DR A-Not A and 3-AFC. DR A-Not A was expected to be more effective. Using skim milk and whole milk powder, five different samples with various fat contents were prepared. An independent samples design was used to compare DR A-Not A and 3-AFC. Each subject performed 24 repeated tests consisting of comparisons of four different test samples from the reference sample. Signal detection d′ results showed that sample discrimination was possible using DR A-Not A, but not 3-AFC. Moreover, the just noticeable difference (JND) was calculated using the results of DR A-Not A. The calculated JND was 0.47% (w/v), and the Weber fraction was 0.82. These results confirm that the DR A-Not A method is more effective for studying the human sensitivity to the fat content in food.

A prominent mandibular angle produces a characteristic quadrangle with a coarse appearance. Asians prefer getting the shape of their jaws surgically corrected into a V-line, which is assumed to give a more intelligent, beautiful, and delicate appearance. According to many studies, mandibular contouring surgery may jeopardize mechanical stability. The aim of this study was to analyse the stress on the mandible during function after mandibular contouring surgery using finite element analysis. Based on computed tomography scans, the three-dimensional models of preoperative mandible, mandibular angle ostectomy, and sagittal cortical ostectomy of the mandibular ramus and body with angle ostectomy were obtained. Boundary conditions to restrict movement on both condyles and clenching tasks (incisal clench, right molar clench, and right group clench) were simulated. The sagittal cortical ostectomy model had the highest strain energy (48.51 J) and von Mises stress (77.39 MPa) during the right molar clench task. The maximum von Mises stress on the sagittal cortical ostectomy was increased by up to approximately four times compared with the cases of preoperative mandible. The stress was concentrated at the site of operation, mandibular condyle, and angle. In the case of the sagittal cortical ostectomy model, bone resorption may occur, and there is a possibility of fracture during the right molar clench task. These results suggest that mandibular contouring surgery may be related to the fragility of the mandible, since surgery significantly alters its biomechanics. The degree of surgery may be a determining factor in the stress and fracture risk of the mandible. Therefore, clinicians should establish an accurate and correct treatment plan for the safe prognosis of patients after surgery.

Besides the great burden that has been placed on the world by the COVID-19 pandemic, radical climate change is causing natural disasters in every corner of the world. According to the IPCC’s most recent report, rising global temperatures already have very negative impacts beyond our expectation. The main cause of this lies in human activities that drive global population growth, ongoing urbanization, excessive use of natural resources, and so on. Every minute, the environment in islands and oceans is changing in different directions and angles. This forum is to have an in-depth discussion on how climate crisis including pandemic and climate change and sprawling development by humans etc., can affect cultures and ecosystem in islands and seascapes and which direction identity of islands will be heading in the future. For this matter, the theme of this forum is fixed as “Changes and Chaos in Islands and Seascapes”.

Prior research in behavioral economics has examined the effects of nudging and the diverse aspects of choice on individuals’ decisions and behaviors. Based on this premise, the current research offers a novel and timely view by examining how communication messages in public service advertisements (PSAs) can alter the perception of threat under uncertain situations such as the SARS-CoV-2 coronavirus pandemic. This article investigates the role of additional relative statistical information on the perception of threat and stockpiling intention. First, we examine whether there is a reduction in the perceived threat of the coronavirus if information about the potential severity of an alternative threat (car accidents) is activated, when compared to offering only statistics on the disease caused by SARS-CoV-2, which is known as COVID-19. Furthermore, we established the mediating role of a perceived threat in consumers’ decisions and behavior in times of severe crisis. This suggests that organizations and policymakers can influence individuals by increasing or decreasing their perceived level of threat depending on the desired outcomes (e.g., respecting authorities’ recommendations or avoiding stockpiling). This research offers a deeper understanding of how consumers can be “nudged” toward desired behavior in the context of public health and safety.

