Convergent MAPK pathway alterations mediate acquired resistance to FGFR inhibitors in FGFR2 fusion-positive cholangiocarcinoma.

BACKGROUND & AIMS: There is a knowledge gap in understanding mechanisms of resistance to fibroblast growth factor receptor (FGFR) inhibitors (FGFRi) and a need for novel therapeutic strategies to overcome it. We investigated mechanisms of acquired resistance to FGFRi in patients with FGFR2-fusion-positive cholangiocarcinoma (CCA). METHODS: A retrospective analysis of patients who received FGFRi therapy and underwent tumor and/or cell-free DNA analysis, before and after treatment, was performed. Longitudinal circulating tumor DNA samples from a cohort of patients in the phase I trial of futibatinib (NCT02052778) were assessed. FGFR2-BICC1 fusion cell lines were developed and secondary acquired resistance mutations in the mitogen-activated protein kinase (MAPK) pathway were introduced to assess their effect on sensitivity to FGFRi in vitro. RESULTS: On retrospective analysis of 17 patients with repeat sequencing following FGFRi treatment, new FGFR2 mutations were detected in 11 (64.7%) and new alterations in MAPK pathway genes in nine (52.9%) patients, with seven (41.2%) patients developing new alterations in both the FGFR2 and MAPK pathways. In serially collected plasma samples, a patient treated with an irreversible FGFRi tested positive for previously undetected BRAF V600E, NRAS Q61K, NRAS G12C, NRAS G13D and KRAS G12K mutations upon progression. Introduction of a FGFR2-BICC1 fusion into biliary tract cells in vitro sensitized the cells to FGFRi, while concomitant KRAS G12D or BRAF V600E conferred resistance. MEK inhibition was synergistic with FGFRi in vitro. In an in vivo animal model, the combination had antitumor activity in FGFR2 fusions but was not able to overcome KRAS-mediated FGFRi resistance. CONCLUSIONS: These findings suggest convergent genomic evolution in the MAPK pathway may be a potential mechanism of acquired resistance to FGFRi. CLINICAL TRIAL NUMBER: NCT02052778. IMPACT AND IMPLICATIONS: We evaluated tumors and plasma from patients who previously received inhibitors of fibroblast growth factor receptor (FGFR), an important receptor that plays a role in cancer cell growth, especially in tumors with abnormalities in this gene, such as FGFR fusions, where the FGFR gene is fused to another gene, leading to activation of cancer cell growth. We found that patients treated with FGFR inhibitors may develop mutations in other genes such as KRAS, and this can confer resistance to FGFR inhibitors. These findings have several implications for patients with FGFR2 fusion-positive tumors and provide mechanistic insight into emerging MAPK pathway alterations which may serve as a therapeutic vulnerability in the setting of acquired resistance to FGFRi.

Phase I study of the irreversible fibroblast growth factor receptor 1-4 inhibitor futibatinib in Japanese patients with advanced solid tumors.

This phase I study was designed to: (1) determine the maximum tolerated dose (MTD) and recommended dose (RD) of the fibroblast growth factor receptor (FGFR) inhibitor futibatinib in Japanese patients with advanced solid tumors, and (2) examine the antitumor activity of the RD in patients with gastric cancer (GC) or other advanced solid tumors who have FGFR or FGF/FGFR abnormalities, respectively. In the dose-escalation phase, patients were assigned to 21-day cycles of oral futibatinib 8-160 mg three times a week (TIW) or 16 or 20 mg once daily (QD). In the expansion phase, patients received oral futibatinib 56, 80, or 120 mg TIW, or 16 or 20 mg QD. Eighty-three patients received futibatinib TIW (n = 40) or QD (n = 43). No dose-limiting toxicities were observed according to the final study protocol definition, and the MTD was not reached. The most common adverse events with both regimens were hyperphosphatemia (TIW, 82.5%; QD, 100.0%) and decreased appetite (TIW, 40.0%; QD, 58.1%). Hyperphosphatemia was asymptomatic, not leading to futibatinib discontinuation. The overall response rate (ORR) was 11.5% in patients with FGF/FGFR abnormalities. Notably, in GC patients harboring FGFR2 copy number (CN) ≥10, the ORR was 36.4% versus 0 in patients with CN <10. Therefore, futibatinib had a generally predictable and manageable safety profile in patients with advanced solid tumors. Antitumor activity was seen in patients with FGF/FGFR abnormalities, particularly those with GC and high FGFR2 CNs. Thus, futibatinib 20 mg QD was chosen as the RD for phase II studies.

