The LAT1 inhibitor JPH203 suppresses the growth of castration-resistant prostate cancer through a CD24-mediated mechanism.

L-type amino acid transporter 1 (LAT1) is specifically expressed in many malignancies, contributes to the transport of essential amino acids, such as leucine, and regulates the mammalian target of rapamycin (mTOR) signaling pathway. We investigated the expression profile and functional role of LAT1 in prostate cancer using JPH203, a specific inhibitor of LAT1. LAT1 was highly expressed in castration-resistant prostate cancer (CRPC) cells, including C4-2 and PC-3 cells, but its expression level was low in castration-sensitive LNCaP cells. JPH203 significantly inhibited [14C] leucine uptake in CRPC cells but had no effect in LNCaP cells. JPH203 inhibited the proliferation, migration, and invasion of CRPC cells but not of LNCaP cells. In C4-2 cells, Cluster of differentiation (CD) 24 was identified by RNA sequencing as a novel downstream target of JPH203. CD24 was downregulated in a JPH203 concentration-dependent manner and suppressed activation of the Wnt/ß-catenin signaling pathway. Furthermore, an in vivo study showed that JPH203 inhibited the proliferation of C4-2 cells in a castration environment. The results of this study indicate that JPH203 may exert its antitumor effect in CRPC cells via mTOR and CD24.

Effects of a novel hepatitis B anti-viral drug E-CFCP in renal organic acid transporters.

Currently, the emergence of drug resistance is an important issue in the treatment of hepatitis B virus (HBV). Recently, our collaborating group developed a novel long-acting anti-HBV drug, E-CFCP. However, until this study, the effects of E-CFCP in the kidney have remained unclarified. Using cell viability and uptake assays, we examined the effects of E-CFCP on the function of renal organic anion transporters (OATs). No cytotoxicity was shown related to the E-CFCP in the renal OATs in either assay. Thus, this study suggested that E-CFCP may be a novel, excellent candidate drug for the treatment of drug-resistant HBV.

Impact of Thickened Liquids on Laryngeal Movement Velocity in Patients with Dysphagia.

Considering that thickened liquids are frequently used for patients with dysphagia, elucidating their impact on laryngeal dynamics is important. Although studies have investigated the impact of thickened liquids on laryngeal movement velocity among healthy young adults, no study has examined the same among patients with dysphagia. We aimed to elucidate the influence of bolus consistency on laryngeal movement velocity and surface electromyographic activity of the suprahyoid muscles in patients with dysphagia. Participants included 18 male, poststroke patients with dysphagia, whereas patients with true bulbar paralysis, head and neck cancer, neuromuscular disease, or recurrent nerve paralysis were excluded. A video fluoroscopic swallowing study (VFSS) was performed while swallowing 3 mL of moderately thick and thin liquids. Quantitative VFSS analysis, including factors such as laryngeal peak velocity, laryngeal mean velocity, laryngeal movement distance, duration of the laryngeal elevation movement, and the temporal location of laryngeal vestibule closure within the laryngeal elevation movement was performed. Muscle activity was evaluated using integrated muscles activity values obtained from electromyography (iEMG) of the suprahyoid muscle during swallowing. VFSS analysis showed that laryngeal peak velocity and laryngeal mean velocity were significantly faster while swallowing moderately thick than while swallowing thin liquids. Laryngeal movement distance was significantly greater while swallowing moderately thick than while swallowing thin liquids. iEMG was significantly higher while swallowing moderately thick liquids than while swallowing thin liquids. Compared to thin liquids, moderately thick induced an increase in laryngeal movement velocity and in suprahyoid muscle activity among patients with dysphagia, a finding consistent with that of a previous study among healthy adults.

Probability Distribution on Full Rooted Trees.