Purpose : The purpose of this study was to measure accommodative response when looking at different direction such as downgaze and sidegaze either right or left. Methods : This study was performed with 13 adult males and females(22.40±0.41 years old) no subject had ophthalmic surgery or disease and placed the targets at the primary, 10° and 20° sidegaze, 10° and 20° downgaze, The accommodative responses was measured by a open-field autorefractometer under the distances of 3 m, 1 m and 40 cm that enable consecutive measurement. Results : In all gaze directions as distance became shorter the accommodative response increased. At each viewing distance 1m and 40 cm, the accommodative responses showed the peaks 1.09± 0.10 D in 10° and 2.04±0.11 D in 20° downgaze. respectively, while the lowest accommodative responses were 0.44±0.05 D and 1.54±0.06 D in 20° and 10° sidegaze, which showed statistical differences(p＜0.050). There were significant differences in each viewing direction except for in 10° and 20° sidegaze(p＜0.050). The gaze direction and the accommodative responses were significantly different(p＜0.050). Conclusion : This study demonstrates that the accommodative responses vary with the gaze direction and gaze angle for the same modulating stimulus. Therefore, it is assumed that 20° downgaze makes the object sharper and minimizes the eye fatigue.

Bifurcation of the characteristic cells into multiple smaller cells and decay of those cells into single large characteristic cell is observed frequently. In the present study the bifurcation phenomenon of the detonation front is investigated for marginally unstable detonations using decomposition technique. Numerical analysis is carried out with detailed chemical kinetics for detonation propagation in H2/O2 mixtures at 10 kPa. The dynamic characteristics of the instability at the detonation front, such as the local oscillation frequency and the coherent spatial structure of the oscillation are also studied with dynamic mode decomposition (DMD) technique. The coherent structures of the primary and secondary detonation cells are analyzed during the cell bifurcation process and the mechanism in which the secondary cells are formed is investigated. It is demonstrated that the modal analysis categorizes the instability phenomena clearly and can be effectively utilized to identify the origin and source of the instability.

The distribution of plant communities in the reclaimed land of the southwestern coasts of South Korea, along with the environmental or plant factors, was studied through canonical correspondence analysis (CCA) and the competitor (C), stress tolerator (S), and ruderal (R) (CSR) ecological strategies. The coastal reclaimed land plants were classified into three plant-factor groups in the CCA biplot diagram. Axis1 was correlated with LS, SLA, CH, and FS. Axis 2 was correlated with LDMC, FP, and LDW. The reclaimed landplants were classified into three soil-factor groups in the CCA biplot diagram. First, the group factor was correlated with SAND. Second, the group factor was distributed according to T-N and TOC. Third, the group factor was distributed according to Salinity content. To clarify the relative significance of competition, stress, and disturbance in the distribution process of plant communities, the CSR distribution model was adopted. Sixteen of the 19 species were allocated to the factors related to the ruderals strategies such as R/CR and CR including R/CSR, SR/CSR, and CR/CSR, and SC strategies. They displayed ruderal and competition adaptation strategies reflecting the ecological environment. Seven species showed R/CR (ruderal/competitor-ruderal) strategies; Aeschno meneindica, Chenopodium album var. centrorubrum, Lolium perenne, Lotus corniculatus var. japonicus, Phragmites communis, Portulaca oleracea, and Soncous brachyotus and 6 species showed CR (competitor-ruderal) strategies; Bidens frondosa, Echinochloa crus-galli, Echino chloaoryzicola, Erigeron canadensis, Fimbristy lislongispica and Setaria viridis. The three species with R-related strategies were Artemisia princeps, Lolium perenne, and Trifolium repens. The distribution patterns of the CCA diagrams and CSR triangles may provide a useful scientific basis for protecting and restoring reclaimed lands and their valuable ecosystem services, from the increasing disturbances.