[Differences in risk of requiring care between screening using queries with and without definitions when determining frequency of going out].

Objectives　This study elucidates the differences in risk for a functional decline in general housebound screening using queries with and without definitions.Methods　This study involved 10,802 community-dwelling older people who lived in four municipalities in Aichi Prefecture. The participants were asked about their frequency of going out in general and for five specific purposes: shopping, hospital visitation, strolling, leisure, and work. A person was defined as being "generally housebound" if he/she answered "less than once per week." However, a query with the definition of "going out" was used in only one of the four municipalities. Furthermore, we defined a person who goes out once a week, for any of the purposes, as "by-purpose non-housebound." If the response to the general and purpose-specific queries were inconsistent, we regarded it as an "inconsistent answer." Additionally, we compared the occurrence rate and hazard ratio for the onset of long-term care insurance certification of general housebound screening using queries with and without definition. We also calculated the occurrence rate and related risk factors for inconsistent answers.Results　The occurrence rate of general housebound screening using query with and without definition was 2.8% and 11.7%, respectively. Additionally, the hazard ratio for the onset of long-term care insurance certification of general housebound screening using the query with definition was 1.56 times more than that of general housebound screening using query without definition. The rate of inconsistent answers in by-purpose non-housebound using query with and without definition was 2.2% and 10.2%, respectively. However, sex, age, living with spouse and child(ren), years of schooling, self-rated health, depression, habitation in islands, and indicating definition of "going out" were related to inconsistent answers. The prevalence ratio of inconsistent answers in respondents using query with definition was significantly lower than among respondents using query without definition (PR=0.29).Conclusion　Query with definition reduced the occurrence rate of general housebound and increased the hazard ratio for the onset of long-term care insurance certification. Therefore, a definition should be added to queries asking for the frequency of going out to screen for housebound.

TAS-119, a novel selective Aurora A and TRK inhibitor, exhibits antitumor efficacy in preclinical models with deregulated activation of the Myc, ß-Catenin, and TRK pathways.

Aurora kinase A, a mitotic kinase that is overexpressed in various cancers, is a promising cancer drug target. Here, we performed preclinical characterization of TAS-119, a novel, orally active, and highly selective inhibitor of Aurora A. TAS-119 showed strong inhibitory effect against Aurora A, with an IC50 value of 1.04 nmol/L. The compound was highly selective for Aurora A compared with 301 other protein kinases, including Aurora kinase B. TAS-119 induced the inhibition of Aurora A and accumulation of mitotic cells in vitro and in vivo. It suppressed the growth of various cancer cell lines harboring MYC family amplification and CTNNB1 mutation in vitro. In a xenograft model of human lung cancer cells harboring MYC amplification and CTNNB1 mutation, TAS-119 showed a strong antitumor activity at well-tolerated doses. TAS-119 induced N-Myc degradation and inhibited downstream transcriptional targets in MYCN-amplified neuroblastoma cell lines. It also demonstrated inhibitory effect against tropomyosin receptor kinase (TRK)A, TRKB, and TRKC, with an IC50 value of 1.46, 1.53, and 1.47 nmol/L, respectively. TAS-119 inhibited TRK-fusion protein activity and exhibited robust growth inhibition of tumor cells via a deregulated TRK pathway in vitro and in vivo. Our study indicates the potential of TAS-119 as an anticancer drug, especially for patients harboring MYC amplification, CTNNB1 mutation, and NTRK fusion.

The Risk of Functional Limitations After Driving Cessation Among Older Japanese Adults: The JAGES Cohort Study.

