Combination therapy with anti-programmed cell death 1 antibody plus angiokinase inhibitor exerts synergistic antitumor effect against malignant mesothelioma via tumor microenvironment modulation.

Malignant pleural mesothelioma (MPM) is an asbestos-related fatal malignant neoplasm. Although there has been no reliable chemotherapeutic regimen other than combination therapy of cisplatin and pemetrexed for two decades, combination of ipilimumab plus nivolumab brought about a better outcome in patients with MPM. Thus, cancer immunotherapy using immune checkpoint inhibitor (ICI) is expected to play a central role in the treatment of MPM. To maximize the antitumor effect of ICI, we evaluated whether nintedanib, an antiangiogenic agent, could augment the antitumor effect of anti-programmed cell death 1 (PD-1) antibody (Ab). Although nintedanib could not inhibit the proliferation of mesothelioma cells in vitro, it significantly suppressed the growth of mesothelioma allografts in mice. Moreover, combination therapy with anti-PD-1 Ab plus nintedanib reduced tumor burden more dramatically compared with nintedanib monotherapy via inducing remarkable necrosis in MPM allografts. Nintedanib did not promote the infiltration of CD8+ T cells within the tumor when used alone or in combination with anti-PD-1 Ab but it independently decreased the infiltration of tumor-associated macrophages (TAMs). Moreover, immunohistochemical analysis and ex vivo study using bone marrow-derived macrophages (BMDMs) showed that nintedanib could polarize TAMs from M2 to M1 phenotype. These results indicated that nintedanib had a potential to suppress protumor activity of TAMs both numerically and functionally. On the other hand, ex vivo study revealed that nintedanib upregulated the expression of PD-1 and PD-ligand 1 (PD-L1) in BMDMs and mesothelioma cells, respectively, and exhibited the impairment of phagocytic activity of BMDMs against mesothelioma cells. Co-administration of anti-PD-1 Ab may reactivate phagocytic activity of BMDMs by disrupting nintedanib-induced immunosuppressive signal via binding between PD-1 on BMDMs and PD-L1 on mesothelioma cells. Collectively, combination therapy of anti-PD-1 Ab plus nintedanib enhances the antitumor activity compared with respective monotherapy and can become a novel therapeutic option for patients with MPM.

BAP1 depletion in human B-lymphoblast cells affects the production of innate immune cytokines and chemokines.

BRCA1 associated protein 1 (BAP1) is a ubiquitin C-terminal hydrolase that deubiquitinates histone H2AK119ub and other proteins and regulates the expression of multiple genes. The knockout of this tumor suppressor gene results in severe thymic atrophy, complete loss of the T cell lineage, and abnormal B cell development in mice. In the current study, we investigated in vitro effects of BAP1 knockout on cytokine and chemokine production using the human B-lymphoblast cell line TSCE5. We confirmed that knockout changed the production of innate immune-associated genes and their receptors. The CCL19, CCR7, CCL2, and CXCR5 genes associated with T and B cell migration were upregulated. Knockout cells producing high levels of CCL19 showed acceleration of actin polymerization, which is essential for cell migration. CD69, PTPRC, and TLR3 genes that activate inflammation were downregulated. The tumor necrosis factor ligand genes TNF, LTA, and TNFSF10 were downregulated by knockout. In knockout cells, TNFα production was strongly downregulated upon the addition of H2 O2 , but NF-κB in the basal condition and when TNFα was added was augmented, suggesting that these cells could respond to TNFα. These results indicated that BAP1 affects the expression of chemokines and cytokines, T and B cell migration, and activated inflammation associating with innate immunity.

The relationship between tooth loss and hypertension: a systematic review and meta-analysis.

