Cost-Effectiveness Analysis of Atezolizumab versus Platinum-Based Chemotherapy as First-Line Treatment for Patients with Unresectable Advanced Non-small Cell Lung Cancer with PD-L1 Expression Status in Japan.

BACKGROUND AND OBJECTIVES: Atezolizumab has demonstrated safety and efficacy in patients with metastatic non-small cell lung cancer (NSCLC) in the IMpower110 trial. The aim of this study was to evaluate the cost-effectiveness of atezolizumab as the first-line treatment for patients with unresectable advanced NSCLC, including programmed cell death ligand-1 (PD-L1)-positive probability testing, from the perspective of healthcare costs in Japan. METHODS: A cost-effectiveness analysis model for atezolizumab, including PD-L1-positive probability testing, was used to construct a partitioned survival model with three health states. To assess the robustness, a probabilistic sensitivity analysis (PSA) was conducted. The acceptable probability was defined as the probability of willingness-to-pay (WTP) over the incremental cost-effectiveness ratio (ICER). Multiple repetitions at WTP thresholds were calculated by continuously reducing the atezolizumab price. RESULTS: The ICER per quality-adjusted life year (QALY) for atezolizumab therapy only for patients with high PD-L1 expression compared to platinum-based chemotherapy for all patients was 31,975,792 yen per QALY. This is higher than the WTP threshold of 15,000,000 yen. If the cost of atezolizumab were reduced to 54% of the original cost (563,917 yen), the strategy of using atezolizumab for patients with high PD-L1 could become more cost-effective. CONCLUSIONS: The results indicated that atezolizumab was not cost-effective compared to platinum-based chemotherapy as a first-line treatment for patients with unresectable advanced NSCLC. However, we suggest that the price of atezolizumab should be reduced to 54% of the original cost to meet the WTP threshold of 15,000,000 yen per QALY.

Survival Prediction of Patients Who Were Terminally Ill Using the EORTC QLQ-C15-PAL Scores and Laboratory Test Values.

Background: Prognostics for patients with cancer is especially important for the supportive care of those who are terminally ill. We previously found that symptom scores as patient-reported outcomes (PROs)-such as dyspnea and fatigue scores-some biochemical parameters, the palliative performance scale (PPS) scores, and symptom clusters were useful prognostic factors; however, the predictability of a prognosis based on these factors remains unclear. Objective: To identify appropriate three-week survival predictive factor(s), in terms of performance, in patients who were terminally ill. Design: We collected symptom scores as PROs using the Japanese version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 15 Palliative Care (EORTC QLQ-C15-PAL). Setting/Subjects: We used data from terminally ill patients with cancer who were hospitalized at the palliative care unit of the Higashisumiyoshi-Morimoto Hospital (Osaka, Japan) from June 2018 to December 2019 (n = 130), as well as additional data obtained from the same clinical study from January to March 2020 (n = 31). Measurements: To evaluate predictive performance, indices such as sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy were calculated. Results: We found that the presence of a symptom cluster showed high sensitivity but low specificity and that a higher PPS value (>30) showed high specificity but low sensitivity, suggesting that these factors could provide relevant information for survival prognosis (less than or equal to three weeks). Conclusion: Symptom clusters obtained from patients is important for effective supportive care of those who are terminally ill.

Butyrate as a Potential Driver of a Dysbiotic Shift of the Tongue Microbiota.

