Relationship between health checkups and cancer screenings of wives and health checkups of their husbands: A cross-sectional study in Japan.

Objectives: This study investigated the relationship between health checkups, cervical cancer screenings, and breast cancer screenings (collectively referred to as wellness examinations) of wives and health checkups of their husbands. We aimed to develop strategies to encourage wellness examinations among married individuals in Japan. Methods: This study used the 2019 Comprehensive Survey of Living Conditions, focusing on married couples aged 40-64. We analyzed the percentage of wives undergoing wellness examinations, grouped based on whether their husbands had undergone health checkups. Subsequently, multivariable modified Poisson regression analysis was performed considering sociodemographic and health-related factors. All analyses considered medical insurance of wives because wellness examination methods varied depending on medical insurance type. Results: The sample comprised 40,560 couples undergoing health checkups, 39,870 undergoing cervical cancer screening, and 39,895 undergoing breast cancer screening. Regardless of the medical insurance type of the wife, a significant positive association was observed between the wellness examination of wives and the health checkup of husbands across all age groups. After adjusting for covariates, prevalence ratios (95% confidence intervals) for wives whose husbands underwent health checkups were 2.24 (2.09-2.40) for national health insurance, 1.18 (1.16-1.21) for employee insurance (employee), and 1.53 (1.44-1.63) for employee insurance (family) for health checkups. Similar trends were observed in cervical and breast cancer screening. Conclusions: Wellness examinations of wives were associated with those of their husbands, suggesting that couples often share similar health-seeking behaviors. Hence, targeted interventions are important for couples who do not undergo wellness examinations.

Associations between cardiorespiratory fitness and lifestyle-related factors with DNA methylation-based ageing clocks in older men: WASEDA'S Health Study.

DNA methylation-based age estimators (DNAm ageing clocks) are currently one of the most promising biomarkers for predicting biological age. However, the relationships between cardiorespiratory fitness (CRF), measured directly by expiratory gas analysis, and DNAm ageing clocks are largely unknown. We investigated the relationships between CRF and the age-adjusted value from the residuals of the regression of DNAm ageing clock to chronological age (DNAmAgeAcceleration: DNAmAgeAccel) and attempted to determine the relative contribution of CRF to DNAmAgeAccel in the presence of other lifestyle factors. DNA samples from 144 Japanese men aged 65-72 years were used to appraise first- (i.e., DNAmHorvath and DNAmHannum) and second- (i.e., DNAmPhenoAge, DNAmGrimAge, and DNAmFitAge) generation DNAm ageing clocks. Various surveys and measurements were conducted, including physical fitness, body composition, blood biochemical parameters, nutrient intake, smoking, alcohol consumption, disease status, sleep status, and chronotype. Both oxygen uptake at ventilatory threshold (VO2 /kg at VT) and peak oxygen uptake (VO2 /kg at Peak) showed a significant negative correlation with GrimAgeAccel, even after adjustments for chronological age and smoking and drinking status. Notably, VO2 /kg at VT and VO2 /kg at Peak above the reference value were also associated with delayed GrimAgeAccel. Multiple regression analysis showed that calf circumference, serum triglyceride, carbohydrate intake, and smoking status, rather than CRF, contributed more to GrimAgeAccel and FitAgeAccel. In conclusion, although the contribution of CRF to GrimAgeAccel and FitAgeAccel is relatively low compared to lifestyle-related factors such as smoking, the results suggest that the maintenance of CRF is associated with delayed biological ageing in older men.

Safety and stable survival of stem-cell-derived retinal organoid for 2 years in patients with retinitis pigmentosa.

Transplantation of induced pluripotent stem cell (iPSC)-derived retinal organoids into retinal disease animal models has yielded promising results, and several clinical trials on iPSC-derived retinal pigment epithelial cell transplantation have confirmed its safety. In this study, we performed allogeneic iPSC-derived retinal organoid sheet transplantation in two subjects with advanced retinitis pigmentosa (jRCTa050200027). The primary endpoint was the survival and safety of the transplanted retinal organoid sheets in the first year post-transplantation. The secondary endpoints were the safety of the transplantation procedure and visual function evaluation. The grafts survived in a stable condition for 2 years, and the retinal thickness increased at the transplant site without serious adverse events in both subjects. Changes in visual function were less progressive than those of the untreated eye during the follow-up. Allogeneic iPSC-derived retinal organoid sheet transplantation is a potential therapeutic approach, and the treatment's safety and efficacy for visual function should be investigated further.