The recursive and hierarchical structure of full rooted trees is applicable to statistical models in various fields, such as data compression, image processing, and machine learning. In most of these cases, the full rooted tree is not a random variable; as such, model selection to avoid overfitting is problematic. One method to solve this problem is to assume a prior distribution on the full rooted trees. This enables the optimal model selection based on Bayes decision theory. For example, by assigning a low prior probability to a complex model, the maximum a posteriori estimator prevents the selection of the complex one. Furthermore, we can average all the models weighted by their posteriors. In this paper, we propose a probability distribution on a set of full rooted trees. Its parametric representation is suitable for calculating the properties of our distribution using recursive functions, such as the mode, expectation, and posterior distribution. Although such distributions have been proposed in previous studies, they are only applicable to specific applications. Therefore, we extract their mathematically essential components and derive new generalized methods to calculate the expectation, posterior distribution, etc.

Immunological and Symptomatic Effects of Oral Intake of Transgenic Rice Containing 7 Linked Major T-Cell Epitopes from Japanese Cedar Pollen Allergens.

BACKGROUND: A rice-based peptide vaccine containing 7 linked human predominant T-cell epitopes (7Crp) derived from Japanese cedar (JC) pollen allergens, Cry j 1 and Cry j 2, was developed. Here, we examined the efficacy and safety of this transgenic rice in JC pollinosis patients. METHODS: Transgenic rice (5, 20, and 80 g) was administered orally. We measured the T-cell proliferative activity against 7Crp, Cry j 1, and Cry j 2; the cytokine expression levels; and specific IgE and IgG4 production levels. In addition, the symptom and medication scores were monitored during the pollen season, and quality of life (QOL) was evaluated. RESULTS: T-cell proliferative activities to Cry j 1, Cry j 2, and 7Crp were significantly depressed in a dose-dependent manner. Oral intake of 80 g transgenic rice for 20 weeks resulted in significant suppression of allergen-specific T-cell proliferation with downregulation of IL-13 and upregulation of IL-10 levels but no changes to specific IgE and IgG4 levels. The QOL symptom scores for allergic rhinitis were not significantly improved. CONCLUSIONS: Allergen-specific T-cell responses were significantly reduced by oral intake of transgenic rice in a dose-dependent manner. However, neither medication score nor QOL symptom scores could be improved during the JC pollen season with oral intake of transgenic rice for 20 weeks.

Gadolinium contrast balloon pulmonary angioplasty for a patient with chronic thromboembolic pulmonary hypertension and severe iodine allergy.

Chronic thromboembolic pulmonary hypertension (CTEPH) is group 4 pulmonary hypertension caused by organized thrombi in the pulmonary arteries. Balloon pulmonary angioplasty (BPA) is an emerging treatment option for patients with inoperable CTEPH but needs contrast media. Therefore, management can be very difficult in patients who have severe iodine allergies. We present a case of a 61-year-old female with CTEPH. Right heart catheterization showed that the mean pulmonary arterial pressure (mPAP) was 47 mmHg. Her organized thrombi were not surgically accessible, so we performed BPA to improve her hemodynamic status. One session of BPA was performed, but the second session was halted because of iodine-induced anaphylactic shock. Despite the administration of pulmonary arterial hypertension-specific drugs for 3 months, the patient's mPAP was still 33 mmHg. CTEPH patients with mPAP ≥30 mmHg have a poor prognosis, so we decided to perform BPA using gadolinium contrast media. A total of six sessions of gadolinium contrast BPA (Gd-BPA) improved the patient's mPAP to the normal range. Gadolinium contrast media could also be used for visualizing pulmonary arteries during BPA. Our report is the first successful case of Gd-BPA, which improved the patient's hemodynamic status to the almost normal range. Gd-BPA may be an attractive treatment option for patients with inoperable CTEPH and severe iodine allergy.

Psychological impact of the state of emergency over COVID-19 for non-permanent workers: a Nationwide follow-up study in Japan.