Cryopreservation, the most common method of preserving stem cells, requires post-processing because it produces trauma to the cells. Post-thawing trauma typically induces cell death, elevates reactive oxygen species (ROS) concentration, and lowers mitochondrial membrane potential (MMP). Although this trauma has been solved using antioxidants, we attempted to use photobiomodulation (PBM) instead of chemical treatment. We used a 950-nm near-infrared LED to create a PBM device and chose a pulsed-wave mode of 30 Hz and a 30% duty cycle. Near-infrared radiation (NIR) at 950 nm was effective in reducing cell death caused by hydrogen peroxide induced-oxidative stress. Cryodamage also leads to apoptosis of cells, which can be avoided by irradiation at 950 nm NIR. Irradiation as post-processing for cryopreservation had an antioxidant effect that reduced both cellular and mitochondrial ROS. It also increased mitochondrial mass and activated mitochondrial activity, resulting in increased MMP, ATP generation, and increased cytochrome c oxidase activity. In addition, NIR increased alkaline phosphatase (ALP) activity, a biomarker of differentiation. As a result, we identified that 950 nm NIR PBM solves cryodamage in human stem cells from the apical papilla, indicating its potential as an alternative to antioxidants for treatment of post-thawing trauma, and further estimated its mechanism.

The use of bone graft materials is required for the treatment of bone defects damaged beyond the critical defect, therefore, injectable calcium phosphate cement (CPC) is actively used after surgery. The application of various polymers to improve injectability, mechanical strength, and biological function of injection-type CPC is encouraged. We previously developed a chitosan–PEG conjugate (CS/PEG) by a sulfur (VI) fluoride exchange reaction, and the resulting chitosan derivative showed high solubility at a neutral pH. We have demonstrated the CPC incorporated with a poly (ethylene glycol) (PEG)-grafted chitosan (CS/PEG) and developed CS/PEG CPC. The characterization of CS/PEG CPC was conducted using Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD). The initial properties of CS/PEG CPCs, such as the pH, porosity, mechanical strength, zeta potential, and in vitro biocompatibility using the WST-1 assay, were also investigated. Moreover, osteocompatibility of CS/PEG CPCs was carried out via Alizarin Red S staining, immunocytochemistry, and Western blot analysis. CS/PEG CPC has enhanced mechanical strength compared to CPC, and the cohesion test also demonstrated in vivo stability. Furthermore, we determined whether CS/PEG CPC is a suitable candidate for promoting the osteogenic ability of Dental Pulp Stem Cells (DPSC). The elution of CS/PEG CPC entraps more calcium ion than CPC, as confirmed through the zeta potential test. Accordingly, the ion trapping effect of CS/PEG is considered to have played a role in promoting osteogenic differentiation of DPSCs. The results strongly suggested that CS/PEG could be used as suitable additives for improving osteogenic induction of bone substitute materials.

BACKGROUND Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation (NIBS) technique designed to improve cognitive and physical function of stroke survivors. There are many studies being conducted in the search for an effective intervention of tDCS. This study focused on cognitive motor learning in relation to hand function of stroke survivors. MATERIAL AND METHODS We enrolled 30 subjects with cognitive and hand function disorders. The participants in each group were inpatients at a hospital in Korea and had undergone neurorehabilitation training (60 min). Groups 1 and 3 had tDCS applied for 20 min, while group 2 received sham tDCS for the same duration. Afterwards, groups 1 and 2 played Nintendo games for 20 min, but group 3 did not. The total intervention period was 40 min/day, 2 days/week, for 8 weeks. The cognitive and hand function of the subjects were assessed using the Trail Making Test (TMT-A, TMT-B), Grip strength, Box and Block Test (BBT), and the Manual Function Test (MFT) before and after intervention. RESULTS The tDCS + Nintendo Switch game group showed significant differences in TMT-A, TMT-B, Grip strength, MFT, and BBT results compared to the other groups between before and after intervention (p

