New Directions for Advanced Targeting Strategies of EGFR Signaling in Cancer.

Epidermal growth factor (EGF)-EGF receptor (EGFR) signaling studies paved the way for a basic understanding of growth factor and oncogene signaling pathways and the development of tyrosine kinase inhibitors (TKIs). Due to resistance mutations and the activation of alternative pathways when cancer cells escape TKIs, highly diverse cell populations form in recurrent tumors through mechanisms that have not yet been fully elucidated. In this review, we summarize recent advances in EGFR basic research on signaling networks and intracellular trafficking that may clarify the novel mechanisms of inhibitor resistance, discuss recent clinical developments in EGFR-targeted cancer therapy, and offer novel strategies for cancer drug development.

An evaluation of rehabilitation students' learning goals in their first year: a text mining approach.

Introduction: Qualitative information in the form of written reflection reports is vital for evaluating students' progress in education. As a pilot study, we used text mining, which analyzes qualitative information with quantitative features, to investigate how rehabilitation students' goals change during their first year at university. Methods: We recruited 109 first-year students (66 physical therapy and 43 occupational therapy students) enrolled in a university rehabilitation course. These students completed an open-ended questionnaire about their learning goals at the time of admission and at 6 and 12 months after admission to the university. Text mining was used to objectively interpret the descriptive text data from all three-time points to extract frequently occurring nouns at once. Then, hierarchical cluster analysis was performed to generate clusters. The number of students who mentioned at least one noun in each cluster was counted and the percentages of students in each cluster were compared for the three periods using Cochran's Q test. Results: The 31 nouns that appeared 10 or more times in the 427 sentences were classified into three clusters: "Socializing," "Practical Training," and "Classroom Learning." The percentage of students in all three clusters showed significant differences across the time periods (p < 0.001 for "Socializing"; p < 0.01 for "Practical Training" and "Classroom Learning"). Conclusion: These findings suggest that the students' learning goals changed during their first year of education. This objective analytical method will enable researchers to examine transitional trends in students' reflections and capture their psychological changes, making it a useful tool in educational research.

Functionalisation of alkali-resistant nanoporous glass via Au nanoparticle decoration using alkaline impregnation: catalytic activity for CO removal.

The concerted use of nano-metal particles with catalytic functions and nanoporous materials holds promise for effective air purification and gas sensing; however, only a few studies have used porous glasses as supports for Au nanoparticles. Furthermore, Au/nanoporous glasses with activities comparable to that of Au/TiO2, which is a typical Au catalyst, have not been reported to date. This study demonstrates that a nanoporous glass, which is highly acid- and alkali-resistant and chemically stable, can be decorated with Au nanoparticles using an alkali impregnation method. The resulting composite exhibits high catalytic activity in CO oxidation. The catalysts reported herein are as active as Au/TiO2 catalysts per active site. Further optimisation of the pore properties of the glass and sizes of the Au nanoparticles is expected to result in excellent catalytic systems for CO removal and sensing.

Cooperative function of oncogenic MAPK signaling and the loss of Pten for melanoma migration through the formation of lamellipodia.

The combination of oncogenes and tumor suppressors is involved in cancer development; however, it is still unknown whether their combination plays a critical role in cancer metastasis. We herein investigated whether genetic combinations affected cell migration ability by establishing the immortalized melanocytes, melan-a cells, with an oncogene, either BRAFV600E or GNA11Q209L, and the loss of mouse Pten. The loss of mouse Pten or human PTEN increased the cell migration ability of our established cells and human melanoma cell lines with oncogenic MAPK signaling and the BRAFV600E or NRASQ61R background, but not with the GNA11Q209L background or no oncogenes. Although increased migration was not related to PI3K-AKT activation, those migration is regulated by the induction of some components in the WAVE regulatory complex, resulting in a higher rate of the formation of lamellipodia. On the other hand, BRAFV600E induced EphA2 phosphorylation at serine 897 through RSK and was also required for cell migration and the formation of lamellipodia. Therefore, the oncogenic MAPK pathway and loss of Pten in melanoma were important for cell migration through the formation of lamellipodia, suggesting the significance of an appropriate combination of genetic alterations not only in cancer development, but also cancer metastasis.

Effects of online frame-of-reference training on assessment accuracy in the objective structured clinical examination for physical therapy students.