BACKGROUND: The outbreak of COVID-19 has caused mental health problems and increased unemployment due to the economic recession. This survey aimed to assess the psychological impact of the state of emergency. We estimated changes in mental health, quality of life, and unemployment experience for general workers during the first COVID-19 outbreak in Japan. METHODS: We conducted a nationwide follow-up study. During the periods of March 26 to April 6, 2020 and June 26 to July 2, 2020, we used the internet to survey general workers aged 15 to 59 years in Japan. The questionnaire items covered employment status and socioeconomic factors, and we used the Center for Epidemiologic Studies Depression Scale (CES-D) and EQ-5D-5L to assess depression and health-related quality of life (HR-QOL), respectively. The differences in outcomes of permanent and non-permanent workers were analyzed using propensity score analysis. A multiple linear regression analysis was performed to examine the relationship between unemployment and CES-D scores. RESULTS: We included 2351 subjects in the analysis. Changes in both CES-D scores and utility were not significantly different between the two groups. However, a significant difference was found regarding the rate of unemployment, which was associated with higher CES-D scores. CONCLUSIONS: The present study demonstrated that the mental health of non-permanent workers was not negatively affected following the state of emergency due to COVID-19 in Japan. Unemployment is an important factor that influences the mental health of general workers.

Age-related composition changes in swallowing-related muscles: a Dixon MRI study.

BACKGROUND: Dysphagia is considered a social problem in the super-aging society. However, age-related changes in swallowing-related muscles have not been fully deciphered. AIMS: We aimed to identify intramuscular fatty infiltration and muscle atrophy in multiple swallowing-related muscles on magnetic resonance imaging (MRI). Moreover, an appropriate muscle strength parameter for the evaluation of swallowing-related muscle mass was examined. METHODS: We analyzed the Dixon MRI results of 20 elderly and 20 young adults without head and neck cancer, stroke, neuromuscular disease, or whole-body sarcopenia to evaluate intramuscular fatty infiltration (IMF) and lean muscle mass (LMM) in the tongue, geniohyoid, and pharyngeal muscles. The pharyngeal lumen size was also assessed. Tongue pressure, jaw-opening strength, occlusal force, and head-lifting strength were evaluated within a week before and after MRI. RESULTS: Aging significantly affected the IMF of the swallowing-related muscles, and the tongue muscle was most affected, followed by the pharyngeal muscle and then the geniohyoid muscle. Only the LMM of the geniohyoid muscle significantly decreased with aging. The pharyngeal lumen size did not significantly differ between the elderly and young participants, and only tongue pressure was significantly correlated with tongue, geniohyoid, and pharyngeal muscle mass. CONCLUSIONS: IMF is primarily associated with age-related composition changes in swallowing-related muscles, and it is commonly observed in the tongue and pharyngeal muscles. The geniohyoid muscle is more at risk of muscle atrophy rather than fatty infiltration. In addition, tongue pressure can be a parameter for the evaluation of swallowing-related muscle mass.

Long-term oral administration of transgenic rice containing cedar pollen T-cell epitopes potentially improves medication- and allergy-related quality-of-life scores.

Background: We previously developed a transgenic rice that contains seven linked human predominant T-cell epitopes (7Crp) derived from Japanese cedar (JC) pollen allergens Cry j 1 and Cry j 2. Oral administration of 80 g of transgenic rice for 20 weeks suppressed allergen-specific T-cell proliferation in participants with JC pollinosis, but their clinical symptoms did not improve. Objective: We examined the clinical efficacy of low-dose (5 g and 20 g) intake of the transgenic rice administered for two successive seasons. Methods: In this randomized, double-blind, placebo controlled study, transgenic rice seeds (5 g or 20 g) were orally administered to the participants for 24 weeks in each of two successive JC pollen seasons. We analyzed T-cell proliferation and cytokine expression, and monitored symptom and medication scores during the pollen season. Quality of life (QOL) was evaluated by using the Japanese Allergic Rhinitis Quality of Life Standard Questionnaire (JRQLQ). Results: Specific T-cell proliferation after stimulation with 7Crp, Cry j 1, and Cry j 2 was significantly suppressed in the second JC pollen season. No significant differences were found among the three groups (5 g, 20 g, and placebo) with regard to clinical symptoms or medication scores in the first season. However, the medication scores and face scale for overall condition of JRQLQ improved in the 5-g transgenic rice group in the second season, although careful re-examination with a large sample size is necessary to confirm the results. Conclusion: Low-dose oral administration of transgenic rice that contains 7Crp significantly reduced allergen-specific T-cell responses and improved medication scores during the second season of administration. Thus, oral intake of the transgenic rice has the potential to induce immune tolerance to JC pollen allergens when administered for at least two successive seasons.