Factors associated with non-participation in breast cancer screening: analysis of the 2016 and 2019 comprehensive survey of living conditions in Japan.

BACKGROUND: The participation rate for breast cancer screening remains to be suboptimal in Japan. Therefore, it is important to identify factors associated with non-participation and identify people at high risk for non-participation. METHODS: We carried out a cross-sectional study using the data of women aged 40-74 years from the 2016 and 2019 Comprehensive Survey of Living Conditions. We selected candidate predictor variables from the survey sheets and conducted a multivariable logistic regression for non-participation in breast cancer screening for the past 2 years. In addition, using data from 2016, we created an integer risk score for non-participation and tested its predictive performance in 2019. RESULTS: The proportion of participants in breast cancer screening in 2016 and 2019 were 46.7% (50,177/107,513) and 48.7% (49,498/101,716), respectively. In multivariable logistic regression analysis, age over 50 years, single/divorced/widowed, lower education level, lower household expenditure, being insured for National Health Insurance, employed to small/middle scale company, non-regularly employed, current smoker, never/quit drinking or middle/high-risk drinking, lower self-rated health status, higher Kessler Psychological Distress Scale score, non-participation in the annual health checkups for diseases other than cancer, not constantly visiting hospitals/clinics showed a positive association with non-participation. The 9-item risk score (age, marital status, education, health insurance plan, employment, smoking, drinking, non-participation in the annual health checkups for diseases other than cancer, and not constantly visiting hospitals/clinics) and 3-item risk score (age, health insurance plan, non-participation in the annual health checkups for diseases other than cancer) showed the area under the receiver operating characteristic curve of 0.744 and 0.720, respectively. CONCLUSION: We identified factors associated with non-participation in breast cancer screening. The simple risk score would be useful for public health sectors to identify people at risk for non-participation.

C/ebpα represses the oncogenic Runx3-Myc axis in p53-deficient osteosarcoma development.

Osteosarcoma (OS) is characterized by TP53 mutations in humans. In mice, loss of p53 triggers OS development, and osteoprogenitor-specific p53-deleted mice are widely used to study the process of osteosarcomagenesis. However, the molecular mechanisms underlying the initiation or progression of OS following or parallel to p53 inactivation remain largely unknown. Here, we examined the role of transcription factors involved in adipogenesis (adipo-TFs) in p53-deficient OS and identified a novel tumor suppressive molecular mechanism mediated by C/ebpα. C/ebpα specifically interacts with Runx3, a p53 deficiency-dependent oncogene, and, in the same manner as p53, decreases the activity of the oncogenic axis of OS, Runx3-Myc, by inhibiting Runx3 DNA binding. The identification of a novel molecular role for C/ebpα in p53-deficient osteosarcomagenesis underscores the importance of the Runx-Myc oncogenic axis as a therapeutic target for OS.

Fat-Free Mass Index as a Surrogate Marker of Appendicular Skeletal Muscle Mass Index for Low Muscle Mass Screening in Sarcopenia.

OBJECTIVES: We aimed to examine the relationship between the fat-free mass index (FFMI; FFM/height2) and appendicular skeletal muscle mass index (ASMI; ASM/height2), measured using both bioelectrical impedance analysis (BIA) and dual-energy X-ray absorptiometry (DXA), and investigate the effects of age and obesity. We also evaluated the suitability of BIA-measured FFMI as a simple surrogate marker of the ASMI and calculated the optimal FFMI cutoff value for low muscle mass screening to diagnose sarcopenia. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: This study included 1313 adults (women, 33.6%) aged 40-87 years (mean age, 55 ± 10 years) from the WASEDA'S Health Study. METHODS: Body composition was measured using multifrequency BIA and DXA. Low muscle mass was defined according to the criteria of the Asian Working Group for Sarcopenia 2019. RESULTS: BIA-measured FFMI showed strong positive correlations with both BIA- (r = 0.96) and DXA-measured (r = 0.95) ASMIs. Similarly, in the subgroup analysis according to age and obesity, the FFMI was correlated with the ASMI. The areas under the receiver operating characteristic curve for screening low muscle mass defined by DXA-measured ASMI using BIA-measured FFMI values were 0.95 (95% CI 0.93-0.97) for men and 0.91 (95% CI 0.87-0.94) for women. The optimal BIA-measured FFMI cutoff values for screening low muscle mass defined by DXA-measured ASMI were 17.5 kg/m2 (sensitivity 89%, specificity 88%) for men and 14.6 kg/m2 (sensitivity 80%, specificity 86%) for women. CONCLUSIONS AND IMPLICATIONS: The FFMI showed a strong positive correlation with BIA- and DXA-measured ASMIs, regardless of age and obesity. The FFMI could be a useful simple surrogate marker of the ASMI for low muscle mass screening in sarcopenia in community settings. The suggested FFMI cutoff values for predicting low muscle mass are <18 kg/m2 in men and <15 kg/m2 in women.