Objectives: This study investigates how online frame-of-reference (FOR) training of raters of the objective structured clinical examination (OSCE) for physical therapy students affects assessment accuracy. Methods: The research was conducted in a 1-month-long randomized controlled trial. Participants: The participants were 36 physical therapists without experience assessing clinical skills using the OSCE. The training group completed the FOR training online, which was conducted once a week in two 90-minute sessions. The control group self-studied the rubric rating chart used in the assessment. As a measure of accuracy, weighted kappa coefficients were used to check the agreement between correct score and those assessment by the participant in the OSCE. Results: The scores of the training group were higher than those of the control group in both post- and follow-up assessments, showing significant differences. No significant difference was found based on the assessment time and group for the high-agreement groups. Furthermore, scores of the low-accuracy training group were higher in the post- and follow-up assessments than those in the pre-assessment, showing significant differences. Conclusions: Online FOR training of the raters of the OSCE for physical therapists improved the assessment accuracy of the raters who had low accuracy in the pre-assessment; this improvement was maintained.

Effect of the Lee Silverman Voice Treatment BIG® on motor symptoms in a participant with progressive supranuclear palsy: A case report.

BACKGROUND: Although the Lee Silverman Voice Treatment BIG® (LSVT BIG®) improves motor symptoms in patients with Parkinson's Disease, no reports exist for patients with Progressive Supranuclear Palsy (PSP). OBJECTIVE: To describe the effect of LSVT BIG® on the motor symptoms of a participant with PSP. CASE DESCRIPTION: The participant was a 74-year-old man with PSP. His goals were to improve limb movement, balance ability, and festinating gait over the 4-week LSVT BIG® program. OUTCOMES: All assessments of limb movement and balance ability showed improvements after intervention for the limb and gait subsections of the PSP rating scale. Scores improved from 9 to 5, and 8 to 6, respectively for the Unified Parkinson's Disease Rating Scale (UPDRS) Part 3, from 30 to 21 and for the Berg balance scale (BBS), from 45 to 50 points. The improvements in UPDRS Part 3 and BBS exceeded the minimum detectable change values (7-8 and 2 points, respectively). After intervention, improvements in festinating gait and rapid walking pace were noted on the UPDRS Part 3 (2 to 1 point) and 10-meter walk test (1.65 m/s to 1.10 m/s). CONCLUSION: The intervention was effective for the participant but further studies with diverse populations are needed.

Changes in Distance between a Wearable Robotic Exoskeleton User and Four-Wheeled Walker during Gait in Level and Slope Conditions: Implications for Fall Prevention Systems.

When walking with wearable robotic exoskeletons (WRE) in people with spinal cord injury, the distance between the user and the walker is one of the most important perspectives for ensuring safety. The purpose of this study was to clarify the distance between WRE users and four-wheeled walkers (4WW) while walking on level and sloping surfaces. To eliminate the effects of variation in neurological conditions, 12 healthy subjects participated. All participants ambulated using the WRE and the 4WW on level and sloping surfaces. The outcomes were the mean distances between the WRE users and the 4WWs in the level and slope conditions. To examine the influence of uphill and downhill slopes on distance, comparisons were conducted between the uphill or downhill conditions and the respective transitional periods. In the uphill condition, the mean distances were significantly greater than that in the level condition. Conversely, the mean distance moving downhill was significantly shorter than that in the level condition. Changes in the distance between the WRE user and the 4WW might increase the risk of falling forward on an uphill slope and backward on a downhill slope. This study's results will assist in developing a new feedback system to prevent falls.

Controllable conformation and reactivity of bicyclic α-methylene cyclopentanones and their NF-κB pathway inhibitory activity.

Tuning the electrophilicities of Michael acceptors is important for the development of targeted covalent drugs. To this end, the electronic effects of electrophilic structures have been well investigated, but not the steric effects. In this work, we synthesized ten α-methylene cyclopentanones (MCPs), screened them for NF-κB inhibitory activity, and analyzed their conformations. We found that MCP-4b, MCP-5b, and MCP-6b are novel NF-κB inhibitors, whereas the corresponding diastereomers MCP-4a, MCP-5a, and MCP-6a are inactive. Conformational analysis suggested that the stereochemistry of the side chain (R) on MCPs dictates the stable conformation of the core bicyclic 5/6 ring system. The conformational preference seemed to influence their reactivity toward nucleophiles. Consequently, a thiol reactivity assay showed that MCP-5b has higher reactivity than MCP-5a. The results indicate that the conformational switching of MCPs may control reactivity and bioactivity in the presence of steric effects.

