Efficacy of natural killer cell therapy combined with chemoradiotherapy in murine models of head and neck squamous cell carcinoma.

BACKGROUND AIMS: Natural killer (NK) cell-based cancer immunotherapy is effective when combined with other treatment modalities such as irradiation and chemotherapy. NK cell's antitumor function to treat solid tumor, including head and neck squamous cell carcinoma (HNSCC), has been targeted recently. This study assessed NK cell recruitment in response to chemoradiation therapy (CRT) in HNSCC. METHODS: Ex vivo expansion of NK cell, flow cytometry, cell viability assay, cytotoxicity assay, immunohistochemistry, and animal model were performed. RESULTS: Mouse NK cells were recruited to the tumor site by CRT in a nude mouse model. Furthermore, expanded and activated human NK cells (eNKs) were recruited to the tumor site in response to CRT, and CRT enhanced the anti-tumor activity of eNK in an NOD/SCID IL-2Rγnull mouse model. Various HNSCC cancer cell lines exhibited different NK cell ligand activation patterns in response to CRT that correlated with NK cell-mediated cytotoxicity. CONCLUSIONS: Identifying the activation patterns of NK cell ligands during CRT might improve patient selection for adjuvant NK cell immunotherapy combined with CRT. This is the first study to investigate the NK cell's antitumor function and recruitment with CRT in HNSCC mouse model.

Memory Monitoring and Control in Japanese and German Preschoolers.

Prior studies explored the early development of memory monitoring and control. However, little work has examined cross-cultural similarities and differences in metacognitive development in early childhood. In the present research, we investigated a total of 100 Japanese and German preschool-aged children's memory monitoring and control in a visual perception task. After seeing picture items, some of which were repeated, children were presented with picture pairs, one of which had been presented earlier and the other was a novel item. They then were asked to identify the previously presented picture. Children were also asked to evaluate their confidence about their selection, and to sort the responses to be used for being awarded with a prize at the end of the test. Both groups similarly expressed more confidence in the accurately remembered items than in the inaccurately remembered items, and their sorting decision was based on their subjective confidence. Japanese children's sorting more closely corresponded to memory accuracy than German children's sorting, however. These findings were further confirmed by a hierarchical Bayesian estimation of metacognitive efficiency. The present findings therefore suggest that early memory monitoring and control have both culturally similar and diverse aspects. The findings are discussed in light of broader sociocultural influences on metacognition.

Metacognition and mindreading in young children: A cross-cultural study.

Prior studies document cross cultural variation in the developmental onset of mindreading. In particular, Japanese children are reported to pass a standard false belief task later than children from Western countries. By contrast, we know little about cross-cultural variation in young children's metacognitive abilities. Moreover, one prominent theoretical discussion in developmental psychology focuses on the relation between metacognition and mindreading. Here we investigated the relation between mindreading and metacognition (both implicit and explicit) by testing 4-year-old Japanese and German children. We found no difference in metacognition between the two cultural groups. By contrast, Japanese children showed lower performance than German children replicating cultural differences in mindreading. Finally, metacognition and mindreading were not related in either group. We discuss the findings in light of the existing theoretical accounts of the relation between metacognition and mindreading.

Learning from multiple informants: Children's response to epistemic bases for consensus judgments.

Consensus has both social and epistemic value. Children conform to consensus judgments in ways that suggest they are sensitive to the social value of consensus. Here we report two experiments providing evidence that 4-year-old children also are sensitive to the epistemic value of consensus. When multiple informants gave the same judgment concerning the hidden contents of a container, based on the observation of one of their members, children's own judgments tended to align with the consensus judgment over the judgment of a lone character, whose observation received no endorsements. This tendency was reduced, however, when children were shown that the group consensus lacked epistemic warrant. Together, the findings provide evidence that young children are sensitive to the epistemic basis of consensus reports.

Molecular determinants of cadherin ideal bond formation: Conformation-dependent unbinding on a multidimensional landscape.