Development and validation of a risk score to predict the frequent emergency house calls among older people who receive regular home visits.

BACKGROUND: The demand for home healthcare is increasing in Japan, and a 24-hour on-call system could be a burden for primary care physicians. Identifying high-risk patients who need frequent emergency house calls could help physicians prepare and allocate medical resources. The aim of the present study was to develop a risk score to predict the frequent emergency house calls in patients who receive regular home visits. METHODS: We conducted a retrospective cohort study with linked medical and long-term care claims data from two Japanese cities. Participants were ≥ 65 years of age and had newly started regular home visits between July 2014 and March 2018 in Tsukuba city and between July 2012 and March 2017 in Kashiwa city. We followed up with patients a year after they began the regular home visits or until the month following the end of the regular home visits if this was completed within 1 year. We calculated the average number of emergency house calls per month by dividing the total number of emergency house calls by the number of months that each person received regular home visits (1-13 months). The primary outcome was the "frequent" emergency house calls, defined as its use once per month or more, on average, during the observation period. We used the least absolute shrinkage and selection operator (LASSO) logistic regression with 10-fold cross-validation to build the model from 19 candidate variables. The predictive performance was assessed with the area under the curve (AUC). RESULTS: Among 4888 eligible patients, frequent emergency house calls were observed in 13.0% of participants (634/4888). The risk score included three variables with the following point assignments: home oxygen therapy (3 points); long-term care need level 4-5 (1 point); cancer (4 points). While the AUC of a model that included all candidate variables was 0.734, the AUC of the 3-risk score model was 0.707, suggesting good discrimination. CONCLUSIONS: This easy-to-use risk score would be useful for assessing high-risk patients and would allow the burden on primary care physicians to be reduced through measures such as clustering high-risk patients in well-equipped medical facilities.

Factors Affecting Care-Level Deterioration among Older Adults with Mild and Moderate Disabilities in Japan: Evidence from the Nationally Standardized Survey for Care-Needs Certification.

This study aims to investigate the factors of care-level deterioration in older adults with mild and moderate disabilities using nationally standardized survey data for care-needs certification. We enrolled people aged 68 years or older, certified as support levels 1-2 (mild disability) or care levels 1-2 (moderate disability) with no cancer. The outcome was care-level deterioration after two years. The possible factors were physical and mental functions which were categorized as the following five dimensions according to the survey for care-needs certification: body function, daily life function, instrumental activities of daily living (IADL) function, cognitive function, and behavioral problems. A multivariate logistic regression analysis was conducted after stratifying the care level at baseline. A total of 2844 participants were included in our analysis. A low IADL function was significantly associated with a risk of care-level deterioration in all participants. In addition, low cognitive function was linked to care-level deterioration, except for those with support level 1 at baseline. Participants with more behavioral problems were more likely to experience care-level deterioration, except for those with care level 2 at baseline. Our study showed the potential utility of the care-needs certification survey for screening high-risk individuals with care-level deterioration.

The combination of cardiorespiratory fitness and muscular fitness, and prevalence of diabetes mellitus in middle-aged and older men: WASEDA'S Health Study.