The tongue dorsum is colonized by a stable microbiota, mostly comprising common commensal taxa. However, the predominance of each taxon varies among individuals. We hypothesized that equilibrium in the tongue microbiota is affected by exposure to butyrate in the oral fluid, which is reported to affect the growth of specific microorganisms. In this study, the bacterial composition of the tongue microbiotas of 69 male adults was determined via 16S rRNA gene sequencing to investigate its relationship to n-butyric acid concentration in oral rinse samples. The tongue microbiotas of individuals with a higher n-butyric acid level had higher relative abundances of Prevotella histicola, Veillonella atypica, and Streptococcus parasanguinis and lower relative abundances of Neisseria subflava and Porphyromonas pasteri. Subsequently, tongue microbiota samples collected from 12 adults were cultivated for 13 h in basal medium containing mucin and different concentrations of sodium butyrate (0, 0.8, 1.6, and 3.2 mM) to assess its effect on the growth of tongue microbiota organisms. The bacterial composition of the cultivated tongue microbiotas also demonstrated a significant gradual shift with an increase in sodium butyrate levels in beta-diversity analysis. N. subflava was significantly less predominant in the microbiota after cultivation with an increased addition of sodium butyrate, although no statistical difference was observed in the other aforementioned taxa. These results suggest that butyrate in the oral fluid is partially involved in the dysbiotic shift of the tongue microbiota. IMPORTANCE Oral microbial populations that are always ingested with saliva have attracted increasing attention because more oral microorganisms than previously known reach distal organs, such as the lungs and intestinal tract, thereby affecting our health. However, although such organisms are predominately derived from the tongue dorsum, the dynamics and determinants of the tongue microbiota composition remain unclear. This study demonstrated that exposure to butyrate could lead to a dysbiotic shift in the tongue microbiota using an observational epidemiological and microbiota cultivation approach. This result adds a new dimension to tongue microbiota ecology.

A Retrospective Cohort Study of Multiple Immune-Related Adverse Events and Clinical Outcomes Among Patients With Cancer Receiving Immune Checkpoint Inhibitors.

BACKGROUND AND OBJECTIVES: Immune checkpoint inhibitors (ICIs) are effective in various types of cancer and cause immune-related adverse events (irAEs). The occurrence of irAEs is associated with improved survival outcome. We investigated the association between the occurrence of irAEs and overall survival (OS) and progression free survival (PFS), and the risk factors for the development of irAEs, in patients with non-small-cell lung cancer (NSCLC), gastric cancer (GC) and melanoma (MM) treated with ICIs. METHODS: This was a retrospective observational cohort study, and the data were taken from inpatients in a hospital. OS and PFS were compared among patients with different numbers of irAEs. Log-rank test and Cox regression and logistic regression analysis were applied, and details of irAEs characteristics were summarized. RESULTS: We obtained data from 200 patients. The major tumor types were NSCLC, GC, and MM. Median OS and PFS in all patients were 9.3 and 3.5 months, respectively. Patients without irAEs tended to have shorter OS or PFS compared with those with a single irAE or multi-system irAEs. Covariate analysis suggested that age (≥75 years), albumin (≥3.5 g/dL) and smoking history were significant for increased occurrence of irAEs. Pneumonitis and thyroiditis tended to occur frequently in patients with NSCLC and MM. The irAE grade was ≤2 in 67.3% of all irAEs, and days of irAEs onset varied. CONCLUSION: We observed patients with irAEs tended to have better OS or PFS in patients with various types of cancers treated with ICIs. We suggest that ICIs should be used appropriately by continuously monitoring the irAEs.

The Occurrence of Encephalitis Due to Immune Checkpoint Inhibitors: A Pharmacovigilance Study.

PURPOSE: Immune checkpoint inhibitors (ICIs) are associated with peculiar adverse events related to the mechanism of action. Less than 1% of patients treated with ICIs develop autoimmune encephalitis. The aim of this study was to compare the frequency of encephalitis development due to ICIs with encephalitis due to other drugs using the Japanese Adverse Drug Event Report (JADER) database and Bayesian confidence propagation neural networks for signal detection. METHODS: Data from the JADER database from April 2004 to December 2020 were downloaded via the Pharmaceuticals and Medical Devices Agency (PMDA) website. The Information Component (IC) values were calculated as an index of signal detection based on the Bayesian method. RESULTS: The lower bound of the 95% credible interval (CI) of the IC values for atezolizumab and pembrolizumab were greater than 0 in most of the periods. Thus, encephalitis occurred more frequently for atezolizumab and pembrolizumab than for other drugs. For nivolumab and ipilimumab, a significant signal was detected only for recent data. In contrast, the lower bounds of the 95% CIs for avelumab and durvalumab were smaller than 0 in most of the periods because encephalitis was seldom reported for avelumab and durvalumab. CONCLUSIONS: We showed that encephalitis occurs more frequently for atezolizumab, pembrolizumab, nivolumab, and ipilimumab compared with the frequency for other drugs. The time of onset varied widely, and patients should be monitored for more than 1 year after the last administration of ICIs.