Classical cadherin cell-cell adhesion proteins are essential for the formation and maintenance of tissue structures; their primary function is to physically couple neighboring cells and withstand mechanical force. Cadherins from opposing cells bind in two distinct trans conformations: strand-swap dimers and X-dimers. As cadherins convert between these conformations, they form ideal bonds (i.e., adhesive interactions that are insensitive to force). However, the biophysical mechanism for ideal bond formation is unknown. Here, we integrate single-molecule force measurements with coarse-grained and atomistic simulations to resolve the mechanistic basis for cadherin ideal bond formation. Using simulations, we predict the energy landscape for cadherin adhesion, the transition pathways for interconversion between X-dimers and strand-swap dimers, and the cadherin structures that form ideal bonds. Based on these predictions, we engineer cadherin mutants that promote or inhibit ideal bond formation and measure their force-dependent kinetics using single-molecule force-clamp measurements with an atomic force microscope. Our data establish that cadherins adopt an intermediate conformation as they shuttle between X-dimers and strand-swap dimers; pulling on this conformation induces a torsional motion perpendicular to the pulling direction that unbinds the proteins and forms force-independent ideal bonds. Torsional motion is blocked when cadherins associate laterally in a cis orientation, suggesting that ideal bonds may play a role in mechanically regulating cadherin clustering on cell surfaces.

Solution single-vesicle assay reveals PIP2-mediated sequential actions of synaptotagmin-1 on SNAREs.

Synaptotagmin-1 (Syt1) is a major Ca(2+) sensor for synchronous neurotransmitter release, which requires vesicle fusion mediated by SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors). Syt1 utilizes its diverse interactions with target membrane (t-) SNARE, SNAREpin, and phospholipids, to regulate vesicle fusion. To dissect the functions of Syt1, we apply a single-molecule technique, alternating-laser excitation (ALEX), which is capable of sorting out subpopulations of fusion intermediates and measuring their kinetics in solution. The results show that Syt1 undergoes at least three distinct steps prior to lipid mixing. First, without Ca(2+), Syt1 mediates vesicle docking by directly binding to t-SNARE/phosphatidylinositol 4,5-biphosphate (PIP(2)) complex and increases the docking rate by 10(3) times. Second, synaptobrevin-2 binding to t-SNARE displaces Syt1 from SNAREpin. Third, with Ca(2+), Syt1 rebinds to SNAREpin, which again requires PIP(2). Thus without Ca(2+), Syt1 may bring vesicles to the plasma membrane in proximity via binding to t-SNARE/PIP(2) to help SNAREpin formation and then, upon Ca(2+) influx, it may rebind to SNAREpin, which may trigger synchronous fusion. The results show that ALEX is a powerful method to dissect multiple kinetic steps in the vesicle fusion pathway.

SOX4 expression is associated with treatment failure and chemoradioresistance in oral squamous cell carcinoma.

BACKGROUND: In humans, sex-determining region-Y (SRY) related high-mobility-group box 4 (SOX4) is linked to development and tumorigenesis. SOX4 is over-expressed in several cancers and has prognostic significance. This study evaluated whether SOX4 affects oncogenic behavior and chemoradiotherapy response in head and neck squamous cell carcinoma (HNSCC) cells, and documented the relationship between its expression and prognosis in oral squamous cell carcinoma (OSCC). METHODS: We used small interfering RNA in HNSCC cells to evaluate the effect of SOX4 on cell proliferation, apoptosis, chemoradiation-induced apoptosis, invasion, and migration. SOX4 expression in OSCC tissues was investigated by immunohistochemistry. RESULTS: SOX4 knockdown (KO) decreased cell proliferation and induced apoptosis by activating caspases-3 and -7, and poly-ADP ribose polymerase and suppressing X-linked inhibitor of apoptosis protein in HNSCC cells; it also enhanced radiation/cisplatin-induced apoptosis; and suppressed tumor cell invasion and migration. Immunostaining showed SOX4 protein was significantly increased in OSCC tissues compared with adjacent normal mucosa. SOX4 expression was observed in 51.8 % of 85 OSCC tissues, and was significantly correlated with treatment failure (P = 0.032) and shorter overall survival (P = 0.036) in patients with OSCC. CONCLUSIONS: SOX4 may contribute to oncogenic phenotypes of HNSCC cells by promoting cell survival and causing chemoradioresistance. It could be a potential prognostic marker for OSCC.

Clarifying the range of social-cognitive processes subserving human teaching.

An evolutionary framework on human teaching is not well equipped to explain the nature of human teaching unless it specifies the subserving cognitive and motivational mechanisms. Only a theory that speculates on the psychological processes provides testable predictions and stimulates further empirical research.

Mediating role of critical thinking disposition in the relationship between perceived barriers to research use and evidence-based practice.

