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.

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.

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.

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.

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.

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.

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.

Direct Observation and Quantitative Measurement of OH Radical Desorption During the Ultraviolet Photolysis of Liquid Nonanoic Acid.

Ultraviolet (UV) photolysis of fatty acid surfactants─which cover the surfaces of atmospheric liquid aerosols and are found in the oceans─such as nonanoic acid (NA) has recently been suggested as a source of hydroxyl (OH) radicals in the troposphere. We used laser-induced fluorescence to directly observe OH radicals desorbed from the surface of neat liquid NA as a primary photoproduct following 213 nm irradiation. The upper limit of photoreaction cross section for the OH radical desorption was estimated to be 9.0(4.1) × 10-22 cm2, which is only 1.2 ± 0.8% of the photoreaction cross section established for the photolysis of gas-phase acetic acid monomers. Vibrational sum-frequency generation spectroscopy for liquid NA revealed the hydrogen-bonded, cyclic, dimer structure of the NA molecules at the liquid surface. This dimerization can inhibit the formation of OH radicals and lead the present low photochemical reactivity of liquid NA.

Cost-effectiveness analysis of patent foramen ovale closure versus medical therapy alone after cryptogenic stroke.

BACKGROUND: Closure of a patent foramen ovale reduces the risk of recurrent stroke compared with medical therapy alone in young patients with cryptogenic strokes revealed by randomized control trials. Some cost-effectiveness analyses outside Japan have shown that patent foramen ovale closure is cost-effective, but no studies have examined cost-effectiveness in Japan. The objective of this study is to assess cost-effectiveness, from the perspective of a Japanese healthcare payer, of patent foramen ovale closure versus medical therapy alone for patients with patent foramen ovale related to cryptogenic strokes. METHODS: A cost-effectiveness study was conducted by developing a decision tree and a Markov model. Probabilities and a 5.9-year time horizon followed the RESPECT study. Utilities and costs were based upon published studies and assumptions. All assumptions were assessed by experts, including a cardiologist and a statistical expert. The target population comprised patients with cryptogenic stroke and patent foramen ovale, aged 60 years or younger. The model was discounted at 2.0% and its cycle was one month. A willingness-to-pay threshold is set at $50,000 / quality-adjusted life years (QALYs). Incremental cost-effectiveness ratio was evaluated. Then one-way sensitivity analyses as deterministic sensitivity analysis, and probabilistic sensitivity analyses were performed to assess data robustness. RESULTS: Incremental quality-adjusted life years, incremental costs, and incremental cost-effectiveness ratio were 0.464, $13,562, and $29,208 per QALY gained, respectively. One-way sensitivity analysis showed that the stable state utility score difference between patent foramen ovale closure and medical therapy had the largest impact on incremental cost-effectiveness ratio. Patent foramen ovale closure is cost-effective at a stable state utility score difference of >0.051, compared with medical therapy. Probabilistic sensitivity analyses demonstrated that patent foramen ovale closure was 50.3% cost-effective. CONCLUSIONS: Patent foramen ovale closure was cost-effective compared with medical therapy for Japanese patients with cryptogenic stroke who were ≤60 years.

Evaluation of the effect of nitric oxide inhalation in the patients with chronic thromboembolic pulmonary hypertension or pulmonary disease during balloon pulmonary angioplasty.

Balloon pulmonary angioplasty (BPA) for chronic thromboembolic pulmonary hypertension (CTEPH) or pulmonary disease (CTEPD) is performed worldwide. High mean pulmonary arterial pressure (mPAP) during BPA is associated with aggravation of procedure-related complications. Inhaled nitric oxide (NO) acts as a pulmonary vasodilator in CTEPH patients. The aim of this retrospective observational study was to evaluate the effects of inhaled NO in CTEPH/CTEPD patients during BPA. We assessed hemodynamic changes and the frequency of procedure-related complications with or without NO inhalation. We performed 338 consecutive BPA in 72 CTEPH/CTEPD patients between April 2016 and November 2020. Since December 2019, all 16 patients (72-BPA sessions) inhaled NO during the procedure as a routine. Inhaled NO significantly reduced mPAP from 31.3 ± 8.5 to 27.2 ± 6.8 mmHg (p < 0.001) without lowering systemic blood pressure (systolic: 139.9 ± 19.9 vs. 135.3 ± 21.8 mmHg; p = 0.247, diastolic: 82.8 ± 13.0 vs. 79.0 ± 9.3 mmHg; p = 0.085, before vs. after NO inhalation, respectively). Procedure-related complications were observed in 46 sessions (13.6%). The incidence of hemoptysis was significantly higher in the NO group than in the non-NO group (20.8% vs. 10.9%; p = 0.031). In contrast, all fatal complications (death and use of positive pressure ventilation) occurred in the non-NO group, but the difference was not statistically significant (0 sessions [0.0%] vs. 7 sessions [2.6%], p = 0.353). Inhaled NO acts as a selective pulmonary vasodilator in CTEPH/CTEPD patients during the BPA procedure.

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.

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.

A nationwide web-based survey of factors associated with depressive symptoms among Japanese workers.

BACKGROUND: Precarious employment has affected mental health, and limited data are available on the association of low stress tolerance with depressive symptoms among Japanese workers. AIMS: This study aimed to examine the relationship between stress tolerance and depressive symptoms among Japanese workers, including company employees, civil servants and self-employed persons in various industries. METHODS: We conducted a nationwide cross-sectional study. From March 26 to April 6, 2020, we performed a web-based survey of Japanese workers. The questionnaire included questions on socioeconomic factors, the SOC scale that assesses stress tolerance, the CES-D, and the EQ-5D-5L. Multivariate regression analyses were performed to determine the factors associated with depressive symptoms. RESULTS: We included 3,001 participants in the analysis. A high SOC score, adequate sleeping time and frequency of exercise were associated with higher depressive symptoms. Employment status and long working hours were not associated with depressive symptoms. Younger workers had lower SOC scores than older workers. An inverse correlation between the SOC score and CES-D score was found among Japanese workers. CONCLUSIONS: Improving stress tolerance among younger workers is needed to prevent worsening mental health regardless of employment status for Japanese workers.

Estimation of Lifetime QALYs Based on Lifestyle Behaviors.

Various lifestyle behaviors have been known to affect health-related quality of life (HRQL) and life expectancy. However, the impact on quality-adjusted life years (QALYs), which can be used for health economics, has not been clarified. The purpose of this study was to estimate the impact of lifestyle behaviors on lifetime QALYs. We first examined the relationship between lifestyle behaviors and HRQL as measured by the EQ-5D-5L among 4000 participants via a web-based survey. The results of multiple regression analysis showed that physical activity and sleep were significantly related to HRQL. Therefore, we used microsimulation to estimate QALYs from physical activity and sleep, which were determined to be significant in the regression analysis. The results showed that there was a difference of 3.6 QALYs between the recommended lifestyle scenario (23.4 QALYs; 95%CI 3.6 to 35.1) and the non-recommended lifestyle scenario (19.8 QALYs; 95%CI 3.1 to 31.6). This difference was greater in the younger age group than in the older age group. The results also indicated a large difference in QALYs between physical activity and sleep. These findings may provide a significant suggestion for future health promotion measures.

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.