Cellular stress induces non-canonical activation of the receptor tyrosine kinase EphA2 through the p38-MK2-RSK signaling pathway.

The receptor tyrosine kinase ephrin type-A receptor 2 (EphA2) is overexpressed in malignant tumors. We previously reported that non-canonical EphA2 phosphorylation at Ser-897 was catalyzed by p90 ribosomal S6 kinase (RSK) via the MEK-ERK pathway in ligand- and tyrosine kinase-independent manners. Non-canonical EphA2 activation plays a key role in tumor progression; however, its activation mechanism remains unclear. In the present study, we focused on cellular stress signaling as a novel inducer of non-canonical EphA2 activation. p38, instead of ERK in the case of epidermal growth factor signaling, activated RSK-EphA2 under cellular stress conditions, including anisomycin, cisplatin, and high osmotic stress. Notably, p38 activated the RSK-EphA2 axis via downstream MAPK-activated protein kinase 2 (MK2). Furthermore, MK2 directly phosphorylated both RSK1 Ser-380 and RSK2 Ser-386, critical residues for the activation of their N-terminal kinases, which is consistent with the result showing that the C-terminal kinase domain of RSK1 was dispensable for MK2-mediated EphA2 phosphorylation. Moreover, the p38-MK2-RSK-EphA2 axis promoted glioblastoma cell migration induced by temozolomide, a chemotherapeutic agent for the treatment of glioblastoma patients. Collectively, the present results reveal a novel molecular mechanism for non-canonical EphA2 activation under stress conditions in the tumor microenvironment.

Simulated medical information system: education for aspiring healthcare information technologists.

Objectives: To determine if a simulated medical information system can improve the level of understanding of healthcare information technology students. Methods: The study involved 40 healthcare information technology students. All the students took the healthcare information technology course using the simulated medical information system. The primary outcome was a measure of their level of understanding assessed with a questionnaire using a five-point Likert-type scale. The questions were all included in the required knowledge for the Specific Behavioral Objectives for Healthcare Information Technologists (2016) and Senior Healthcare Information Technologists (ver. 1.1, 2017). To measure the level of understanding, median with 10th-90th percentile CI values for both sets of questionnaires were calculated for all the students. The Wilcoxon signed-rank test was used to compare level of understanding before and after the training. Results: Some students were excluded because they failed to complete the questionnaires. For both Healthcare Information Technologists (n=37) and Senior Health Information Technologists (n=34), the level of understanding was significantly different before (median [10th-90th percentile]: 1175 [935-1271], 416 [302-513]) and after (1200 [1016-1472], 469.5 [351-527]) the training (p<0.05). Conclusions: A simulated medical information system may be an effective tool for students to learn about healthcare information technology.

The use of a companion robot to improve depression symptoms in a community-dwelling older adult during the coronavirus disease 2019 state of emergency.

Objective: We investigated the impact of using a companion robot on the mental state of a community-dwelling older adult who was receiving home-visit rehabilitation services during the state of emergency for coronavirus disease 2019 (COVID-19). Methods: This case involved an 80-year-old woman with compression fractures of lumbar vertebrae 1 and 2. Her medical history included hypothyroidism, hypertension, dyslipidemia, and depression. The companion robot used was Smibi®, a healing baby robot that responds in various ways depending on how the user interacts with it. The patient interacted (e.g., hugging, conversing) with Smibi® for 30 minutes per day for 1 month, from April 2020 (immediately before the declaration of a state of emergency in Japan) to May 2020. The patient was evaluated with the Self-Rating Depression Scale (SDS) before and after using Smibi®. Results: The SDS score decreased from 37 points to 26 points after the use of Smibi®. The items related to diurnal variation, sleep, despair about the future, and dissatisfaction decreased by 2-3 points. Conclusion: Our findings suggest that interacting with Smibi® may improve depression in older adults who have been forced to refrain from going out due to the spread of COVID-19. Future studies with long-term follow-up and large sample sizes are required to confirm the effectiveness of companion robots in improving depression among community-dwelling older adults.

Acquisition Status of Basic Clinical Skills in Japanese Novice Rehabilitation Therapists: A Preliminary Single-Center Study.