Background and Aim: This study investigated the administration of combination therapy, allogeneic natural killer (NK) cells and pembrolizumab in the treatment of advanced biliary tract cancer to determine the safety and tolerability (phase 1) and the efficacy and safety (phase 2a). Methods: Forty patients (phase 1, n = 6; phase 2a, n = 34) were enrolled between December 2019 and June 2021. The patients received highly activated allogeneic NK cells (“SMT-NK”) on weeks 1 and 2 and pembrolizumab on week 1. This 3-week schedule (one cycle) was repeated until confirmed disease progression, intolerable adverse events (AEs), patient withdrawal, or finishing the maximum treatment schedule. The tumor response was evaluated after every three cycles. Results: In phase 1, four patients (66.7%) experienced seven AEs, but no severe AE was observed. In phase 2a, 126 AEs occurred in 29 patients (85.3%). Severe AEs (≥grade 3) were reported in 16 patients (47.1%). The overall response rate (ORR) was 17.4% in the full analysis set and 50.0% in the per-protocol set. Conclusions: SMT-NKs plus pembrolizumab resulted in no severe AEs directly related to the drug combination. The combination therapy also exerted antitumor activity with improved efficacy compared to the recent monotherapy with pembrolizumab in patients with advanced biliary tract cancer.

Graphical abstract Image 1, Highlights • The information presented and the design of health campaigns significantly influence perceived threats and irrational behaviors such as stockpiling intentions. • Childhood socioeconomic status of individuals has an impact on the effectiveness of these advertising strategies. • The results lead to definite practical implications for organizations and policy makers for increasing the effectiveness of their campaigns.

Supramolecular hydrogels are considered promising drug carriers in the tissue engineering field due to their versatile nature. Chitosan hydrogels without chemical cross-linkers have low cytotoxicity and good delivery capacity, however, they have lower mechanical properties for injectable hydrogel usage. In this study, we developed novel chitosan derivatives via click chemistry for fabricating supramolecular hydrogels with higher mechanical strength under mild conditions. The chitosan derivative was successfully synthesized by a sulfur fluoride exchange reaction, and the synthesized chitosan-mPEG/Pluronic-F127 (CS-mPEG/F127) interacted with &alpha, cyclodextrin (&alpha, CD) to form a supramolecular hydrogel via a host-guest reaction. The gelation dynamics, hydrogel properties, and bovine serum albumin (BSA) release could be modulated by the concentration ratio of chitosan-mPEG and F127. This supramolecular hydrogel is a promising protein releasing carrier candidate for long term regeneration therapy.

We report a novel versatile method for writing charged areas on diamond nanowire (DNW) surfaces using an atomic force microscopy (AFM) tip. Transmission electron microscopy (TEM) investigations revealed the existence of abundant plate-like diamond aggregates, which were encased in layers of graphite, forming nano-sized diamond-graphite composites (DGCs) on DNW surfaces. These DGCs are the main feature, acting as charge-trapping centers and storing electrostatic charge. A hydrogenation process has been observed effectively enhancing the charge-trapping properties of these DNW materials. The effective charge trapping properties with hydrogenation are ascribed to the disintegration of the DGCs into smaller pieces, with an overall increase in the metallic nanographitic phase fractions in a dielectric diamond matrix. Moreover, the written charge on the surface can be easily modified, re-written, or completely erased, enabling application in diamond-based re-writable electronic devices. However, excessive hydrogenation degrades the charge-trapping properties, which is attributed to the etching of the DGCs from the surface. This study demonstrates the potential importance of a simple hydrogenation process in effective electrostatic charge trapping and storage for diamond related nanocarbon materials and the role of DGCs to further enhance it. This work was supported by the Institute for Basic Science (IBS) [IBS-R004] and by the European Commission under the project, QUEFORMAL [829035] and Graphene Flagship [881603]. Panda, K; Park, JY (corresponding author), Korea Adv Inst Sci & Technol KAIST, Dept Chem, Daejeon 34141, South Korea ; Univ Bundeswehr Munchen, Fac Elect Engn & Informat Technol, Inst Phys, EIT 2, Werner Heisenberg Weg 39, D-85577 Neubiberg, Germany. Park, JY (corresponding author), Inst Basic Sci IBS, Ctr Nanomat & Chem React, Daejeon 34141, South Korea. phy.kalpa@gmail.com; jeongypark@kaist.ac.kr