BACKGROUND: Population ageing and stringent licensing policies will increase the number of older drivers who stop driving. Adverse health outcomes owing to driving cessation and their prevention are emerging concerns. Therefore, we longitudinally examined the impact of driving cessation and alternative transportation use after cessation on the risk of functional limitations in a cohort of community-dwelling people (65 years and older) in Japan. METHODS: Using cohort data of those who drove as of 2006/07, we compared the risk of functional limitations between 2,704 current drivers and 140 former drivers (who stopped driving by 2010). Of the former drivers, 77 did not use public transportation or bicycles after driving cessation (thus losing independent mobility). We calculated the hazard ratios (HRs) for the incidence of functional limitations with 95% confidence intervals (CIs) based on the Cox proportional hazards model with the covariates influencing the functional limitations. RESULTS: From 2010 through 2016, 645 people had functional limitations, which included 38, 82, and 119 per 1,000 person-years among current drivers, former drivers who used public transportation or bicycles, and former drivers who were only driven by others, respectively (HR 1.69; 95% CI, 1.15-2.49 and HR 2.16; 95% CI, 1.51-3.10, relative to current drivers). CONCLUSION: Driving cessation is associated with an increased risk of functional limitations among older adults, but this risk might be alleviated if they are able to maintain independent mobility using public transportation or bicycles after driving cessation.

Influence of socioeconomic status on the association between body mass index and cause-specific mortality among older Japanese adults: The AGES Cohort Study.

OBJECTIVE: Many studies have suggested a U-shaped curve for the association between body size and mortality risks, i.e., mortality risks increase in those who are both overweight and underweight. The strength of the associations may vary according to socioeconomic statuses (SES), as they determine levels of access to healthcare and psychosocial stresses. We investigated the modifying effects of SES on the relationship between body mass index (BMI) and mortality. METHOD: We used prospective cohort data of participants in the Aichi Gerontological Evaluation Study in 2003 (n=14,931), who were 65years or older and physically and cognitively independent at baseline, and residing in eight municipalities in Japan. Data on all-causes mortality and mortality from cancer, cardiovascular disease, and respiratory disease was obtained from municipal government registries. RESULTS: Proportional hazard regression analyses showed that, among men, the associations between overweight (BMI≥25kg/m(2)) and higher mortality risks by any cause were stronger among lower income groups. Even adjusting for multiple confounding factors, hazard ratios (95% confidence intervals) for mortality by all causes among low income group (household income<1.5 million yen) were 1.96 (1.02-3.73) for overweight compared with BMIs between 23.0 and 24.9, whereas they were 0.94 (0.57-1.38) among men in high income group (income>3 million yen). The modifying effects of income were not marked among women. CONCLUSION: Household income, which may directly reflect accessibility to healthcare and psychosocial stress among older Japanese men, may be an important modifying factor in the health risks attributable to overweight.

Distance to retail stores and risk of being homebound among older adults in a city severely affected by the 2011 Great East Japan Earthquake.

BACKGROUND: after the Great East Japan Earthquake in 2011, inactivity and the homebound status of older victims in affected areas have been a serious public health concern owing to the victims' prolonged existence as evacuees in mountainous areas. OBJECTIVE: to evaluate the association between distances to retail stores and risks of being homebound. DESIGN: secondary analysis of cross-sectional interview survey data with a geographical information analysis. SETTING: Rikuzentakata, Iwate, a municipality seriously damaged by the 2011 earthquake and tsunami. SUBJECTS: all Rikuzentakata residents aged 65 or older except for those living in temporary housing (n = 2,327). METHODS: we calculated road distances between each residential address and retail stores, hawker sites and shopping bus stops, accounting for the extra load caused by walking on slopes. The prevalence ratio of being homebound adjusted for age, source of income and morbidity by road distance was estimated using Poisson regression with a generalised estimating equation. RESULTS: those living at distances of 1,200 m or more were 1.78 (95% confidence intervals, 1.03-3.08) times more likely to be homebound (going out only every 4 or more days a week) among men and 1.85 (1.13-3.02) among women, compared with those residing in places <400 m from retail stores or shopping bus stops. The distances were reduced by new hawker and shopping bus services, but the improvements varied greatly across the districts. CONCLUSIONS: access to daily needs is essential to prevent homebound status. Post-disaster community diagnosis in terms of the built environment is important for strategic community restoration.

[Criteria for social isolation based on associations with health indicators among older people. A 10-year follow-up of the Aichi Gerontological Evaluation Study].