BACKGROUND: Despite the importance of critical thinking in clinical and educational settings, little is known about its role in evidence-based practice (EBP). AIM: This study examined whether critical thinking disposition (CTD) mediates the relationship between perceived barriers to research use and EBP in clinical nurses (N=409). METHODS/DESIGN: A path diagram using structural equation modeling was used to estimate the direct and indirect effects of perceived barriers to research use on EBP, controlling for CTD as a mediator. RESULTS: CTD partially mediated the relationship between perceived barriers to research use and EBP. Furthermore, the hypothesized mediation model demonstrated an appropriate fit to the data. CONCLUSIONS: Individual and organizational efforts are needed to help nurses further improve their critical thinking skills. CTD is important as research barriers to engage effectively in EBP. Without the skills to evaluate evidence carefully, research utilization may be compromised.

Nonaggregated α-synuclein influences SNARE-dependent vesicle docking via membrane binding.

α-Synuclein (α-Syn), a major component of Lewy body that is considered as the hallmark of Parkinson's disease (PD), has been implicated in neuroexocytosis. Overexpression of α-Syn decreases the neurotransmitter release. However, the mechanism by which α-Syn buildup inhibits the neurotransmitter release is still unclear. Here, we investigated the effect of nonaggregated α-Syn on SNARE-dependent liposome fusion using fluorescence methods. In ensemble in vitro assays, α-Syn reduces lipid mixing mediated by SNAREs. Furthermore, with the more advanced single-vesicle assay that can distinguish vesicle docking from fusion, we found that α-Syn specifically inhibits vesicle docking, without interfering with the fusion. The inhibition in vesicle docking requires α-Syn binding to acidic lipid containing membranes. Thus, these results imply the existence of at least two mechanisms of inhibition of SNARE-dependent membrane fusion: at high concentrations, nonaggregated α-Syn inhibits docking by binding acidic lipids but not v-SNARE; on the other hand, at much lower concentrations, large α-Syn oligomers inhibit via a mechanism that requires v-SNARE interaction [ Choi et al. Proc. Natl. Acad. Sci. U. S. A. 2013 , 110 ( 10 ), 4087 - 4092 ].

Metacognition of curiosity: People underestimate the seductive lure of non-instrumental information.

Curiosity - the desire to seek information - is fundamental for learning and performance. Studies on curiosity have shown that people are intrinsically motivated to seek information even if it does not bring an immediate tangible benefit (i.e., non-instrumental information), but little is known as to whether people have the metacognitive capability to accurately monitor their motivation for seeking information. We examined whether people can accurately predict their own non-instrumental information-seeking behavior. Across six experiments (Experiments 1A-1E and 2, total N = 579), participants predicted that they would engage in information-seeking behavior less frequently than they actually did, suggesting that people tend to underestimate the motivational lure of curiosity. Overall, there was no consistent statistical evidence that this underestimation was altered by contextual factors (e.g., the cost to seek information). These results were consistent with the theoretical account that it is difficult for people to make sense of the internally rewarding value of information in advance.

Carcass quality and meat tenderness of Hawaii pasture-finished cattle and Hawaii-originated, mainland feedlot-finished cattle.

The objective of this study was to compare the carcass quality and meat tenderness of Hawaii cattle finished on subtropical pasture with those of mainland US feedlot-finished cattle that were shipped from Hawaii after weaning. Rib-eye steak samples were collected from 30 feedlot-finished cattle harvested at a slaughter house in Washington State, USA and from 13 subtropical pasture-finished cattle harvested at a local slaughter house in Hawaii, then shipped to meat science laboratory at the University of Hawaii, Manoa. Samples were aged for 2 weeks at 4°C and frozen for later proximate analysis and meat tenderness measurement. Feedlot-finished cattle had significantly heavier carcass weight (353 vs 290 kg) and thicker backfat (13.5 vs 6.6 mm), but no significant difference was observed in rib-eye area between the two groups. Marbling score (Small) and United States Department of Agriculture quality grade (Choice) of the pasture-finished beef were not significantly (P < 0.05) different from those of feedlot-finished beef. The shear force value of pasture-finished beef (5.18 kg) was not statistically different (P < 0.05) from that of feedlot-finished beef (4.40 kg). In conclusion, results of this study suggest that Hawaii cattle finished on subtropical pasture produced as tender beef as mainland feedlot-finished cattle with less intramuscular fat.

Factors Influencing the Health-Related Quality of Life of Workers According to the Type of Work.