The number of post-graduate rehabilitation therapists (novice therapists) is increasing due to the growing demand for rehabilitation services in Japan. This study investigated the acquisition status of Japanese novice therapists' basic clinical skills to clarify their quality and characteristics. Eleven participants' basic clinical skills (eight physical and three occupational therapists) were assessed using an Objective Structured Clinical Examination. Tasks included exercises of joint range of motion, muscle strengthening, getting up, standing up and sitting down, and transferring between wheelchair and bed. Assessment items were subdivided into categories: attitude, preparation, intervention, safety management, and feedback. One-way ANOVA and Friedman test were used for statistical analysis to compare the data between tasks and categories. The scores for each task's achievement rate were not statistically significant. However, the achievement rate of each category including tasks was 92.6% (SD 4.0%) for attitude, 81.4% (SD 11.1%) for preparation, 77.9% (SD 14.7%) for intervention, 87.6% (SD 17.3%) for safety management, and 64.0% (SD 14.2%) for feedback. There were significant differences between attitude and feedback (p < 0.001), and between safety management and feedback (p = 0.012). Post-graduate training programs should focus on improving the quality of clinical skills, especially in skills related to feedback.

Finger Tapping Test for Assessing the Risk of Mild Cognitive Impairment.

Aim: A testing method for early diagnosis of Mild cognitive dementia (MCI) that can be easily applied in clinical practice was investigated in this study. We examined whether MCI risk can be determined through finger movements. Methods: Between 2013 and 2020, 1097 individuals were screened. After applying propensity-score matching to adjust for variability between the groups, 173 individuals each in the mild cognitive impairment and control groups were selected. Thereafter, differences between groups in mean values of parameters extracted from finger tap movements were determined using unpaired t-test and effect size. Furthermore, area under the curve, sensitivity, and specificity were calculated from the receiver operating characteristic curve for parameters with significant difference. Results: A significant difference was observed, especially in the number of taps in the MCI group compared with that in the control group (p < .001; 95% CI, -12.7 to -8.8; r = 0.51). A cut-off value of 30 taps was applied (sensitivity, 0.77; specificity, 0.67; AUC, 0.79). Significant differences were also observed in rhythm-related parameters. Conclusions: These parameters might be useful for capturing MCI risk. Finger taps are easily measured and may be suitable for screening large populations. This tool might be used as a supplemental method to increase the sensitivity of traditional cognitive tests.

Relationship between finger movement characteristics and brain voxel-based morphometry.

BACKGROUND: Aging is the most significant risk factor for dementia. Alzheimer's disease (AD) accounts for approximately 60-80% of all dementia cases in older adults. This study aimed to examine the relationship between finger movements and brain volume in AD patients using a voxel-based reginal analysis system for Alzheimer's disease (VSRAD) software. METHODS: Patients diagnosed with AD at the Center for Comprehensive Care and Research on Memory Disorders were included. The diagnostic criteria were based on the National Institute on Aging-Alzheimer's Association. A finger-tapping device was used for all measurements. Participants performed the tasks in the following order: with their non-dominant hand, dominant hand, both hands simultaneously, and alternate hands. Movements were measured for 15 s each. The relationship between distance and output was measured. Magnetic resonance imaging measurements were performed, and VSRAD was conducted using sagittal section 3D T1-weighted images. The Z-score was used to calculate the severity of medial temporal lobe atrophy. Pearson's product-moment correlation coefficient analyzed the relationship between the severity of medial temporal lobe atrophy and mean values of the parameters in the finger-tapping movements. The statistical significance level was set at <5%. The calculated p-values were corrected using the Bonferroni method. RESULTS: Sixty-two patients were included in the study. Comparison between VSRAD and MoCA-J scores corrected for p-values showed a significant negative correlation with the extent of gray matter atrophy (r = -0. 52; p< 0.001). A positive correlation was observed between the severity of medial temporal lobe atrophy and standard deviation (SD) of the distance rate of velocity peak in extending movements in the non-dominant hand (r = 0. 51; p< 0.001). CONCLUSIONS: The SD of distance rate of velocity peak in extending movements extracted from finger taps may be a useful parameter for the early detection of AD and diagnosis of its severity.

Non-canonical Regulation of EGFR by the Air Pollutant 9,10-Phenanthrenequinone.