Symptom clusters and their influence on prognosis using EORTC QLQ-C15-PAL scores in terminally ill patients with cancer.

PURPOSE: The aims of the present study were to investigate the symptom clusters in terminally ill patients with cancer using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 15 Palliative Care (EORTC QLQ-C15-PAL), and to examine whether these symptom clusters influenced prognosis. METHODS: We analyzed data from 130 cancer patients hospitalized in the palliative care unit from June 2018 to December 2019 in an observational study. Principal component analysis was used to detect symptom clusters using the scored date of 14 items in the QLQ-C15-PAL, except for overall QOL, at the time of hospitalization. The influence of the existence of these symptom clusters and Palliative Performance Scale (PPS) on survival was analyzed by Cox proportional hazards regression analysis, and survival curves were compared between the groups with or without existing corresponding symptom clusters using the log-rank test. RESULTS: The following symptom clusters were identified: cluster 1 (pain, insomnia, emotional functioning), cluster 2 (dyspnea, appetite loss, fatigue, and nausea), and cluster 3 (physical functioning). Cronbach's alpha values for the symptom clusters ranged from 0.72 to 0.82. An increased risk of death was significantly associated with the existence of cluster 2 and poor PPS (log-rank test, p = 0.016 and p < 0.001, respectively). CONCLUSION: In terminally ill patients with cancer, three symptom clusters were detected based on QLQ-C15-PAL scores. Poor PPS and the presence of symptom cluster that includes dyspnea, appetite loss, fatigue, and nausea indicated poor prognosis.

Protease inhibitor concentrations in the saliva of individuals experiencing oral dryness.

BACKGROUND: Oral dryness is a common symptom that may interfere with swallowing, chewing, and taste. The most common reason for oral dryness is hyposalivation. Some individuals experiencing oral dryness do not have hyposalivation, however, and the reverse is also true. Here, we focused on healthy individuals with a lower salivary flow rate and evaluated the relationship between the perception of oral dryness and salivary parameters to clarify the cause underlying the perception of oral dryness. METHODS: A total of 59 participants were divided into 2 groups with a lower or higher salivary flow rate according to the median salivary flow rate. In participants with a lower salivary flow rate, we assessed salivary bacterial counts, protease activities, protein concentrations, oral parameters, and the subjective perception of oral dryness. RESULTS: Protease activities and concentrations of protease inhibitors such as cystatin-D and cystatin-SA in the saliva of participants experiencing oral dryness were significantly higher and lower, respectively, than in those not experiencing oral dryness, even though no difference in the salivary flow rate was detected. Salivary cystatin-D and cystatin-SA concentrations correlated negatively with salivary protease activities. CONCLUSIONS: The composition of salivary protease inhibitors and increased protease activities affect the subjective perception of oral dryness.

ß-Glycyrrhetinic acid inhibits the bacterial growth and biofilm formation by supragingival plaque commensals.