This paper describes a descriptive cross-sectional study that was conducted to identify and compare the factors affecting health-related quality of life (HRQoL) according to the type of work. The method involved a secondary analysis of 4131 workers who participated in the first year of the 8th Korea National Health and Nutrition Examination Survey (2019). In this study, a complex sample plan file was created and then weighted and analyzed. For the analyses, frequency, χ2-test, t-test, and linear regression analyses were used for complex sample analysis. Factors that significantly affected the HRQoL of daytime workers were educational background, living with a spouse, regular work, depression for two consecutive weeks, and suicidal thoughts. The explanatory power was 18.9% (p < 0.001). The factor that significantly affected the HRQoL of shift workers was whether they took dietary supplements for 2 weeks or more during the past year, and the explanatory power was 17.6% (p = 0.007). This study confirmed that the factors affecting HRQoL differ according to the type of work. Based on the results of this study, when developing a program to improve the HRQoL of workers, it is necessary to establish a differentiated strategy according to the type of work.

Knowing minds: Linking early perspective taking and later metacognitive insight.

Recent metacognitive research using a partial knowledge task indicates that a firm understanding of 'knowing about knowing' develops surprisingly late, at around 6 years of age. To reveal the mechanisms subserving this development, the partial knowledge task was used in a longitudinal study with 67 children (33 girls) as an outcome measure at 5;9 (years;months). In addition, first- and second-order false belief was assessed at 4;2, 5;0, and 5;9. At 2;6, perspective taking and executive abilities were evaluated. Metacognition at 5;9 was correlated with earlier theory of mind and perspective taking - even when verbal intelligence and executive abilities were partialled out. This highlights the importance of perspective taking for the development of an understanding of one's own mind.

Inhibitor of apoptosis protein Livin promotes tumor progression and chemoradioresistance in human anaplastic thyroid cancer.

Anaplastic thyroid cancer (ATC) is characterized by a rapid and aggressive course of progression. Despite significant advances in surgery, radiotherapy and chemotherapy, the disease­specific mortality due to ATC is approximately 100%. New strategies, such as molecular targeted therapies, are imperative for improving survival. Livin, a member of the human inhibitor of apoptosis protein family, has been found to be associated with tumor progression and poor prognosis in various human cancers. The aim of the present study was to evaluate the role of Livin in cancer progression and chemoradioresistance of ATC and to investigate its potential as a therapeutic target. Endogenous Livin expression in the human BHT101 ATC cell line was silenced by Livin­specific small interfering RNA. To assess the impact of Livin on cancer cell behavior in human ATC cells, various methods such as cell invasion, cell viability and cell apoptosis assays were applied. To assess the expression of Livin and the change of apoptosis­related proteins associated with Livin expression, reverse transcription­quantitative PCR and western blotting were performed. Immunohistochemistry was performed to detect Livin protein expression in human ATC tissues. The association between Livin expression and apoptotic/proliferation index was analyzed in human ATC cells. Livin­knockdown suppressed tumor cell invasion; and conversely, it enhanced cell apoptosis, with elevated expression levels of cleaved caspase­3 and ­7 and cleaved PARP. Livin­knockdown enhanced radiation­induced apoptosis, while reducing cell viability following radiotherapy, as well as lenvatinib treatment. In addition, human ATC tissues with high Livin­expression exhibited a high Ki­67 labeling index and low apoptotic index. In summary, these findings indicate the contribution of Livin to tumor progression and chemoradioresistance in ATC.

12- and 24-Month-Old Infants' Search Behavior Under Informational Uncertainty.

Infants register and react to informational uncertainty in the environment. They also form expectations about the probability of future events as well as update the expectation according to changes in the environment. A novel line of research has started to investigate infants' and toddlers' behavior under uncertainty. By combining these research areas, the present research investigated 12- and 24-month-old infants' searching behaviors under varying degree of informational uncertainty. An object was hidden in one of three possible locations and probabilistic information about the hiding location was manipulated across trials. Infants' time delay in search initiation for a hidden object linearly increased across the level of informational uncertainty. Infants' successful searching also varied according to probabilistic information. The findings suggest that infants modulate their behaviors based on probabilistic information. We discuss the possibility that infants' behavioral reaction to the environmental uncertainty constitutes the basis for the development of subjective uncertainty.

Fusion step-specific influence of cholesterol on SNARE-mediated membrane fusion.