Background Immune checkpoint inhibitors (ICIs) including anti-CTLA-4, anti-PD-1, and anti-PD-L1 have been clinically used for the treatment of various types of cancer. However, ICIs have a limited efficacy, and it is required to develop a strategy to enhance the efficacy of ICIs. Hematopoietic progenitor kinase 1 (HPK1) was recently known to inhibit T cell receptor (TCR) signaling by targeting SLP76 thus suppress T-cell effector functions. Methods In the present study, we examined the expression of HPK-1 and SLP76 in tumor-infiltrating lymphocytes (TILs) obtained from renal cell carcinoma tissues, in relation with the expression of PD-1 and other immune checkpoint receptors by performing flow cytometry analysis. In addition, we examined if inhibition of the kinase activity of HPK1 by CMPD0914, that is a potent, selective and orally available HPK1 inhibitor, enhanced effector functions of tumor-infiltrating CD8+ T cells in the presence of anti-PD-1 blocking antibodies. Results First, we found that HPK1 and SLP76 are expressed in both CD8+ and CD4+ T cells including Foxp3+ regulatory T cells irrespective of PD-1 expression. Intriguingly, the expression levels of HPK1 and SLP76 were significantly higher in the PD-1bright population compared to the PD-1- or PD-1dim populations. Further characterization revealed that HPK1 and SLP76 were highly expressed in CD8+ T-cell populations expressing TOX, a transcription regulator of T-cell exhaustion, or TCF-1, a transcription factor related to progenitor-like exhausted T cells. In ex vivo functional assays, anti-PD-1 treatment increased the production of IFN-γ and TNF, and the expression of a proliferation marker, Ki-67 among tumor-infiltrating CD8+ T cells. Interestingly, the effects of anti-PD-1 treatment were further enhanced by the combination treatment with CMPD0914. Conclusions In summary, we demonstrated that HPK1 and SLP76 are expressed by human tumor-infiltrating T cells, particularly PD-1brightCD8+ T cells, and that anti-PD-1-induced T-cell reinvigoration is significantly enhanced by an HPK1 inhibitor, CMPD0914, rationalizing the combination of anti-PD1/PD-L1 and HPK1 inhibitors for the treatment of cancer.

Hydroxyapatite (HA) is a representative substance that induces bone regeneration. Our research team extracted nanohydroxyapatite (EH) from natural resources, especially equine bones, and developed it as a molecular biological tool. Polyethylenimine (PEI) was used to coat the EH to develop a gene carrier. To verify that PEI is well coated in the EH, we first observed the morphology and dispersity of PEI-coated EH (pEH) by electron microscopy. The pEH particles were well distributed, while only the EH particles were not distributed and aggregated. Then, the existence of nitrogen elements of PEI on the surface of the pEH was confirmed by EDS, calcium concentration measurement and fourier transform infrared spectroscopy (FT-IR). Additionally, the pEH was confirmed to have a more positive charge than the 25 kD PEI by comparing the zeta potentials. As a result of pGL3 transfection, pEH was better able to transport genes to cells than 25 kD PEI. After verification as a gene carrier for pEH, we induced osteogenic differentiation of DPSCs by loading the BMP-2 gene in pEH (BMP-2/pEH) and delivering it to the cells. As a result, it was confirmed that osteogenic differentiation was promoted by showing that the expression of osteopontin (OPN), osteocalcin (OCN), and runt-related transcription factor 2 (RUNX2) was significantly increased in the group treated with BMP-2/pEH. In conclusion, we have not only developed a novel nonviral gene carrier that is better performing and less toxic than 25 kD PEI by modifying natural HA (the agricultural byproduct) but also proved that bone differentiation can be effectively promoted by delivering BMP-2 with pEH to stem cells., Graphical abstract Image 1, Highlights • The hydroxyapatite (EH) derived from equine bone decorated with PEI (pEH) is not only very well distributed, but also has a very strong positive charge. • Through experiments, it was proved that the pEH has excellent gene transfer ability and low toxicity. • The osteogenic differentiation of dental pulp stem cells (DPSCs) was induced by delivering BMP-2 plasmid gene with pEH (BMP-2/pEH).