Meta-Tree Random Forest: Probabilistic Data-Generative Model and Bayes Optimal Prediction.

This paper deals with a prediction problem of a new targeting variable corresponding to a new explanatory variable given a training dataset. To predict the targeting variable, we consider a model tree, which is used to represent a conditional probabilistic structure of a targeting variable given an explanatory variable, and discuss statistical optimality for prediction based on the Bayes decision theory. The optimal prediction based on the Bayes decision theory is given by weighting all the model trees in the model tree candidate set, where the model tree candidate set is a set of model trees in which the true model tree is assumed to be included. Because the number of all the model trees in the model tree candidate set increases exponentially according to the maximum depth of model trees, the computational complexity of weighting them increases exponentially according to the maximum depth of model trees. To solve this issue, we introduce a notion of meta-tree and propose an algorithm called MTRF (Meta-Tree Random Forest) by using multiple meta-trees. Theoretical and experimental analyses of the MTRF show the superiority of the MTRF to previous decision tree-based algorithms.

Change in tongue pressure in patients with head and neck cancer after surgical resection.

Tongue pressure is reportedly associated with dysphagia. This study investigated relationships among characteristics of head and neck cancer, tongue pressure and dysphagia screening tests performed in patients with head and neck cancer during the acute phase after surgical resection. Fifty-seven patients (36 men, 21 women; age range 26-95 years) underwent surgical resection and dysphagia screening tests (Repetitive Saliva Swallowing Test, Water Swallowing Test, Modified Water Swallowing Test and Food Test) and pre- and postoperative measurement of tongue pressure at 5 time points (preoperatively, and 1-2 weeks and 1, 2, and 3 months postoperatively). Progression of cancer (stage), tracheotomy, surgical reconstruction, chemotherapy, radiotherapy and neck dissection were factors associated with postoperative tongue pressure. Data were analyzed by linear mixed-effect model, Spearman correlation coefficient and receiver operating characteristic (ROC) curve. Tongue pressure was significantly reduced 1-2 weeks after surgery, and recovered over time. Changes in tongue pressure were significantly associated with stage, radiotherapy and reconstruction. All screening tests showed a significant relationship with tongue pressure. Analysis of ROC and area under the effect curve suggested that a tongue pressure of 15 kPa can be used as a cut-off value to detect dysphagia after surgery for head and neck cancer. Our results suggest that tongue pressure evaluation might offer a safe, useful and objective tool to assess dysphagia immediately postoperatively in patients with head and neck cancer.

Clinical prediction rules for multi surfaces walking independence using the Berg Balance Scale or Mini-Balance Evaluation Systems Test in persons with stroke.

BACKGROUND: A Clinical prediction rule (CPR) for determining multi surfaces walking independence in persons with stroke has not been established. OBJECTIVES: To develop a CPR for determining multi surfaces walking independence in persons with stroke. METHODS: This was a multicenter retrospective analysis of 419 persons with stroke. We developed a Berg Balance Scale (BBS)-model CPR combining the BBS, comfortable walking speed (CWS) and cognitive impairment, and a Mini-Balance Evaluation Systems Test (Mini-BESTest)-model CPR combining the Mini-BESTest, CWS, and cognitive impairment. A logistic regression analysis was conducted with multi surfaces walking independence as the dependent variable and each factor as an independent variable. The identified factors were scored (0, 1) based on reported cutoff values. The CPR's accuracy was verified by the area under the curve (AUC). We used a bootstrap method internal validation and calculated the CPR's posttest probability. RESULTS: The logistic regression analysis showed that the BBS, CWS, and cognitive impairment were factors in the BBS model, and the Mini-BESTest was a factor in the Mini-BESTest model. The CPRs were 0-3 points for the BBS model and 0-1 points for the Mini-BESTest model. The AUCs (bootstrap mean AUC) of the CPR score were 0.89 (0.90) for the BBS model and 0.72 (0.72) for the Mini-BESTest model. The negative predictive value (negative likelihood ratio) was 97% (0.054) for CPR scores < 2 for the BBS model and 94% (0.060) for CPR scores < 1 for the Mini-BESTest model. CONCLUSIONS: The CPR developed herein is useful for determining multi surfaces walking independence.