BACKGROUND: Although the negative relationship between cardiorespiratory fitness (CRF) or muscular fitness and diabetes mellitus were respectively observed in many previous studies, there is still a lack of studies that include CRF and muscular fitness simultaneously. Therefore, this study aimed to investigate the relationship between the combination of CRF and muscular fitness and diabetes through a cross-sectional study.  METHODS: This study was part of WASEDA'S Health Study, a cohort study launched in 2014. We used a part of the baseline data collected for this study. Maximal exercise test using a cycle ergometer and leg extension power (LEP) test were respectively used to evaluate CRF and muscular fitness. Since LEP is affected by body weight, relative LEP (rLEP) which is LEP per body weight, was used as an index of muscular fitness. 796 men (56.5 ± 10.4 years old) who completed a medical examination and fitness tests, were divided into two groups based on CRF and rLEP, respectively. The prevalence of diabetes was collected based on a self-reported questionnaire or blood test. Odds ratios and 95% confidence intervals (CIs) for the prevalence of diabetes were obtained using logistic regression models while adjusting for age, body mass index, exercise habits, family history of diabetes, smoking habits, and drinking habits. RESULTS: 55 (7%) participants had diabetes. Compared to participants with lower CRF or rLEP, the odds ratio (95% CIs) of diabetes in those with higher CRF or rLEP was 0.46 (0.21-0.98) or 0.34 (0.16-0.74), respectively. Furthermore, using the lower CRF and lower rLEP group as the reference, the odds ratio (95% CIs) for the lower CRF and higher rLEP group was 0.32 (0.12-0.88), and higher CRF and higher rLEP group was 0.21 (0.07-0.63), after adjusting for potential confounding factors. CONCLUSIONS: CRF and rLEP have independent and joint inverse associations with diabetes prevalence. In addition, participants with high CRF and high rLEP had a lower prevalence of diabetes compared to those with only high CRF or only high rLEP.

Runx3 is required for oncogenic Myc upregulation in p53-deficient osteosarcoma.

Osteosarcoma (OS) in human patients is characterized by genetic alteration of TP53. Osteoprogenitor-specific p53-deleted mice (OS mice) have been widely used to study the process of osteosarcomagenesis. However, the molecular mechanisms responsible for the development of OS upon p53 inactivation remain largely unknown. In this study, we detected prominent RUNX3/Runx3 expression in human and mouse p53-deficient OS. Myc was aberrantly upregulated by Runx3 via mR1, a consensus Runx site in the Myc promoter, in a manner dependent on p53 deficiency. Reduction of the Myc level by disruption of mR1 or Runx3 knockdown decreased the tumorigenicity of p53-deficient OS cells and effectively suppressed OS development in OS mice. Furthermore, Runx inhibitors exerted therapeutic effects on OS mice. Together, these results show that p53 deficiency promotes osteosarcomagenesis in human and mouse by allowing Runx3 to induce oncogenic Myc expression.

Factors Associated with Outpatient Cardiac Rehabilitation Participation in Older Patients: A Population-Based Study Using Claims Data from Two Cities in Japan.

BACKGROUND: Although outpatient cardiac rehabilitation has been shown to be effective, the participation status of older cardiac patients is unclear in real-world settings. We investigated the proportion and associated factors of outpatient cardiac rehabilitation participation among older patients with heart diseases after cardiac intervention. METHODS: We analyzed data from medical and long-term care insurance claims data from two municipalities in Japan. The data coverage period was between April 2014 and March 2019 in City A and between April 2012 and November 2016 in City B. We identified patients aged ≥65 years with post-operative acute myocardial infarction, angina pectoris, or heart valve disease. We estimated the proportion of cardiac rehabilitation participation and conducted logistic regression to identify factors (age, sex, type of cardiac disease, open-heart surgery, Charlson comorbidity index, long-term care need level, catecholamine use, inpatient cardiac rehabilitation, and hospital volume for cardiac rehabilitation) associated with outpatient cardiac rehabilitation participation. RESULTS: A total of 690 patients were included in this study. The proportion of patients receiving outpatient cardiac rehabilitation was 9.0% overall. Multivariable logistic regression analysis suggested that men (adjusted OR 3.98; 95% CI 1.69-9.37), acute myocardial infarction (adjusted OR 2.76; 95% CI 1.20-6.36; reference angina pectoris), inpatient cardiac rehabilitation (adjusted OR 17.01; 95% CI 5.33-54.24), and "hospital volume" for cardiac rehabilitation (adjusted OR 4.35; 95% CI 1.14-16.57 for high-volume hospitals; reference low-volume hospital) were independently associated with outpatient cardiac rehabilitation. CONCLUSIONS: The participation rate of outpatient cardiac rehabilitation among older post-operative cardiac patients was suboptimal. Further studies are warranted to examine its generalizability and whether a targeted approach to a group of patients who are less likely to receive outpatient cardiac rehabilitation could improve the participation rate.