Cholesterol is a major component of biological membranes and is known to affect vesicle fusion. However, the mechanism by which cholesterol modulates SNARE-dependent intracellular fusion is not well understood. Using the fluorescence assay and dye-labeled SNAREs and the fluorescent lipids, we dissected cholesterol effects on individual fusion steps including SNARE complex formation, hemifusion, pore formation, and pore dilation. At physiological high concentrations, cholesterol stimulated hemifusion as much as 30-fold, but its stimulatory effect diminished to 10-fold and three-fold for subsequent pore formation and pore expansion at 40 mol %, respectively. The results show that cholesterol serves as a strong stimulator for hemifusion but acts as mild stimulators for pore opening and expansion. Strong stimulation of hemifusion and mild stimulation of pore formation are consistent with the fusion model based on the intrinsic negative curvature of cholesterol. However, even a milder effect of cholesterol on pore expansion is contradictory to such a simple curvature-based prediction. Thus, we speculate that cholesterol also affects the conformation of the transmembrane domains of SNAREs, which modulates the fusion kinetics.

The effects of different attentional focus on poststroke gait.

Attention may influence the motor performance of poststroke patients. The attentional focus implies "where" attention is focused while performing a specific movement. Focusing attention on the inside of the body while performing a specific exercise is called an internal focus (IF) and focus on the external environment is called an external focus (EF). This study examined the effect of attention on the gait of patients with chronic stroke. Sixteen subjects voluntarily participated in the study. The subjects were guided to walk while maintaining the required attentional focus, which is control, IF, and EF condition. Dependent variables were as follows: step length, stride length, step width, 10-m walk time, and weight distribution on the paretic limb. The results are as follows. First, the step length and the stride length were observed to be longer in the EF condition. Second, 10-m walk time was faster in EF condition. Third, under the EF condition, more weight was applied to the paretic limb. We suggest that EF instruction useful to improve the poststroke gait.

Receptor tyrosine kinase, RON, promotes tumor progression by regulating EMT and the MAPK signaling pathway in human oral squamous cell carcinoma.

The receptor tyrosine kinase, recepteur d'origine nantais (RON), is known to be associated with the progression, metastasis, and prognosis of various types of cancers. Nevertheless, the role of RON in human oral squamous cell carcinoma (OSCC) is unclear. This study evaluated whether RON affects oncogenic behavior, oncogenic signaling pathways, and clinical outcomes, including survival, in human OSCC. Reverse transcription­PCR, quantitative PCR, western blotting and immunohistochemical staining were used to determine mRNA and protein expression levels of RON. Cell invasion, migration and apoptosis assays were used to assess the functional effects of small interfering RNA­mediated knockdown of RON or snail family transcriptional repressor 2 (SLUG). RON knockdown suppressed tumor cell invasion and migration and enhanced apoptosis in human OSCC cells. RON knockdown also decreased the phosphorylation of MAPK signaling proteins, such as ERK1/2, JNK and p38. In addition, RON knockdown suppressed the expression of the epithelial mesenchymal transition (EMT)­related transcription factor, SLUG. SLUG knockdown blocked the enhancement of cell invasion and migration induced by macrophage­stimulation protein (MSP)­mediated RON activation in OSCC cells. The cell morphology was changed to spindle­like shape under MSP­mediated RON activation in OSCC cells. RON was overexpressed in both fresh and paraffin­embedded human OSCC tissues. Taken together, these results indicate that RON contributed to tumor progression by regulating the EMT­related factor, SLUG, and the MAPK pathway in OSCC. This study may provide a theoretical basis for the application of RON­targeting agents, currently being studied in various cancer fields, for the treatment of OSCC.

Selective learning and teaching among Japanese and German children.

Despite an increasing number of studies demonstrating that young children selectively learn from others, and a few studies of children's selective teaching, the evidence almost exclusively comes from Western cultures, and cross-cultural comparison in this line of work is very rare. In the present research, we investigated Japanese and German children's selective learning and teaching abilities. We found clear cultural differences. Japanese children were better at selectively teaching an ignorant person over a knowledgeable person than at selectively learning from knowledgeable others. By contrast, German children were better at choosing to learn from a knowledgeable rather than from an ignorant person than at selectively teaching ignorant others. The present findings suggest that the development of human learning and teaching, especially the tendency to take into account others' knowledge status, is strongly affected by cultural background. (PsycINFO Database Record