We report the enhanced charge storage characteristics of ultrananocrystalline diamond (UNCD) by contact electrification-induced hydrogenation. The non-catalytic hydrogenation of UNCD films was achieved by using platinum as an electron donor and sulfuric acid as a hydrogen proton donor, confirmed by Raman spectroscopy and time-of-flight secondary ion mass spectroscopy (TOF-SIMS). Chemical treatment with only a H2SO4 solution is responsible for the surface oxidation. The oxidation of UNCD resulted in an increase in the quantity and duration of the tribocharges. After non-catalytic hydrogenation, the generation of friction-induced tribocharges was enhanced and remained for three hours and more. We show that the hydrogen incorporation on grain boundaries is responsible for the improvement of charge storage capability, because the doped hydrogen acts as a trap site for the tribocharges. This lab-scale and succinct method can be utilized to control charge trap capability in nanoscale memory electronics.

Correction for ‘Synergistic photodynamic therapeutic effect of indole-3-acetic acid using a pH sensitive nano-carrier based on poly(aspartic acid-graft-imidazole)-poly(ethylene glycol)’ by Taehoon Sim et al., J. Mater. Chem. B, 2017, 5, 8498–8505.

The near-perivascular accumulation in solid tumors and short-lived span in circulation, derails even the most competent nanoparticles (NPs) from achieving their maximum therapeutic potential. Moreover, delivering them across the blood brain/tumor barrier (BBB/BTB) is further challenging to sought anticancer effect. To address these key challenges, we designed a linearly aligned nucleic acid-complexed polydixylitol-based polymeric nanochains (X-NCs), with inherent hyperosmotic properties enabling transmigration of the BBB/BTB and navigation through deeper regions of the brain tumor. The high aspect ratio adds shape-dependent functional aspects to parent particles by providing effective payload increment and nuclear factor of activated T cells-5 (NFAT5)-mediated cellular uptake. Therefore, serine hydroxymethyltransferase 1 (SHMT1) siRNA-loaded nanochains not only demonstrated to transmigrate the BTB, but also resulted in remarkably reducing the tumor size to 97% in the glioblastoma xenograft brain tumor mouse models. Our study illustrates how the hyperosmotic nanochains with high aspect ratio and aligned structure can accelerate a therapeutic effect in aggressive brain tumors post-transmigration of the BBB/BTB by utilizing an NFAT5 mode of uptake mechanism.

Four issues that can affect statistical conclusions from mediation analysis are presented here: The implications of omitting mediators; not conducting reverse mediation analysis; using inappropriate measures; and not considering a wider array of experiment-based methods. Suggestions for addressing each of these are advanced. Previous issues of AMJ, JMR and JCR are then examined to gauge the extent to which these suggestions were used. Less than half of the published papers inspected (44.4% of the total) endeavored to address at least three of the four issues raised above. AMJ authors will realize higher statistical as well as theoretical rigor if they consider these suggestions.