Association between Having Cancer and Psychological Distress among Family Caregivers Using Three Years of a Nationwide Survey Data in Japan.

We aimed to describe the characteristics of caregivers with cancer compared to those without and analyze the association between having cancer and caregivers' psychological distress in Japan. We used data from the Japanese Comprehensive Survey of Living Conditions in 2010, 2013, and 2016. The participants were 5258 family caregivers aged ≥40 years, caring for only one family member whose information in the dataset was available for all the covariates included in the model. The family caregivers' psychological distress was defined by the Kessler Psychological Distress Scale (K6) score (K6 ≥ 5). We conducted a Poisson regression analysis to examine the association between having cancer and family caregivers' distress. The sample of family caregivers consisted of mostly females (69.3%) and people within the 40-64 years age group (51.8%). As a result, family caregivers with cancer increased across the survey periods; a higher number of participants were unemployed. When adjusted for covariates, including the presence of other diseases, having cancer was significantly associated with distress (risk ratio 1.33, 95% confidence interval 1.05-1.69) among family caregivers. Family caregivers with cancer are expected to increase in the future; it is important to provide them with more support in managing both their treatment and caregiving to cope with their distress.

Amine modification of calcium phosphate by low-pressure plasma for bone regeneration.

Regeneration of large bone defects caused by trauma or tumor resection remains one of the biggest challenges in orthopedic surgery. Because of the limited availability of autograft material, the use of artificial bone is prevalent; however, the primary role of currently available artificial bone is restricted to acting as a bone graft extender owing to the lack of osteogenic ability. To explore whether surface modification might enhance artificial bone functionality, in this study we applied low-pressure plasma technology as next-generation surface treatment and processing strategy to chemically (amine) modify the surface of beta-tricalcium phosphate (ß-TCP) artificial bone using a CH4/N2/He gas mixture. Plasma-treated ß-TCP exhibited significantly enhanced hydrophilicity, facilitating the deep infiltration of cells into interconnected porous ß-TCP. Additionally, cell adhesion and osteogenic differentiation on the plasma-treated artificial bone surfaces were also enhanced. Furthermore, in a rat calvarial defect model, the plasma treatment afforded high bone regeneration capacity. Together, these results suggest that amine modification of artificial bone by plasma technology can provide a high osteogenic ability and represents a promising strategy for resolving current clinical limitations regarding the use of artificial bone.

Determinants of Resting Oxidative Stress in Middle-Aged and Elderly Men and Women: WASEDA'S Health Study.

Previous studies have not investigated the determinants of resting oxidative stress, including physical fitness, as it relates to redox regulation. The present study therefore was aimed at identifying lifestyle and biological factors that determine resting oxidative stress, including objectively measured physical fitness. In 873 middle-aged and elderly men and women, age and anthropometric parameters, lifestyle-related parameters, medication and supplementation status, physical fitness, biochemical parameters, and nutritional intake status, as well as three plasma oxidative stress markers: protein carbonyl (PC), F2-isoprostane (F2-IsoP), and thiobarbituric acid reactive substances (TBARS), were surveyed and measured. The determinants of PC, F2-IsoP, and TBARS in all participants were investigated using stepwise multiple regression analysis. In PC, age (ß = -0.11, P = 0.002), leg extension power (ß = -0.12, P = 0.008), BMI (ß = 0.12, P = 0.004), and HDL-C (ß = 0.08, P = 0.040) were included in the regression model (adjusted R 2 = 0.018). In the F2-IsoP, smoking status (ß = 0.07, P = 0.060), BMI (ß = 0.07, P = 0.054), and HbA1c (ß = -0.06, P = 0.089) were included in the regression model (adjusted R 2 = 0.006). In TBARS, glucose (ß = 0.18, P < 0.001), CRF (ß = 0.16, P < 0.001), age (ß = 0.15, P < 0.001), TG (ß = 0.11, P = 0.001), antioxidant supplementation (ß = 0.10, P = 0.002), and HbA1c (ß = -0.13, P = 0.004) were included in the regression model (adjusted R 2 = 0.071). In conclusion, the present study showed that age, anthropometric index, lifestyle-related parameters, medication and supplementation status, objectively measured physical fitness, biochemical parameters, and nutritional intake status explain less than 10% of oxidative stress at rest.