ß-Glycyrrhetinic acid (BGA) is a natural antibacterial agent. Previous studies reported that BGA has antibacterial effects against several bacteria. This study evaluated the effects of BGA on the regulation of supragingival plaque bacteria. First, the minimum inhibitory concentrations (MICs) of BGA against oral bacteria were measured. Next, the minimum concentrations for inhibition of biofilm formation were evaluated against Streptococcus mutans and Streptococcus sobrinus, possessing insoluble glucan synthesis abilities. The MICs of biofilm formation by these bacteria ranged from 1/8 to 2× MIC. Furthermore, the inhibition effects of BGA against the coaggregation of Porphyromonas gingivalis and Streptococcus gordonii were evaluated. BGA at 32 or 64 µg/mL inhibited the coaggregation of these bacteria after a 30 min incubation. Lastly, the inhibition effects of BGA against human supragingival plaque bacteria were evaluated. Human supragingival plaque samples were obtained from 12 healthy donors. The inhibition effects of BGA against biofilm formation by these plaque bacteria were evaluated. Of 12 samples, the biofilm formation by 11 was significantly attenuated by 128-256 µg/mL of BGA. The number of colony forming units in these biofilms was also significantly attenuated. In conclusion, it was revealed that BGA inhibits the growth and biofilm formation of bacteria, furthermore, the same effect was confirmed with supragingival plaque bacteria. BGA is a good candidate for a natural agent that prevents the outbreak and progression of periodontal disease because it suppresses not only the growth and biofilm formation of bacteria, but also the coaggregation of P. gingivalis with plaque bacteria.

Optimal vial sizes for infliximab injection: a simulation study of Japanese demographic data.

OBJECTIVES: Drug wastage costs in the medical field must be reduced, particularly for expensive biological drugs. In Japan, the Ministry of Health, Labour and Welfare (MHLW) has developed specific criteria for the divided use of injectable vials and vial sharing of anticancer injection drugs to reduce drug wastage. This study investigates the optimal vial size for infliximab infusion to reduce drug wastage in Japan. METHOD: A log-normal distribution was assumed for body weight, and hypothetical data were simulated using the software R. We assumed the average wastage in milligrams (mg) by considering different vial sizes in addition to the existing 100 mg size. We also assumed 18 different vial size combinations for rheumatism patients by gender. The range was 10-95 mg with 5 mg increments. Using the total amount of wasted doses for the existing 100 mg size as a baseline, we evaluated the effect of using additional vial sizes on the total amount of wasted doses. KEY FINDINGS: The average cost of infliximab wastage per case was found to be US$ 353.8 for males and US$ 359.6 for females. For a 15 mg plus 100 mg combination, the average cost of infliximab wastage per case became US$ 20.2 for males and US$ 26.1 for females. In other words, infliximab wastage would be reduced by 94.3% for males and 92.8% for females. CONCLUSIONS: Adding a 15 mg vial size to the existing 100 mg size can reduce wastage. Producing drugs in different vial sizes can thus help significantly reduce the cost burden on the national health care system.

Relationship between Pain Scores and EORTC QLQ-C15-PAL Scores in Outpatients with Cancer Pain Receiving Opioid Therapy.

Cancer pain is one of the most frequent and distressing symptoms associated with cancer and has a serious impact on the QOL of patients. However, inadequate pain treatment has also been reported in outpatients with cancer pain. The aims of this study were (1) to evaluate the relationship between pain intensity using the Numerical Rating Scale (NRS) and QOL scores using the Japanese version of the European Organization for Research and Treatment of Cancer (QOL Questionnaire Core 15 for Palliative Care (QLQ-C15-PAL)), and (2) to investigate their association with various pain patterns, especially with baseline and breakthrough pain. Forty outpatients who were receiving opioid therapy and obtained informed consent participated. We collected a total of 222 pharmacist consultations during the study period. Global QOL scores and pain scores (PA) in the QLQ-C15-PAL (PA score, 0-100) at the first visit were significantly correlated with worst pain intensity. In addition, the scores for the worst pain were significantly correlated with not only physical functioning scores but also with emotional functioning scores. The correlations between the worst pain NRS and PA scores were positive. Specifically, patients tended to report large variability of NRS scores when the PA score was less than 40 and also when they exhibited pain patterns with "baseline and breakthrough cancer pain in the same day" or "baseline pain throughout the day." Reducing the worst pain NRS and relieving breakthrough pain appear to be important measures to improve the QOL of outpatients receiving opioid therapy for cancer pain.

The role of EORTC QLQ-C15-PAL scores and inflammatory biomarkers in predicting survival in terminally ill patients with cancer.