As tooth loss is the high end of periodontal problems and edentulous individuals are at higher risk of nutritional problems like obesity, understanding the association between tooth loss and hypertension is important for improving cardiovascular health. We searched for publications from the last two decades using three electronic databases (PubMed, Web of Science and Scopus) and conducted a systematic review and meta-analysis on the association between tooth loss and hypertension according to PRISMA-P guidelines. Quality assessments were performed using the Newcastle-Ottawa Scale and the GRADE approach. Twenty-four studies (20 cross-sectional, and 4 cohort) met the inclusion criteria for this review. Most cross-sectional studies showed that subjects with more tooth loss exhibited a greater proportion of hypertension and higher systolic blood pressure than those with less tooth loss. Meta-analyses revealed a statistically significant association between tooth loss and hypertension. The pooled odds ratios of hypertension for having tooth loss with no tooth loss and for edentulous with dentate were 2.22 (95% CI 2.00-2.45) and 4.94 (95% CI 4.04-6.05), respectively. In cohort studies, subjects with more tooth loss had a greater incidence of hypertension than those with less tooth loss during the follow-up period. The present systematic review and meta-analysis suggests that tooth loss is associated with an increased risk of hypertension and higher systolic blood pressure.

The Impact of Oral Health on Respiratory Viral Infection.

Influenza virus and severe acute respiratory syndrome coronavirus (SARS-CoV-2) have caused respiratory diseases worldwide. Coronavirus disease 2019 (COVID-19) is now a global health concern requiring emergent measures. These viruses enter the human body through the oral cavity and infect respiratory cells. Since the oral cavity has a complex microbiota, influence of oral bacteria on respiratory virus infection is considered. Saliva has immune molecules which work as the front line in the biophylactic mechanism and has considerable influence on the incidence and progression of respiratory viral infection. Salivary scavenger molecules, such as gp340 and sialic acid, have been reported to exert anti-influenza virus activity. Salivary secretory immunoglobulin A (SIgA) has potential to acquire immunity against these viruses. Biological features of the oral cavity are thought to affect viral infection in respiratory organs in various ways. In this review, we reviewed the literature addressing the impact of oral conditions on respiratory infectious diseases caused by viruses.

Adenosine Deaminase in Pleural Effusion and Its Relationship with Clinical Parameters in Patients with Malignant Pleural Mesothelioma.

Pleural effusion adenosine deaminase (ADA) levels are elevated in various diseases. We investigated whether pleural effusion ADA levels differ among patients with malignant pleural mesothelioma (MPM), lung cancer (LC), and benign diseases, including tuberculous pleurisy. We examined 329 patients from February 2002 to July 2013. There were 131 MPM cases with ADA levels of 32.29 IU/L; 117 LC cases with ADA levels of 21.12 IU/L; 54 benign disease cases with ADA levels of 20.98 IU/L. A significant difference existed in pleural effusion ADA levels between MPM and benign disease patients. Pleural effusion ADA levels were significantly higher in MPM patients.

The Relationship between Vitamin C and Periodontal Diseases: A Systematic Review.

Vitamin C is important for preventing and slowing the progression of many diseases. There is significant evidence linking periodontal disease and vitamin C. We aimed to systematically review the studies addressing the relationship between vitamin C and periodontal disease, and the preventive ability of vitamin C against periodontal disease. Electric searches were performed using PubMed, EMBASE, Cochrane Library, and Web of Science. Studies addressing the relationships between periodontal disease and vitamin C in adults aged over 18 years were included. Quality assessment was done using the Critical Appraisal Skills Program guideline and GRADE-CERQual. There were 716 articles that were retrieved and 14 articles (seven cross-sectional studies, two case-control studies, two cohort studies, and three randomized controlled trials (RCT)) were selected after reviewing all of the articles. The vitamin C intake and blood levels were negatively related to periodontal disease in all seven cross-sectional studies. The subjects who suffer from periodontitis presented a lower vitamin C intake and lower blood-vitamin C levels than the subjects without periodontal disease in the two case-control studies. The patients with a lower dietary intake or lower blood level of vitamin C showed a greater progression of periodontal disease than the controls. The intervention using vitamin C administration improved gingival bleeding in gingivitis, but not in periodontitis. Alveolar bone absorption was also not improved. The present systematic review suggested that vitamin C contributes to a reduced risk of periodontal disease.

Successful Treatment of Pulmonary Pleomorphic Carcinoma with Nivolumab: A Case Report.

Pulmonary pleomorphic carcinoma (PPC) has a poor prognosis due to the poor results of treatment with systemic chemotherapy. We report the case of a 73-year-old woman with PPC who showed a favorable response to nivolumab. As first-line treatment for postoperative recurrence, she received carboplatin and nanoparticle albumin-bound paclitaxel. However, 12 months later, a new metastatic lymph node appeared. Nivolumab was administered as second-line treatment, and the patient showed a favorable prolonged response. The effects of treatment of PPC with nivolumab seem promising. The results of a future prospective study are expected to identify indicators for the treatment of PPC.