Perilla Seed Oil Enhances Cognitive Function and Mental Health in Healthy Elderly Japanese Individuals by Enhancing the Biological Antioxidant Potential.

Oxidative stress plays an important role in age-associated cognitive decline. We recently reported that dietary intake of perilla seed oil (PO), a rich source of α-linolenic acid (LNA, C18:3, ω-3), helps in maintaining good mental health in adults. This study aimed to investigate the impacts of dietary PO intake on cognitive functions and mental health in healthy, elderly Japanese individuals. Seventy-five healthy volunteers aged 64-84 years were randomly divided into two groups: a control group and a PO-administered group. At baseline and at 12 months of intervention, cognitive function, mental health condition, fatty acid profile of the red blood cell plasma membranes (RBC-PM), and serum biochemical parameters were evaluated. Results showed that serum biological antioxidant potential and LNA levels in the RBC-PM at 12 months after the trial were significantly higher in the PO group compared to the control group. Further, both the cognitive function measures, as evaluated by the Frontal Assessment Battery test and the apathy scores, tended to be improved after 12 months in the PO group. Our results demonstrate that dietary PO intake enhances the antioxidant potential and prevents the age-related cognitive and mental decline in healthy elderly individuals by enhancing the blood LNA levels.

Days Spent at Home near the End of Life in Japanese Elderly Patients with Lung Cancer: Post hoc Analysis of A Prospective Study.

OBJECTIVE: Days spent at home (DASH) near the end of life is considered an important patient-centered goal and outcome because many patients want to stay at home toward the end of life. This study aimed to estimate the individual DASH near the end of life and identify its early predictors, including muscle mass and physical function, among elderly patients with advanced non-small-cell lung cancer (NSCLC). METHODS: We conducted a post hoc analysis of the prospective observational study (UMIN000009768) that recruited patients aged ≥ 70 years who were scheduled to undergo first-line chemotherapy because of advanced NSCLC. We measured the muscle mass by bioelectrical impedance analysis at baseline. DASH was calculated as 30 days minus the number of days spent in hospitals, palliative care facilities, or nursing homes during the last 30 days of life. We performed linear regression analyses to evaluate the predictors of DASH. RESULTS: Altogether, 16 women and 28 men with a median overall survival of 15.5 months (range: 2.9-58.9) were included. The median DASH in the last 30 days of life was 8 days (range: 0-30, interquartile range: 0-23). Men had longer DASH than women by 7.3 days. Patients who had good trunk muscle mass index and hand-grip strength had significantly longer DASH than those who did not (4.7 days per kg/m2 increase [P = 0.017] and 0.4 days per kg increase [P = 0.032], respectively). CONCLUSIONS: Most elderly patients with advanced NSCLC had a limited DASH near the end of life. The risk factors for reduced DASH were women, reduced muscle mass, and poor physical function at the time of diagnosis of advanced NSCLC. Our findings would encourage early discussions about end-of-life care for patients with advanced cancers with risk factors for short DASH at the time of diagnosis, and thus, improve the quality of end-of-life care.

Microbial Antigen-Presenting Extracellular Vesicles Derived from Genetically Modified Tumor Cells Promote Antitumor Activity of Dendritic Cells.

Tumor-derived extracellular vesicles (EVs), as tumor vaccines, carry tumor-associated antigens (TAAs), and were expected to transfer TAAs to antigen-presenting cells. However, treatment with tumor-derived EVs exhibited no obvious antitumor effect on the established tumors, likely due to their immuno-suppressive functions, and also to the poor immunogenicity of TAAs. In order to improve the immune stimulating properties, EVs expressing a highly immunogenic bacterial antigen, 6 kDa early secretory antigenic target (ESAT-6), from Mycobacterium tuberculosis were prepared by genetically modifying the parent tumor cells with a plasmid coding for ESAT-6. Cultured B16 tumor cells were transfected with a ternary complex system consisting of pDNA, polyethylenimine (PEI), and chondroitin sulfate. The cells that were transfected with the ternary complex secreted EVs with a higher number of ESAT-6 epitopes than those transfected by a conventional DNA/PEI binary complex, due to the low cytotoxicity, and durable high expression efficiency of the ternary complex systems. The EVs presenting the ESAT-6 epitope (ESAT-EV) were collected and explored as immune modulatory agents. Dendritic cells (DCs) were differentiated from mouse bone marrow cells and incubated with ESAT-EV. After incubating with the EVs for one day, the DCs expressed a significantly higher level of DC maturation marker, CD86. The DCs treated with ESAT-EV showed a significantly improved antitumor activity in tumor-bearing mice.