OBJECTIVES: No clear evidence for a cut-off point for social isolation has been established so far. The purpose of this study was to evaluate the criteria for social isolation based on associations with objective health outcomes in a 10-year follow-up study. METHODS: We performed a prospective study of functionally independent residents aged 65 years or older who lived in six municipalities as part of the Aichi Gerontological Evaluation Study (response rate: 50.4%) that began in 2003. Data on the onset of functional disability, dementia, and death were obtained from municipal databases of the public long-term care insurance system. A total of 12,085 participants were followed up for up to 10 years. We used frequencies of face-to-face and non-face-to-face contact with non-resident children, relatives and friends, or neighbors as indicators of social isolation. The overall frequency of contact with others was categorized from "less than once a month" to "frequently, every day." RESULTS: Cox's proportional hazard model revealed that, after controlling for sex, age, education level, marital status, equivalent household income, need for medical care, self-recognition of forgetfulness, and residential area, the hazard ratios for functional disability (over long-term care level 2), dementia, and premature death increase in those with contact frequency of "less than once a month" were 1.37 (95% confidence interval [CI]: 1.16-1.61), 1.45 (95% CI: 1.21-1.74), and 1.34 (95% CI: 1.16-1.55), respectively. The "from once a month to once a week" frequency was also associated with these health indicators, although the "more than once a week" frequency was not significantly associated with any measured outcome. The prevalence of "less than once a month" contact was 7.4% (men=10.2%, women=4.7%), and this was 15.8% (men=21.2%, women=10.6%) when including those with "less than once a week" contact. CONCLUSION: These findings suggest that "less than once a week" or "less than once a month" contact with non-cohabitant others are valid operational definitions of social isolation that are closely associated with premature death and other health indicators.

Neighbourhood transportation, elapsed years, and well-being after surrendering the driver's licence in older Japanese adults: The JAGES longitudinal study.

This study aimed to examine how the associations between surrendering driving licence and changes in self-rated health and social interactions among older adults differ by the years elapsed since surrendering and the number of public transportation systems (PTS) in the neighbourhood. We used the 2013 and 2016 survey data from the Japan Gerontological Evaluation Study targeting residents aged ≥65 years in 30 municipalities in Japan. Two-waves longitudinal data from 4894 older adults were evaluated. Based on the difference-in-differences method, the interaction terms of respondents' driving status, which was the categorical exposure variable representing respondents' driving status for three years during the study period, and a dummy variable of year (2016) were used as explanatory variables in logistic regression analyses to examine changes in outcomes (poor self-rated health and infrequent meeting with friends) between 2013 and 2016 by driving status during this period. Analyses were stratified based on neighbourhood PTS ('more PTS' and 'fewer PTS' groups). We found that, while surrendering licence within three years was associated with increased probability of poor self-rated health in more PTS group, the confidence interval was large. Although surrendering licence within three years was associated with decreased social interactions, this association weakened if licence was surrendered more than three years ago. These associations were not markedly affected by neighbourhood PTS. Our findings suggested that, regardless of neighbourhood PTS, support and care to promote social interactions at or shortly after surrendering licence may be beneficial to the well-being of older adults who lost their driving licence.

Discovery of Futibatinib: The First Covalent FGFR Kinase Inhibitor in Clinical Use.

Deregulating fibroblast growth factor receptor (FGFR) signaling is a promising strategy for cancer therapy. Herein, we report the discovery of compound 5 (TAS-120, futibatinib), a potent and selective covalent inhibitor of FGFR1-4, starting from a unique dual inhibitor of mutant epidermal growth factor receptor and FGFR (compound 1). Compound 5 inhibited all four families of FGFRs in the single-digit nanomolar range and showed high selectivity for over 387 kinases. Binding site analysis revealed that compound 5 covalently bound to the cysteine 491 highly flexible glycine-rich loop region of the FGFR2 adenosine triphosphate pocket. Futibatinib is currently in Phase I-III trials for patients with oncogenically driven FGFR genomic aberrations. In September 2022, the U.S. Food & Drug Administration granted accelerated approval for futibatinib in the treatment of previously treated, unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma harboring an FGFR2 gene fusion or other rearrangement.