Association of mastication and factors affecting masticatory function with obesity in adults: a systematic review.

BACKGROUND: A substantial number of adults suffer from obesity, that is caused by the risk factor, masticatory dysfunction. The association between mastication and obesity, however, is inconclusive. This systematic review aims to provide literature regarding the association between mastication and factors affecting masticatory function, and obesity in adults. METHODS: Four electronic databases (PubMed, EMBASE, Cochrane Library, and Web of Science) were used to search for publications that met the following criteria: published between 2007 and 2016, written in English, and assessed the associations between mastication and obesity among the population aged ≥18 years. The included publications were analyzed based on the study design, main conclusions, and strength of evidence identified by the two authors who screened all the abstracts and full-text articles and, abstracted data, and performed quality assessments by using a critical appraisal tool, the Critical Appraisal Skills Programme Cohort Studies Checklists. RESULTS: A total of 18 articles (16 cross-sectional, 1 cohort studies, and 1 randomized controlled trial [RCT]) met our inclusion criteria and were evaluated. Poorer mastication was associated with obesity in 12 out of 16 cross-sectional studies. One cohort study showed that the obesity group displayed higher tooth loss than the normal weight group. One RCT demonstrated that gum-chewing intervention for 8 weeks significantly decreased waist circumference. CONCLUSIONS: Most studies revealed a positive association between mastication and obesity among adults. Nonetheless, most of them are cross-sectional studies, which are insufficient to demonstrate a causal relation. Further advancement requires RCT, especially an intervention of improvement of mastication and obesity needed to confirm this association.

Psychological effects of exercise on community-dwelling older adults.

BACKGROUND: In recent years, there have been an increasing number of older adults who suffer from mental disorders globally. OBJECTIVE: The objective of this study was to examine the effect of an intervention that consisted of an exercise program to improve the mental health of community-dwelling older adults. PARTICIPANTS AND METHODS: The recruited participants of this study were community-dwelling older adults aged ≥60 years who participated in a comprehensive health promotion program in Kakogawa, Japan. Participants in the intervention group received an exercise program that was developed for older adults using Thera-Band. To measure participants' mental health status, a Japanese version of the short form of the Profile of Mood States (POMS-SF) was used. Stress markers were measured, such as salivary cortisol, alpha-amylase, and sIgA levels. All participants provided salivary samples and completed psychological questionnaires at baseline and 6-month follow-up. RESULTS: No significant differences were observed between the intervention and control groups with respect to POMS-SF score and salivary biomarker profile at baseline. After the intervention, the intervention group showed a significant decrease in the POMS-SF "fatigue" score and cortisol level. No significant changes were observed in the control group. CONCLUSION: Simultaneous changes in feelings of fatigue and cortisol levels were observed among subjects who had received the intervention of regular exercise. Further research is needed to investigate the effectiveness of exercise intervention in improving mental health among older adults.

The Associations among Psychological Distress, Coping Style, and Health Habits in Japanese Nursing Students: A Cross-Sectional Study.

Background: Nursing students in many countries have been reported to experience high levels of stress and psychological distress. Health habits could potentially mediate the association between coping styles and psychological status. The purpose of this study was to evaluate the mediation effect of health habits in the relationship between stress coping styles and psychological distress in Japanese nursing students. Methods: A total of 181 nursing students completed anonymous self-reported questionnaires comprised of the General Health Questionnaire-12 (GHQ-12), the Brief Coping Orientation questionnaire, and an additional questionnaire on health behavior. A mediation analysis using path analysis with bootstrapping was used for data analysis. Results: Multivariate linear regression analysis showed that psychological distress was significantly and positively associated with "Avoidance coping" (ß = 0.39, p < 0.001), and was negatively associated with "Active coping" (ß = -0.30, p < 0.001), "exercise habit" (ß = -0.25, p = 0.001), and "sleeping" (ß = -0.24, p = 0.002). In the path model, "Active coping" and "Avoidance coping" had significant or marginally significant associations with "exercise habits" (active: ß = 0.19, p = 0.008, avoidance: ß = -0.12, p = 0.088), and psychological distress (active: ß = -0.25, p < 0.001, avoidance: ß = 0.363, p < 0.001). However, these coping style variables did not have a significant association with "sleep". In general, the size of the correlations was below 0.4. Conclusions: Exercise habits mediated the relationship between coping styles and psychological distress to a greater extent than sleep. The present study suggests the possibility that complex interactions between health habits and coping styles may influence the psychological status of nursing students.