Combinatorial allogeneic NK cell therapy with Pembrolizumab for cholangiocarcinoma; interim report of open label Phase1/2a study Background: There are several things needed to be resolved for successful efficacy when NK cell therapy is applied for solid tumor; improvement of NK cell invasion into tumor, activation and production of a large number of NK cells, etc. Basically, in human, NK cell number is relatively small compared to other immune cells such as T cell and the number becomes severely low when NK cell is obtained from cancer patients. For these reasons, allogeneic NK cell has been used for clinical studies against various cancer types. Recently, we also have finished a phase1 study of allogeneic NK cell therapy for cholangiocarcinoma, enrolling 9 patients at inoperable and no chemotherapy favorable stage due to side effects. Four of nine patients (44%) showed SD (stable disease) after six NK cell injections and no severe AE (adverse event) was found. In this following phase 2a study, to bring out immuno-synergetic effect of NK cell therapy against the inoperably advanced bile duct cancer, we have designed a combinatorial protocol with using Pembrolizumab. Methods: Enrollment of 40 bile duct cancer patients has been finished for a combinatorial study of allogeneic NK cell therapy with Pembrolizumab at two different sites in Korea (ClinicalTrials gov, NCT03937895). Patients were eligible for the enrollment when they were inoperable and no chemotherapy favorable stage due to side effects, and also when they had PD-L1-positive score. For treatment, the most favorable method for highly activated allogeneic NK cell production has been determined from our previous study, resulting that 3x106 NK cells per kg are injected for each dose along with Pembrolizumab injection. Pembrolizumab (200mg) was given every 3 weeks for up to 9 times and NK cell injection was given for up to 18 times during the maximum injection period of Pembrolizumab. Results: Six patients (pts) were first enrolled for the pilot combinatorial study, dosing 6 times of NK cells and 3 times of Pembrolizumab. The result showed no severe AE from the injections. Among the five pts finished the injections, 2 pts showed SD (Stable Disease) and continued the treatment, being enrolled into the Phase 2a in which 34 more pts were enrolled. Among the 20 pts finished 6 NK cell and 3 Pembrolizumab injections (1st RECIST), 65% of pts showed SD. When 12 NK cell and 6 Pembrolizumab injections finished (2nd RECIST), pts had 40% and 20% of SD and PR (Partial remission). Of the 3 pts at 3rd RECIST (18 NK cell and 9 Pembrolizumab), 1 and 2 pts showed SD and PR, respectively. Finding pts experienced AE, a total of 6 AEs has been reported: no treatment-related AE, one grade 3 (Encephalopathy), and five grade 1-2 with common AE. In a recent safety and efficacy study of pembrolizumab alone (10mg/kg, every 2 weeks for up to 2 years) with 28 pts of advanced bile duct cancer showing PD-L1 expression, 17% pts showed PR, 17% pts and 52% had SD and PD (progressive disease), respectively. Although our study is still ongoing, continuing the combinatorial treatment gives rise to PR, suggesting that NK cell therapy with Pembrolizumab shows an immuno-synergetic effect for the cancer. Biomarker experiments with the injected NK cells supports our finding and we will discuss this at presentation. Citation Format: Yong Yoon Chung, Seung Woo Park, Jung-Min Im, Da-Kyung Yoo, Hyo-Cheon Cheon, Jae-Eun Kim, Kyeong-Pill Lim, Eun-Hee Yang, Hye-Jin choi, Hyo-Sun Chung, Seo-Yeon Kim, Ju-Yong Lee, In-Hye Jung, Seung Min Bang, Moon Jae Chung, Sung Ill Jang, Jae Hee Cho, Hee Seung Lee, Jung Youp Park, Jung Hyun Jo. Combinatorial allogeneic NK cell therapy with Pembrolizumab for cholangiocarcinoma; interim report of open label Phase1/2a study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT171.

BACKGROUND Handgrip strength and walking speed predict and influence cognitive function. We aimed to investigate an exercise protocol for improving handgrip strength and walking speed, applied to patients with chronic stroke who had cognitive function disorder. MATERIAL AND METHODS Twenty-nine patients with cognitive function disorder participated in this study, and were randomly divided into one of two groups: exercise group (n=14) and control group (n=15). Both groups underwent conventional physical therapy for 60 minutes per day. Additionally, the exercise group followed an exercise protocol for handgrip using the hand exerciser, power web exerciser, Digi-Flex (15 minutes); and treadmill-based weight loading training on their less-affected leg (15 minutes) using a sandbag for 30 minutes, three times per day, for six weeks. Outcomes, including cognitive function and gait ability, were measured before and after the training. RESULTS The Korean version of Montreal Cognitive Assessment (K-MoCA), Stroop test (both simple and interference), Trail Making-B, Timed Up and Go, and 10-Meter Walk tests (p