Preclinical Evaluation of the FGFR-Family Inhibitor Futibatinib for Pediatric Rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. Despite decades of clinical trials, the overall survival rate for patients with relapsed and metastatic disease remains below 30%, underscoring the need for novel treatments. FGFR4, a receptor tyrosine kinase that is overexpressed in RMS and mutationally activated in 10% of cases, is a promising target for treatment. Here, we show that futibatinib, an irreversible pan-FGFR inhibitor, inhibits the growth of RMS cell lines in vitro by inhibiting phosphorylation of FGFR4 and its downstream targets. Moreover, we provide evidence that the combination of futibatinib with currently used chemotherapies such as irinotecan and vincristine has a synergistic effect against RMS in vitro. However, in RMS xenograft models, futibatinib monotherapy and combination treatment have limited efficacy in delaying tumor growth and prolonging survival. Moreover, limited efficacy is only observed in a PAX3-FOXO1 fusion-negative (FN) RMS cell line with mutationally activated FGFR4, whereas little or no efficacy is observed in PAX3-FOXO1 fusion-positive (FP) RMS cell lines with FGFR4 overexpression. Alternative treatment modalities such as combining futibatinib with other kinase inhibitors or targeting FGFR4 with CAR T cells or antibody-drug conjugate may be more effective than the approaches tested in this study.

Association between self-reported dental health status and onset of dementia: a 4-year prospective cohort study of older Japanese adults from the Aichi Gerontological Evaluation Study (AGES) Project.

OBJECTIVES: Studies have shown that people with cognitive impairment have poor dental health. However, the direction of causality remains unknown. This prospective cohort study aimed to determine the association between four self-reported dental health variables and dementia onset in older Japanese people. METHODS: Analysis was conducted on 4425 residents 65 years or older. Four self-reported dental health variables included the number of teeth and/or use of dentures, ability to chew, presence/absence of a regular dentist, and taking care of dental health. Data were collected using self-administered questionnaires given in 2003. Records of dementia onset during 2003 to 2007 were obtained from municipalities in charge of the public long-term care insurance system. Age, income, body mass index, present illness, alcohol consumption, exercise, and forgetfulness were used as covariates. RESULTS: Dementia onset was recorded in 220 participants. Univariate Cox proportional hazards models showed significant associations between the dental health variables and dementia onset. In models fully adjusted for all covariates, hazard ratios (95% confidence intervals) of dementia onset of respondents were as follows: 1.85 (1.04-3.31) for those with few teeth and without dentures; 1.25 (0.81-1.93) for those who could not chew very well; 1.44 (1.04-2.01) for those who did not have a regular dentist; and 1.76 (0.96-3.20) for those who did not take care of their dental health. CONCLUSIONS: Few teeth without dentures and absence of a regular dentist, not poor mastication and poor attitudes toward dental health, were associated with higher risk of dementia onset in the older Japanese cohort even after adjustment for available covariates.

Cell death induction in resting lymphocytes by pan-Cdk inhibitor, but not by Cdk4/6 selective inhibitor.

Immunosuppression is one of the common side effects of many anti-tumor agents targeting proliferating cells. We previously reported the development of a new class of pan-cyclin-dependent kinase (Cdk) inhibitor compounds that induce immunosuppression in rodents. Here, we demonstrated that a pan-Cdk inhibitor, Compound 1 very rapidly reduced white blood cells in mice, only 8 h after administration. Compound 1 induced death of peripheral blood cells or purified resting (non-stimulated) lymphocytes ex vivo. Cell death was induced very rapidly, after 4 h of incubation, suggesting that acute immunosuppression observed in rodents might be, at least in part, due to direct cytotoxic effects of Compound 1 on resting lymphocytes. While cell cycle-related Cdks were not activated, the carboxyl terminal domain (CTD) of the largest subunit of RNA polymerase II was phosphorylated, indicating activation of Cdk7 or Cdk9, which phosphorylates this domain, in resting lymphocytes. Indeed, the pan-Cdk inhibitor suppressed CTD phosphorylation in resting cells at the dose required for cell death induction. Inhibition of Cdk7 or Cdk9 by Compound 1 was also confirmed by suppression of nuclear factor-kappa B (NF-κB)-dependent transcription activity in the human cancer cell line U2OS. Interestingly, a Cdk4/6 inhibitor with selectivity against Cdk7 and Cdk9 did not induce cell death in resting lymphocytes. These results suggest that CTD phosphorylation possibly by Cdk7 or Cdk9 might be important for survival of resting lymphocytes and that Cdk inhibitors without inhibitory activity on these kinases might be an attractive agent for cancer chemotherapy.