Association between mastication and cognitive status: A systematic review.

PURPOSE: A substantial number of elderly people suffer from cognitive impairment and dementia, which are considered to have various risk factors, including masticatory dysfunction; however, the association between mastication and cognition is inconclusive. The objectives of this systematic review were to provide an overview of the literature on (1) the association between mastication and cognitive function and (2) the association between mastication and dementia incidence, in elderly people. MATERIALS AND METHODS: Searches were conducted on five electronic databases (PubMed, EMBASE, CINHL, Cochrane Library, and Pro Quest) and publications were selected that met the following criteria: published between 2005 and 2015, written in English, and assessed associations between mastication and cognitive function, cognitive decline and dementia among population over 40 years old. The included publications were analyzed for study design, main conclusions, and strength of evidence by two reviewers who screened all abstracts and full-text articles, abstracted data and performed quality assessments by using a critical appraisal tool. RESULTS: A total of 33 articles (22 cross-sectional, and 11 prospective cohort studies) were evaluated. Poorer mastication was associated with lower cognitive function in 15 of the 17 cross-sectional studies and steeper decline in 5 of the 6 prospective studies. Poorer mastication was one of significant risk factors for having dementia or mild memory impairment (MMI) in 4 of 5 cross-sectional studies and for the incidence of dementia or MMI in 4 of 5 prospective studies. CONCLUSIONS: Most studies point to a positive association between mastication and cognitive function, including dementia among elderly people.

CD56(dim)CD16(high) and CD56(bright)CD16(-) cell percentages associated with maximum knee extensor strength and incidence of death in elderly.

Physical fitness is an indicator of systemic well-being in humans. Little is known about the role of physical fitness for maintaining systemic health in the elderly. Here, we study elderly subjects to determine the relationships between physical fitness and CD56 and CD16 surface NK cell markers on peripheral blood lymphocytes, as well as to analyze the relationship between the surface markers and incidence of death. We selected 253 independent elderly subjects (122 female; 131 male) who were 79-80 years old. Subjects having a higher proportion of CD56(dim)CD16(high) within CD56(+)CD16(+) cells, or ration of CD56(dim)CD16(high) and CD56(dim)CD16(-) cells had a significant positive correlation with maximum bilateral knee extensor strength/weight (kg) (r = 0.425; P < 0.0001 or r = 0.323; P < 0.0001). In contrast, an increased proportion of CD56(bright)CD16(-) cells within lymphocyte significantly negatively correlated with the maximum bilateral knee extensor strength/weight (kg) (r = -0.290; P = 0.0004); and these subjects had a significantly lower mortality during the 5 years following measurement of death. Therefore, we found that a synergistic effect of the right and left leg muscle strength was associated with proportion of matured NK and NKT cells and induced a low proportion of CD56(bright)CD16(-) cells within lymphocyte. Moreover, the low proportion of CD56(bright)CD16(-) cells was associated with incidence of death. In conclusion, measurements of physical fitness, the proportion of CD56(dim)CD16(high) within CD56(+)CD16(+) cells, the ratio of CD56(dim)CD56(high) and CD56(dim)CD16(-) cells, and the proportion of CD56(bright)C16(-) cells in lymphocytes are important indicators to check elderly health.

Factors affecting changes in compliance with infection control practices by dentists in Japan.

We surveyed compliance with infection control practices (ICPs) and factors associated with ICPs reported by dentists in Japan in 2008 and 2011. ICPs improved during this period as did the proportion of dentists specializing in oral surgery, the proportion of dentists reporting a willingness to treat HIV and AIDS patients, and the proportion of dentists reporting knowledge about universal and standard precautions. Stronger associations between ICPs and these 3 factors were found in 2011 than in 2008.