9,10-Phenanthrenequinone (9,10-PQ), a polycyclic aromatic hydrocarbon that is present in air pollutants, such as diesel exhaust gas and PM2.5, causes the production of excess reactive oxygen species. 9,10-PQ was recently shown to induce the activation of epidermal growth factor receptor (EGFR) by inhibiting protein tyrosine phosphatase 1B. In the present study, we focused on the non-canonical regulation of EGFR, including negative feedback and internalization. In contrast to previous findings, 9,10-PQ inhibited the constitutive tyrosine phosphorylation of EGFR via the mitogen-activated protein extracellular kinase (MEK)/extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Thr-669 in EGFR-overexpressing A431 and MDA-MB-468 cells. In addition, 9,10-PQ induced the clathrin-mediated endocytosis of EGFR via the p38 phosphorylation of Ser-1015 in HeLa and A549 cells. These results revealed that 9,10-PQ strongly induced the non-canonical regulation of EGFR by activating mitogen-activated protein kinase (MAPK).

Effect of moderation on rubric criteria for inter-rater reliability in an objective structured clinical examination with real patients.

Objectives: Objective structured clinical examinations (OSCEs) are used to assess clinical competence in medical education. Evaluations using video-recorded OSCEs are effective in reducing costs in terms of time and human resources. To improve inter-rater reliability, these evaluations undergo moderation in the form of a discussion between the raters to obtain consistency in grading according to the rubric criteria. We examined the effect of moderation related to the rubric criteria on the inter-rater reliability of a video-recorded OSCE with real patients. Methods: Forty OSCE videos in which students performed range-of-motion tests at shoulder abduction on real patients were assessed by two raters. The two raters scored videos 1 to 10 without moderation and videos 11 to 40 with moderation each time. The inter-rater reliability of the OSCE was calculated using the weighted kappa coefficient. Results: The mean scores of the weighted kappa coefficients were 0.49 for videos 1 to 10, 0.57 for videos 11 to 20, 0.66 for videos 21 to 30, and 0.82 for videos 31 to 40. Conclusions: An assessment of video-recorded OSCEs was conducted with real patients in a real clinical setting. Repeated moderation improved the inter-rater reliability. This study suggests the effectiveness of moderation in OSCEs with real patients.

Synchronous intracellular delivery of EGFR-targeted antibody-drug conjugates by p38-mediated non-canonical endocytosis.

Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR), including cetuximab and panitumumab, have been used in clinic settings to treat cancer. They have also recently been applied to antibody-drug conjugates (ADCs); however, their clinical efficacy is limited by several issues, including lower internalization efficiency. The binding of cetuximab to the extracellular domain of EGFR suppresses ligand-induced events; therefore, we focus on ligand-independent non-canonical EGFR endocytosis for the delivery of ADCs into cells. Tumor necrosis factor-α (TNF-α) strongly induces the endocytosis of the cetuximab-EGFR complex within 15 min via the p38 phosphorylation of EGFR in a tyrosine kinase-independent manner. A secondary antibody conjugated with saporin, a ribosome-inactivating protein, also undergoes internalization with the complex and enhances its anti-proliferative activity. Anti-cancer agents, including cisplatin and temozolomide, also induce the p38-mediated internalization. The results of the present study demonstrate that synchronous non-canonical EGFR endocytosis may be a feasible strategy for promoting the therapeutic efficacy of EGFR-targeting ADCs in clinical settings.

RSK-Mediated Non-canonical Activation of EphA2 by Tamoxifen.

The long-term administration of tamoxifen to estrogen receptor α (ERα)-positive breast cancer patients is an established treatment that reduces mortality and recurrence. However, resistance to tamoxifen and an increased risk of endometrial cancer may occur; therefore, the mechanisms by which tamoxifen causes these adverse effects warrant further study. Tamoxifen has been shown to activate mitogen-activated protein kinase (MAPK) in an ERα-independent manner; therefore, we investigated its effects on the MAPK-mediated non-canonical activation of EphA2, a critical event regulating cell migration. Tamoxifen at slightly higher concentrations induced the rapid phosphorylation of EphA2 at Ser-897 via the MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK-ribosomal S6 kinases (RSK) pathway in HeLa cells. In addition, tamoxifen significantly enhanced the migration ability of ERα-negative MDA-MB-231 breast cancer cells in RSK- and EphA2-dependent manners. Phosphorylated EphA2 was internalized and re-localized to the plasma membrane, including lamellipodia, in an RSK-dependent manner. Collectively, the present results provide novel insights into the tumor-promoting activity of tamoxifen.