Potent anti-tumor activity of a macrocycle-quinoxalinone class pan-Cdk inhibitor in vitro and in vivo.

Deregulation of cell-cycle control is a hallmark of cancer. Thus, cyclin-dependent kinases (Cdks) are an attractive target for the development of anti-cancer drugs. Here, we report the biological characterization of a highly potent pan-Cdk inhibitor with a macrocycle-quinoxalinone structure. Compound M inhibited Cdk1, 2, 4, 5, 6, and 9 with equal potency in the nM range and was selective against kinases other than Cdks. This compound inhibited multiple events in the cell cycle in vitro, including retinoblastoma protein (pRb) phosphorylation, E2F-dependent transcription, DNA replication (determined by bromodeoxyuridine incorporation), and mitosis completion (assayed by flow cytometry) in the 10 nM range. Moreover, this compound induced cell death, as determined by induction of the subG1 fraction, activated caspase-3, and anexin V. In vivo, Compound M showed anti-tumor efficacy at a tolerated dose. In a nude rat xenograft tumor model, an 8-h constant infusion of Compound M inhibited pRb phosphorylation and induced apoptosis in tumor cells at ~ 30 nM, which led to the inhibition of tumor growth. Immunosuppression was the only liability observed at this dose, but immune function returned to normal after 10 days. Suppression of pRb phosphorylation in tumor cells was clearly correlated with tumor cell growth inhibition and cell death in vitro and in vivo. In vivo, Compound M inhibited pRb phosphorylation in both tumor and gut crypt cells. Rb phosphorylation may be a suitable pharmacodynamic biomarker in both tumors and normal tissues for monitoring target engagement and predicting the efficacy of Compound M.

Cohort profile: the ages 2003 cohort study in Aichi, Japan.

BACKGROUND: The longevity of Japanese is thought to be associated with psychosocial factors such as sense of coherence, social support, and social capital. However, the actual factors responsible and the extent of their contribution to individual health status are not known. METHODS: The Aichi Gerontological Evaluation Study (AGES) 2003 Cohort Study is a prospective cohort study of community-dwelling, activities of daily living-independent people aged 65 or older living in 6 municipalities in Chita peninsula, Aichi Prefecture, Japan. Information on psychosocial factors and other individual- and community-level factors was collected in the second half of 2003 using a baseline questionnaire. Vital status and physical and cognitive decline have been followed using data derived from long-term care insurance certification. Geographical information on the study participants was also obtained. RESULTS: A total of 13 310 (6508 men; 6802 women) study participants were registered in the study. For an interim report, we followed the cohort for 48 months, yielding 24 753 person-years of observation among men and 26 456 person-years among women. CONCLUSIONS: The AGES 2003 Cohort Study provides useful evidence for research in social epidemiology, gerontology, and health services.

Neighborhood food environment and body mass index among Japanese older adults: results from the Aichi Gerontological Evaluation Study (AGES).

BACKGROUND: The majority of studies of the local food environment in relation to obesity risk have been conducted in the US, UK, and Australia. The evidence remains limited to western societies. The aim of this paper is to examine the association of local food environment to body mass index (BMI) in a study of older Japanese individuals. METHODS: The analysis was based on 12,595 respondents from cross-sectional data of the Aichi Gerontological Evaluation Study (AGES), conducted in 2006 and 2007. Using Geographic Information Systems (GIS), we mapped respondents' access to supermarkets, convenience stores, and fast food outlets, based on a street network (both the distance to the nearest stores and the number of stores within 500 m of the respondents' home). Multiple linear regression and logistic regression analyses were performed to examine the association between food environment and BMI. RESULTS: In contrast to previous reports, we found that better access to supermarkets was related to higher BMI. Better access to fast food outlets or convenience stores was also associated with higher BMI, but only among those living alone. The logistic regression analysis, using categorized BMI, showed that the access to supermarkets was only related to being overweight or obese, but not related to being underweight. CONCLUSIONS: Our findings provide mixed support for the types of food environment measures previously used in western settings. Importantly, our results suggest the need to develop culture-specific approaches to characterizing neighborhood contexts when hypotheses are extrapolated across national borders.