Systematic review of the association of mastication with food and nutrient intake in the independent elderly.

Substantial number of elderly people suffer from poor mastication, which is considered to have a detrimental effect on their dietary habits. However, the association between mastication and diet is far from conclusive. The objective of this systematic review was to assess the association of mastication with food and nutrient intake in the community dwelling elderly. We searched the PubMed, Web of Science, Cochrane Library, and Scirus databases to obtain information on the epidemiological studies in this research area. The included publications were analyzed for study design, main conclusions, and strength of evidence. A comprehensive quality assessment of all the included studies (28 cross-sectional and 7 intervention studies) was performed. In 22 of the 28 cross-sectional studies, elderly persons with better mastication and dentition reported significantly higher consumption of foods and intake of some nutrients than those with poorer oral health; however, the remaining studies showed no such differences. Five of the 7 intervention studies with an intervention involving the provision of new prostheses did not show significant improvement in food and/or nutrient intake. These discrepant findings suggest that masticatory ability explains only part of the variance in food and nutrient intake of the elderly. Two intervention studies with the combination of prosthetic treatment and dietary intervention produced changes in intake of foods such as fruits and vegetables.

Quantification of periodontopathic bacteria in saliva using the invader assay.

When quantifying periodontopathic bacteria, it is important to use a convenient method that does not produce false negative results. The Invader assay is a convenient method because it does not involve gene amplification. The purpose of this study was to evaluate the validity of the Invader assay to quantify periodontopathic bacteria. The Invader technology was applied in quantifying five periodontopathic bacteria (Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, Prevotella intermedia, and Treponema denticola). The Invader assay produced a linear quantitative detection range over concentrations spanning seven exponential values, with a detection limit of 10(3.7) copies/tube and intra-day and inter-day variance of 0.1% to 4.7% and 0.1% to 3.4%, respectively, in quantifying five periodontopathic bacteria. We compared the results of the Invader assay with those of real-time polymerase chain reaction (PCR) performed for quantifying five periodontopathic bacteria in 22 patients with periodontitis. Among the Invader-detectable bacterial strains of each species, significant correlations were observed in the counts of concerned bacterial species between these two methods, with correlation coefficients ranging from 0.757 to 0.996. This study validated repeatability and reproducibility of the Invader assay in quantifying periodontopathic bacteria and demonstrated consistent agreement between the Invader assay and real-time PCR in quantifying periodontopathic bacteria.

Prevention of aspiration pneumonia (AP) with oral care.

AP is a major cause of morbidity and mortality in elderly patients, especially frail elderly patients. The aim of this article is to review effect of oral care, including oral hygiene and improvement of oral function, on the prevention of AP among elderly people in hospitals and nursing homes. There is now a substantial body of work studying the effect of oral care on the prevention of respiratory diseases. Oral hygiene, consisting of oral decontamination and mechanical cleaning by dental professionals, has resulted in significant clinical effects (decreased incidence of pneumonia and decreased mortality from respiratory diseases) in clinical randomized trials. Moreover, studies examining oral colonization by pneumonia pathogens have shown the effect of oral hygiene on eliminating these pathogens. In addition, swallowing training has been shown to improve the movement and function of swallowing-related muscles, also resulting in decreased incidence of pneumonia. These findings support the contention that oral care is effective in the prevention of AP.

A quick statistically accurate diagnosis for caries risk in the elderly.