BACKGROUND: The clinical use of patient-reported outcomes as compared to inflammatory biomarkers for predicting cancer survival remains a challenge in palliative care settings. We evaluated the role of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 15 Palliative scores (EORTC QLQ-C15-PAL) and the inflammatory biomarkers C-reactive protein (CRP), albumin (Alb), and neutrophil-lymphocyte ratio (NLR) for survival prediction in patients with advanced cancer. METHODS: This was an observational study in terminally ill patients with cancer hospitalized in a palliative care unit between June 2018 and December 2019. Patients' data collected at the time of hospitalization were analyzed. Cox regression was performed to examine significant factors influencing survival. A receiver operating characteristic (ROC) analysis was performed to estimate cut-off values for predicting survival within 3 weeks, and a log-rank test was performed to compare survival curves between groups divided by the cut-off values. RESULTS: Totally, 130 patients participated in the study. Cox regression suggested that the QLQ-C15-PAL dyspnea and fatigue scores and levels of CRP, Alb, and NLR were significantly associated with survival time, and cut-off values were 66.67, 66.67, 3.0 mg/dL, 2.5 g/dL, and 8.2, respectively. The areas under ROC curves of these variables were 0.6-0.7. There were statistically significant differences in the survival curves between groups categorized using each of these cut-off values (p < .05 for all cases). CONCLUSION: Our findings suggest that the assessment of not only objective indicators for the systemic inflammatory response but also patient-reported outcomes using EORTC QLQ-C15-PAL is beneficial for the prediction of short-term survival in terminally ill patients with cancer.

Cost-effectiveness Analysis of Atezolizumab Plus Nab-Paclitaxel for Advanced PD-L1 Positive Triple-Negative Breast Cancer in Japan.

BACKGROUND AND OBJECTIVES: Atezolizumab is an anti-programmed death ligand 1 (PD-L1) antibody that shows good safety and efficacy for patients with PD-L1-positive triple-negative breast cancer (TNBC). The cost of atezolizumab therapy is expensive, and its economic burden is an important problem. In this study, we evaluated the cost effectiveness of atezolizumab plus nab-paclitaxel therapy (AnP) compared with nab-paclitaxel monotherapy (nP) for PD-L1-positive TNBC under Japanese medical conditions and environments using a Markov model. METHODS: The medical information was collected from data published by the IMpassion130 trial. A Markov model was established to simulate the number of patients in each disease state after AnP or nP therapy during each time period. As indices for cost effectiveness, total cost, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICER) were calculated. Probabilistic sensitivity analysis (PSA) was used to assess the uncertainty of the model using 10,000 Monte Carlo simulations with difference parameters. RESULTS: The QALYs for AnP treatment were longer than for nP treatment (1.12 vs 0.82 QALYs), but the total cost of AnP treatment was more expensive than that of nP treatment (¥11,070,143 vs ¥2,056,164). The ICER values comparing AnP treatment with nP treatment were ¥30,208,143/QALY. The ICER/QALY was more expensive than the willingness-to-pay (WTP) of ¥15,000,000 per QALY. To achieve a 50% cost-effective probability with a WTP threshold, the price of the atezolizumab should be reduced by 55.1%. CONCLUSIONS: AnP was not cost effective compared to nP for PD-L1-positive inoperable TNBC under the Japanese condition.

Effectiveness of protocol-based pharmacotherapy management collaboration between hospital and community pharmacists to address capecitabine-related hand-foot syndrome in cancer patients: a retrospective study.