Preferences for Rehabilitation in Persons with a History of Stroke: A Discrete Choice Experiment.

Objective: To investigate the preferences of persons with a history of stroke for various attributes of rehabilitation using a discrete choice experiment (DCE). Design: Cross-sectional study. Setting: A web-based survey. Participants: A total of 600 adults with a history of stroke who were not asked whether or not they had participated in previous rehabilitation. Intervention: None. Main Outcome Measures: Preference weights by attribute ie, treatment time (30 minutes, one hour, one and a half hours), treatment content (walking exercises, activities of daily living; ADL exercises), priority treatment of paralyzed limbs (upper extremity, lower upper extremity), treatment location (hospital visit, home visit), therapist gender, and out-of-pocket costs for stroke rehabilitation using discrete choice experiment. Results: The most common self-reported diagnosis was cerebral infarction (408 patients, 68%). The mean age was 62.0 ± 9.8 years, and 515 (85.8%) were male. Of the five attributes, excluding out-of-pocket costs, the highest relative importance score was treatment location (0.331), followed by treatment time (0.304). Among the rehabilitation programs, the statistically significant coefficients calculated were one hour of therapy (0.173, 95% CI = 0.088-0.258), hospital visits (0.241, 95% CI = 0.180-0.303), and female therapists (0.186, 95% CI = 0.125-0. 247). No significant differences were obtained regarding the treatment contents or the paralyzed limb to be treated. Conclusion: A discrete choice experiment revealed that persons with a history of stroke prefer a one-hour hospital rehabilitation program with a female therapist, with cost being a major consideration for rehabilitation. The results of this study may provide useful information for rehabilitation professionals.

Characteristics of Extranodal NK/T-Cell Lymphoma, Nasal Type, Compared with Nasal Diffuse Large B-cell Lymphoma.

Background: Extranodal NK/T-cell lymphoma, nasal type (ENKL), is an aggressive tumour with poor prognosis. Its early diagnosis may improve the prognosis of patients; however, it is often overlooked in many cases and misdiagnosed as an inflammatory sinus disease during its initial stage. Identifying the clinical characteristics of ENKL may aid otorhinolaryngologists in indicating cases early for a pathologic examination. In this study, we aimed to investigate the clinical characteristics of ENKL compared with that of diffuse large B-cell lymphoma (DLBCL), which is the most common nasal malignant lymphoma. Methods: The backgrounds, clinical symptoms, blood test results, and computed tomography images of patients with nasal/paranasal malignant lymphoma in our hospital between 2012 and 2017 were investigated. The characteristics of ENKL and nasal DLBCL were compared to differentiate them. Results: A total of 27 patients with nasal cavity and/or paranasal sinus lymphoma were included. Extranodal NK/T-cell lymphoma, nasal type, was diagnosed in 10 patients, while DLBCL was diagnosed in 17 patients. The median age of patients with ENKL was significantly lower than that of patients with DLBCL. All patients with ENKL had a unilateral lesion in the nasal cavity, with most located at the inferior turbinate. They also experienced nasal symptoms with significantly higher incidence of nasal obstruction and tendency of bleeding. Conclusion: ENKL was often unilateral and caused nasal obstruction, unlike DLBCL. Those who are younger in age and have sinonasal tumour with unilateral nasal obstruction and bleeding should be considered for early and repeated biopsies at multiple sites, with ENKL taken into consideration.

Impurity contribution to ultraviolet absorption of saturated fatty acids.

Saturated fatty acids are abundant organic compounds in oceans and sea sprays. Their photochemical reactions induced by solar radiation have recently been found as an abiotic source of volatile organic compounds, which serve as precursors of secondary organic aerosols. However, photoabsorption of wavelengths longer than 250 nanometers in liquid saturated fatty acids remains unexplained, despite being first reported in 1931. Here, we demonstrate that the previously reported absorption of wavelengths longer than 250 nanometers by liquid nonanoic acid [CH3(CH2)7COOH)] originates from traces of impurities (0.1% at most) intrinsically contained in nonanoic acid reagents. Absorption cross sections of nonanoic acid newly obtained here indicate that the upper limit of its photolysis rate is three to five orders of magnitude smaller than those for atmospherically relevant carbonyl compounds.