Structural basis for transcriptional coactivator recognition by SMAD2 in TGF-ß signaling.

Transforming growth factor-ß (TGF-ß) proteins regulate multiple cellular functions, including cell proliferation, apoptosis, and extracellular matrix formation. The dysregulation of TGF-ß signaling causes diseases such as cancer and fibrosis, and therefore, understanding the biochemical basis of TGF-ß signal transduction is important for elucidating pathogenic mechanisms in these diseases. SMAD proteins are transcription factors that mediate TGF-ß signaling-dependent gene expression. The transcriptional coactivator CBP directly interacts with the MH2 domains of SMAD2 to activate SMAD complex-dependent gene expression. Here, we report the structural basis for CBP recognition by SMAD2. The crystal structures of the SMAD2 MH2 domain in complex with the SMAD2-binding region of CBP showed that CBP forms an amphiphilic helix on the hydrophobic surface of SMAD2. The expression of a mutated CBP peptide that showed increased SMAD2 binding repressed SMAD2-dependent gene expression in response to TGF-ß signaling in cultured cells. Disrupting the interaction between SMAD2 and CBP may therefore be a promising strategy for suppressing SMAD-dependent gene expression.

Bioadhesive and biodissolvable hydrogels consisting of water-swellable poly(acrylic acid)/poly(vinylpyrrolidone) complexes.

Films that can form bioadhesive hydrogels on wet biotissues absorbing blood or body fluids are useful for medical devices such as hemostats, adhesion barriers, wound dressings, and drug release devices. We focused on a hydrogen-bonding polymer complex consisting of poly(acrylic acid) (PAA) and poly(vinylpyrrolidone) (PVP). PAA is known as a tissue-adhesive polymer. However, simple mixing of aqueous PAA and PVP solutions resulted in the formation of an insoluble nonadhesive precipitate. We developed a novel solid/solution interface complexation method to afford a PAA/PVP complex that forms a strongly bioadhesive hydrogel with low cytotoxicity. The complex hydrogel can be slowly dissociated and dissolved in the body. The formation of the complexes as well as their swelling and degradation behavior depended strongly on the molecular weights and cross-linking densities of the component polymers. When the complex film was applied to a clipped incised jugular vein of a rat, it immediately formed a hydrogel and closed the incision. After removal of the clip, blood flowed through the vessel without any leakage. Application of the complex film to the surface of an incised mouse liver resulted in firm adhesion and the hemorrhage was effectively stopped. Such bioadhesive and biodissolvable materials consisting of low-toxicity synthetic polymers have high potential for implantable medical devices.

Long-term renal follow up of preterm neonates born before 35 weeks of gestation.

BACKGROUND: The hypothesis of the Developmental Origins of Health and Disease states that environmental factors during fetal and infantile life are risk factors for some chronic diseases in adulthood. Few studies, however, have confirmed this hypothesis early in childhood. Therefore, we assessed how premature birth and low-birthweight (LBW) affect the renal function of Japanese children. METHODS: This retrospective study surveyed 168 patients who were born before 35 weeks of gestation and were cared for at the present neonatal intensive care unit. Follow-up duration was >2 years. Serum creatinine (sCr) and estimated glomerular filtration rate (eGFR) recorded in medical records were reviewed. RESULTS: The eGFR at 2 years of age was significantly correlated with birthweight and gestational age (P < 0.01). Approximately 10.7% of the children had low eGFR (<90 mL/min/1.73 m2 ) without clinical symptoms or abnormal urine examination. These children had high sCr on day 7 after birth (P < 0.01) and delayed recovery of these levels during the first month after birth. CONCLUSION: Premature gestational age and LBW directly affect renal function in young children. High sCr on day 7 after birth is a risk factor for chronic kidney disease in children. Careful follow up of renal function is therefore required for premature infants and infants with LBW beginning in early childhood to prevent renal dysfunction.