BACKGROUND: Pharmaceutical care of capecitabine-related hand-foot syndrome (HFS) is extremely important to avoid the progression of the syndrome. Protocol-based pharmacotherapy management (PBPM) of HFS by community pharmacists has been introduced in our community, whereby the community pharmacist instructs patients to use steroid creams if they develop HFS of grade 2 or higher. This study aimed to evaluate the effectiveness of PBPM in cancer patients with HFS by comparing it to conventional pharmaceutical care using monitoring reports for pharmacotherapy management by community pharmacists. METHODS: From September 2017 to August 2019, we retrospectively investigated the medical records of 396 cancer patients who received capecitabine adjuvant chemotherapy. Before PBPM implementation, conventional pharmaceutical care was administered from September 2017 to August 2018; these patients served as the control group. Care was switched to PBPM in September 2018, and PBPM was applied from September 2018 to August 2019; these patients served as the PBPM group. We excluded patients who received both conventional pharmaceutical care and PBPM. We categorized all cases into two groups: age ≤ 69 years and age ≥ 70 years. RESULTS: In all, 396 cases were included, of which 227 were ineligible, such as those of cancer patients who received both conventional pharmaceutical care and PBPM. Among patients aged higher than 70 years, the incidence and severity of HFS associated with PBPM were significantly lower than those associated with conventional care (grade 0: 59.5% [44/74] vs. 30.6% [11/36], grade 1: 33.8% [25/74] vs. 63.9% [23/36]). All patients continued to receive the capecitabine, HFS severity improved to grade 1 during the study period, and treatment of HFS was not stopped. CONCLUSION: Our findings suggest that PBPM is effective for addressing capecitabine-related HFS among cancer patients aged higher than 70 years, in that it helps prevent an increase in HFS severity.

Comparison of Patient Self-Reported Quality of Life and Health Care Professional-Assessed Symptoms in Terminally ill Patients With Cancer.

BACKGROUND: Few studies evaluated whether health care professionals accurately assess several symptoms for patients with cancer in palliative care units. We determined the agreement level for several symptoms related to quality of life (QOL) between patient-reported QOL assessment and health care professional-assessed symptoms based on the Support Team Assessment Schedule (STAS). METHOD: An observational study was performed with terminally ill patients with cancer hospitalized in the palliative care unit between June 2018 and December 2019. Patients and health care professionals independently assessed 7 symptoms at the time of hospitalization and after 1 week. Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C15-PAL). In examining the proportions of exact agreement, "exact agreement" referred to the pairs of the scores (QLQ-C15-PAL vs STAS) being (1 vs 0), (2 vs 1), (3 vs 2 or 3), or (4 vs 4). The relationships of physical functioning between QLQ-C15-PAL and Palliative Performance Scale (PPS) were examined. RESULTS: Of 130 patients, approximately 60% had PPS scores from 40 to 60. The highest mean score on QLQ-C15-PAL was for fatigue (63.8). The exact agreement on symptoms between patients and health care professionals ranged from 15.4% (fatigue) to 57.7% (nausea and vomiting). The mean of the transformed QLQ-C15-PAL and proportions of exact agreement were negatively correlated (R 2 = 0.949, P < .05). The physical function scores in QLQ-C15-PAL for each PPS group showed no differences. CONCLUSION: We expect patient-reported outcomes including QLQ-C15-PAL to be added to health care professionals' assessment of serious symptoms such as fatigue in terminally ill patients with cancer.

Factors Associated With Efficacy and Nivolumab-Related Interstitial Pneumonia in Non-Small Cell Lung Cancer: A Retrospective Survey.

BACKGROUND AND OBJECTIVES: Immune-checitors have been established as a novel standard treatment for non-small cell lung cancer (NSCLC). The aim of this study was to identify factors associated with efficacy and nivolumab-related interstitial pneumonia in NSCLC by evaluating clinical data at the initiation of and during treatment. METHODS: We retrospectively reviewed the medical records of patients who underwent treatment with nivolumab between October 2015 and December 2017. Using pretreatment patient data, we investigated factors associated with overall survival (OS) and the onset of nivolumab-related pneumonitis. We investigated serum biochemistry during treatment to identify the determinants associated with progressive disease (PD) and the onset of nivolumab-related pneumonitis. RESULTS: A total of 94 patients were included. Eleven patients continued treatment, and 54 patients were diagnosed with progressive disease. Nivolumab-related pneumonitis occurred in 15 patients. A pretreatment Eastern Cooperative Oncology Group Performance Status (ECOG PS) = 0 was linked to significantly longer OS than ECOG PS = 1 (median: 20.1 vs. 6.5 months, respectively; p < 0.001). There was a higher incidence of nivolumab-related pneumonitis in patients with a history of interstitial pneumonia than in those without it (p = 0.008). During treatment, the level of albumin gradually decreased prior to PD and onset of nivolumab-related pneumonitis. CONCLUSION: These results suggest that the pretreatment ECOG PS is the determining factor that is associated with OS, whereas history of interstitial pneumonia is the factor associated with nivolumab-related pneumonitis. A decrease in albumin during treatment may be associated with both PD and nivolumab-related pneumonitis.