Central administered xenin induced Fos expression in nesfatin-1 neurons in rats.

Xenin is a 25-amino acid peptide identified in human gastric mucosa, which is widely expressed in peripheral and central tissues. It is known that the central or peripheral administration of xenin decreases food intake in rodents. Nesfatin-1/NUCB2 (nesfatin-1) has been identified as an anorexic neuropeptide, it is often found co-localized with many peptides in the central nervous system. After the intracerebroventricular administration of xenin on nesfain-1-like immunoreactivity (LI) neurons, we examined its effects on food intake and water intake in rats. As a result, Fos-LI neurons were observed in the organum vasculosum of the laminae terminalis (OVLT), the median preoptic nucleus (MnPO), the subfornical organ (SFO), the supraoptic nucleus (SON), the paraventricular nucleus (PVN), the arcuate nucleus (Arc), the lateral hypothalamic area (LHA), the central amygdaloid nucleus (CAN), the dorsal raphe nucleus (DR), the locus coeruleus (LC), the area postrema (AP) and the nucleus of the solitary tract (NTS). After the administration, the number of Fos-LI neurons was significantly increased in the LC and the OVLT, the MnPO, the SFO, the SON, the PVN, the Arc, the LHA, the CAN, the DR, the AP and the NTS, compared with the control group. After the administration of xenin, we conducted double immunohistochemistry for Fos and nesfatin-1, and found that the number of nesfatin-1-LI neurons expressing Fos were significantly increased in the SON, the PVN, the Arc, the LHA, the CAN, the DR, the AP and the NTS, compared with the control group. The pretreatment of nesfatin-1 antisense significantly attenuated this xenin-induced feeding suppression, while that of nesfatin-1 missense showed no improvement. These results indicate that central administered xenin may have anorexia effects associated with activated central nesfatin-1 neurons.

Cost-effectiveness of combination therapy of polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisolone for previously untreated diffuse large B-cell lymphoma in Japan.

AIM: The POLARIX trial showed that Pola + R-CHP (polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisolone) prolongs progression-free survival (PFS) in patients with previously untreated diffuse large B-cell lymphoma (DLBCL) compared with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone), the conventional standard of care, with a similar safety profile. However, Pola + R-CHP has not been evaluated from the viewpoint of health economics in Japan. This study evaluates the cost-effectiveness of Pola + R-CHP for previously untreated DLBCL from a Japanese public healthcare payer's perspective. METHODS: A partitioned survival analysis model was constructed to estimate lifetime costs and effectiveness of Pola + R-CHP and R-CHOP in previously untreated DLBCL who had an International Prognostic Index score (IPI) score of ≥2. A parametric survival model was applied to data analyzed in the POLARIX trial to estimate the lifetime overall survival (OS) and PFS for each treatment. The parameters required for the model were based on the results of a literature search and expert opinion. RESULTS: The incremental cost-effectiveness ratio (ICER) of Pola + R-CHP vs. R-CHOP was JPY2,710,238 per quality-adjusted life year (QALY), less than the ICER of JPY7.5 million per QALY that is considered to be cost-effective based on the threshold of the Japanese cost-effectiveness evaluation system. One-way sensitivity analysis showed that the parameters influencing the results of the analysis were median PFS and the total cost per regimen of salvage chemotherapy, patient weight, and patient age. Probabilistic sensitivity analysis showed that the probability of Pola + R-CHP having superior cost-effectiveness was 99.2% when the reference value was JPY7.5 million. The results of scenario analysis suggested that prolongation of PFS was an important factor in the evaluation of cost-effectiveness in previously untreated DLBCL with or without prolongation of OS. CONCLUSIONS: This study suggests that Pola + R-CHP is a cost-effective treatment for previously untreated DLBCL in Japan under the public health insurance system.