BACKGROUND: In the elderly, the necessity to promote oral health is increasing to improve their quality of life. The prediction of dental caries risk makes it possible to prolong the life span of teeth. To develop a quick diagnosis system for caries risk, two methods, the modified Saliva Check SM and Saliva Check sIgA, were investigated in elderly patients. METHODS: We developed a caries risk quick assessment system using Saliva Check sIgA that specifically recognizes secretory IgA (sIgA) in saliva against the binding site of the mutans streptococci (MS) to the salivary-coated tooth surface; and combined it with a modified Saliva Check SM to determine the number of MS. One hundred eighty three patients (80 females, 103 males) who participated in 2005 (average age 77 years) and in 2006 (average age 78 years) were assessed for caries risk using the systems in this cohort study. RESULTS: Subjects with a positive Saliva Check sIgA showed a significantly lower increment of decayed and filled teeth number (DFT) on the coronal surface; whereas those testing negative had root decay and increased filled teeth numbers (RDFT) at the root surface during the following year. The combination of Saliva Check sIgA and modified Saliva Check SM showed the subjects with Saliva Check sIgA positive and modified Saliva Check SM negative had less than half of the increment of DFT than other groups. In the other groups, Saliva Check sIgA negative and modified Saliva Check SM positive detected >90% of the subjects with an MS level of >5 x 10(5)/mL of saliva in patients that were assessed in 2006. This suggests these subjects may need extensive care. CONCLUSIONS: This new combination system significantly evaluates the caries risk to predict future incidence for dental caries on the coronal surface and may be useful for risk diagnosis of caries during a visit to the dental office.

Opportunistic respiratory pathogens in the oral cavity of the elderly.

The oral cavity of the hospitalized or bedridden elderly is often a reservoir for opportunistic pathogens associated with respiratory diseases. Commensal flora and the host interact in a balanced fashion and oral infections are considered to appear following an imbalance in the oral resident microbiota, leading to the emergence of potentially pathogenic bacteria. The definition of the process involved in colonization by opportunistic respiratory pathogens needs to elucidate the factors responsible for the transition of the microbiota from commensal to pathogenic flora. The regulatory factors influencing the oral ecosystem can be divided into three major categories: the host defense system, commensal bacteria, and external pathogens. In this article, we review the profile of these categories including the intricate cellular interaction between immune factors and commensal bacteria and the disturbance in homeostasis in the oral cavity of hospitalized or bedridden elderly, which facilitates oral colonization by opportunistic respiratory pathogens.

Wireless capsule endoscopy in pediatric patients: the first series from Japan.

PURPOSE: The aim of our study was to determine the safety and usefulness of capsule endoscopy (CE) in pediatric patients. METHODS: We prospectively examined children (aged 10-18 years) with suspected small bowel disease and recorded capsule transit times, findings, and complications. RESULTS: We performed 19 CE examinations in 12 patients (median age 11.8 years; range 10-18 years). One of the two patients with obscure gastrointestinal bleeding (OGIB), a 14-year-old girl whose OGIB occurred after cord-blood transplantation due to leukemia, was diagnosed with thrombotic microangiopathy. Repeated CE allowed visualization of real-time mucosal changes, such as the improvement of ulcers and bleeding, and newly emerged lymphangiectasia, without causing the patient physical and mental stress. This information facilitated both subsequent evaluation of the clinical course and determination of the appropriate treatment strategy. In the second patient with chronic OGIB, a 10-year-old girl, the detection of severe ileal stenoses by capsule retention led to the diagnosis of non-specific multiple ulcers of the small intestine. After ileal resection, repeated CE detected the recurrence of multiple ulcers and enabled the optimal treatment strategy to be applied. CE confirmed small bowel involvement in a patient with unresponsive Crohn's disease (CD) and excluded CD in all five patients with suspected CD. Similarly, CE confirmed the absence of small bowel involvement in three of the four patients with recurrent abdominal pain, although one patient had nodular lymphoid hyperplasia. CONCLUSIONS: Based on our results, CE is a valuable tool in the differential diagnoses of small bowel diseases, and repeated examination can provide real-time information that will enable evaluation of the clinical course in pediatric patients.

[Combined irinotecan (CPT-11) and nedaplatin (254-S) therapy for advanced and/or recurrent cervical cancer].

We performed combination therapy with irinotecan (CPT-11) plus nedaplatin (254-S) for patients with cervical cancer. A total of 9 patients with cervical cancer (5 patients treated in neoadjuvant setting and 4 patients for recurrent disease) were administered 80 mg/m(2) of 254-Sintravenously on day 1 and 50 mg/m(2) of CPT-11 intravenously on day 1, 8 and 15. Treatment was repeated every 4 weeks. The average number of courses administered was 3.8 (range, 2-6). Grade 3 or 4 adverse events were leukopenia in 4 patients, thrombocytopenia in 1 patient and vomiting in 1 patient. The response rate was 40% in the neoadjuvant setting (2 PRs) and 75% in recurrent disease (3 PRs).