Association of Protein and Endotoxin in Outdoor Air with Emergency Department Visits for Children and Adults with Asthma in Fukuoka, Japan.

We examined the association of biological components in airborne particles, i.e., proteins and endotoxins, in outdoor air with asthma exacerbation in the Fukuoka metropolitan area, Fukuoka, Japan. Data on emergency department (ED) visits for asthma in children (age, 0-14 years) and adults (age, 15-64 years) were collected at a medical center from December 2014 to November 2015. One hundred eighty-one children and 143 adults visited the ED for asthma, and the weekly number of ED visits in children increased in autumn, i.e., September (second week) to November (first week). Fine (aerodynamic diameter ≤2.5 µm) and coarse (≥2.5 µm) particles were collected for 3 or 4 weeks per month, and protein and endotoxin concentrations were analyzed. Protein was largely prevalent in fine particles (0.34-7.33 µg/m3), and concentrations were high in April, May, June, and October. In contrast, endotoxin was mainly included in coarse particles (0.0010-0.0246 EU/m3), and concentrations were high in September (third week), October (first, second, and fourth weeks), February (fourth week), and July (first week). The results of a Poisson regression analysis indicated that endotoxin (in fine and coarse particles alike) was a significant factor for ED visits related to asthma in children, even after adjusting for meteorological factors, i.e., temperature, relative humidity, and wind speed. However, there was no association between environmental factors and ED visits for asthma in adults. These results suggest that endotoxin in outdoor air is significantly associated with an increased risk of asthma exacerbation in children.

6-Hydroxythiobinupharidine Inhibits Migration of LM8 Osteosarcoma Cells by Decreasing Expression of LIM Domain Kinase 1.

BACKGROUND/AIM: Osteosarcoma is the most malignant type of bone tumor. Patients with osteosarcoma metastases have a poorer prognosis than those without metastases. Thus, the prognosis of osteosarcoma patients with metastases must be improved. MATERIALS AND METHODS: The present study investigated the inhibitory effects of 6-hydroxythiobinupharidine isolated from Nuphar pumilum on migration of LM8 murine osteosarcoma cells by a migration assay and also examined the expression of proteins related to actin dynamics by western blot. The present study also developed an automatic cell counting system using machine learning to count migrated cells by Fiji and Trainable Weka Segmentation. RESULTS: 6-Hydroxythiobinupharidine inhibited migration of LM8 osteosarcoma cells in a dose-dependent manner, and decreased protein expression of Lin11, Isl-1, and Mec-3 domain kinase 1 (LIMK1) and the levels of phosphorylated Cofilin. CONCLUSION: 6-Hydroxythiobinupharidine suppressed migration of LM8 osteosarcoma cells by decreasing expression of LIMK1. 6-Hydroxythiobinupharidine could be potentially used as an anti-metastatic compound.

Age-related changes in gingival blood flow parameters measured using laser speckle flowmetry.

Previous studies have suggested a possible relationship between age-related changes to human gingival hemodynamics and periodontal disease. However, firmly establishing this has been difficult because of a lack of suitable tools. Our study investigated whether a non-invasive laser speckle flowgraphy (LSFG)-based 2-dimensional technique could be used to assess maxillary anterior gingival blood flow under resting conditions. In total, 124 healthy male volunteers aged between 22 and 69 years were included in the study and delineated into young (Y; 22-37 years, n = 45), middle-aged (M; 38-53 years, n = 43), and elderly groups (E; 54-69 years, n = 36). The differences in gingival hemodynamics were compared among age groups and pulse waveform analysis performed to calculate blood flow indices, mean blur rate (MBR), gingival vascular conductance (MBR/mean blood pressure [MBP]), and three pulse waveform parameters (acceleration time index [ATI], falling rate, and blowout time [BOT]). Although no statistically significant differences were observed in the MBR of the three age groups, vascular conductance (MBR/MBP) was lower in groups M and E compared to group Y and correlated negatively with age. ATI and falling rates were also significantly higher in group E relative to group Y, whereas average BOT was significantly lower. All of the assessed parameters correlated with age. These data suggest that there are age-related decreases in the ability to maintain blood flow in the human maxillary anterior gingiva under resting conditions which may impact the likelihood of periodontal disease.

Association of airborne particles, protein, and endotoxin with emergency department visits for asthma in Kyoto, Japan.

BACKGROUND: The health effects of biological aerosols on the respiratory system are unclear. The purpose of this study was to clarify the association of airborne particle, protein, and endotoxin with emergency department visits for asthma in Kyoto City, Japan. METHODS: We collected data on emergency department visits at a hospital in Kyoto from September 2014 to May 2016. Fine (aerodynamic diameter ≤ 2.5 µm) and coarse (≥ 2.5 µm) particles were collected in Kyoto, and protein and endotoxin levels were analyzed. The association of the levels of particles, protein, endotoxin, and meteorological factors (temperature, relative humidity, wind speed, and air pressure) with emergency department visits for asthma was estimated. RESULTS: There were 1 to 15 emergency department visits for asthma per week, and the numbers of visits increased in the autumn and spring, namely many weeks in September, October, and April. Weekly concentration of protein in fine particles was markedly higher than that in coarse particles, and protein concentration in fine particles was high in spring months. Weekly endotoxin concentrations in fine and coarse particles were high in autumn months, including September 2014 and 2015. Even after adjusting for meteorological factors, the concentrations of coarse particles and endotoxin in both particles were significant factors on emergency department visits for asthma. CONCLUSIONS: Our results suggest that atmospheric coarse particles and endotoxin are significantly associated with an increased risk of asthma exacerbation.

Bone-Marrow-Derived Microglia-Like Cells Ameliorate Brain Amyloid Pathology and Cognitive Impairment in a Mouse Model of Alzheimer's Disease.

Microglia, the primary immune cells in the brain, sense pathogens and tissue damage, stimulate cytokine production, and phagocytosis to maintain homeostasis. Accumulation of amyloid-ß peptides (Aß) in the brain triggers the onset of Alzheimer's disease (AD). Accordingly, promotion of Aß clearance represents a promising strategy for AD therapy. We previously demonstrated that primary-cultured rat microglia phagocytose Aß, and that transplantation of these cells ameliorates the Aß burden in brains of Aß-injected rats. In this study, we demonstrate that stimulation with colony-stimulating factor-1 efficiently differentiates mouse bone marrow cells into bone marrow-derived microglia-like (BMDML) cells that express markers for microglia, including the recently identified transmembrane protein 119. BMDML cells effectively phagocytose Aß in vitro, with effects comparable to primary-cultured mouse microglia and greater than peritoneal macrophages. RT-qPCR analysis for cytokine mRNA levels revealed that BMDML cells polarize to a relatively anti-inflammatory state under non-stimulated and inflammatory conditions but exert a pro-inflammatory reaction after lipopolysaccharide treatment. Moreover, BMDML cells hippocampally injected into a mouse model of AD are morphologically similar to the ramified and amoeboid types of residential microglia. Comparisons with simulations assuming a uniform distribution of cells suggest that BMDML cells migrate directionally toward Aß plaques. We also detected Aß phagocytosis by BMDML cells, concomitant with a reduction in the number and area of Aß plaques. Finally, we observed amelioration of cognitive impairment in a mouse model of AD after hippocampal injection of BMDML cells. Our results suggest that BMDML cells have potential as a cell-based disease-modifying therapy against AD.