Neighborhood built environment and physical activity of Japanese older adults: results from the Aichi Gerontological Evaluation Study (AGES).

BACKGROUND: Although many studies have reported the association between neighborhood built environment (BE) and physical activity (PA), less is known about the associations for older populations or in countries besides the US and Australia. The aim of this paper is to examine the associations for older adult populations in Japan. METHODS: Our analyses were based on cross-sectional data from the Aichi Gerontological Evaluation Study (AGES), conducted in 2003. The respondents were older adults, aged 65 years or over (n = 9,414), from 8 municipalities across urban, suburban, and rural areas. The frequency of leisure time sports activity and total walking time were used as the outcome variables. Using geographic information systems (GIS), we measured residential density, street connectivity, number of local destinations, access to recreational spaces, and land slope of the respondents' neighborhoods, based on network distances with multiple radii (250 m, 500 m, 1,000 m). An ordinal logistic regression model was used to analyze the association between PA and BE measures. RESULTS: Population density and presence of parks or green spaces had positive associations with the frequency of sports activity, regardless of the selected buffer zone. The analysis of total walking time, however, showed only a few associations. CONCLUSIONS: Our findings provide mixed support for the association between PA and the characteristics of BE measures, previously used in Western settings. Some characteristics of the neighborhood built environment may facilitate leisure time sports activity, but not increase the total walking time for Japanese older adults.

Assessing the association between all-cause mortality and multiple aspects of individual social capital among the older Japanese.

BACKGROUND: Few prospective cohort studies have assessed the association between social capital and mortality. The studies were conducted only in Western countries and did not use the same social capital indicators. The present prospective cohort study aimed to examine the relationships between various forms of individual social capital and all-cause mortality in Japan. METHODS: Self-administered questionnaires were mailed to subjects in the Aichi Gerontological Evaluation Study (AGES) Project in 2003. Mortality data from 2003 to 2008 were analyzed for 14,668 respondents. Both cognitive and structural components of individual social capital were collected: 8 for cognitive social capital (trust, 3; social support, 3; reciprocity, 2) and 9 for structural social capital (social network). Cox proportional hazard models stratified by sex with multiple imputation were used. Age, body mass index, self-rated health, current illness, smoking history, alcohol consumption, exercise, equivalent income and education were used as covariates. RESULTS: During 27,571 person-years of follow-up for men and 29,561 person-years of follow-up for women, 790 deaths in men and 424 in women were observed. In the univariate analyses for men, lower social capital was significantly related to higher mortality in one general trust variable, all generalised reciprocity variables and four social network variables. For women, lower social capital was significantly related to higher mortality in all generalised reciprocity and four social network variables. After adjusting for covariates, lower friendship network was significantly associated with higher all-cause mortality among men (meet friends rarely; HR = 1.30, 95%CI = 1.10-1.53) and women (having no friends; HR = 1.81, 95%CI = 1.02-3.23). Among women, lower general trust was significantly related to lower mortality (most people cannot be trusted; HR = 0.65, 95%CI = 0.45-0.96). CONCLUSIONS: Friendship network was a good predictor for all-cause mortality among older Japanese. In contrast, mistrust was associated with lower mortality among women. Studies with social capital indices considering different culture backgrounds are needed.

Physical Activity and Cumulative Long-Term Care Cost among Older Japanese Adults: A Prospective Study in JAGES.

This study aimed to determine the impact of physical activity on the cumulative cost of long-term care insurance (LTCI) services in a cohort of community-dwelling people (65 years and older) in Japan. Using cohort data from the Japan Gerontological Evaluation Study (JAGES) on those who were functionally independent as of 2010/11, we examined differences in the cumulative cost of LTCI services by physical activity. We followed 38,875 participants with LTCI service costs for 59 months. Physical activity was assessed by the frequency of going out and time spent walking. We adopted a generalized linear model with gamma distribution and log-link function, and a classical linear regression with multiple imputation. The cumulative LTCI costs significantly decreased with the frequency of going out and the time spent walking after adjustment for baseline covariates. LTCI's cumulative cost for those who went out once a week or less was USD 600 higher than those who went out almost daily. Furthermore, costs for those who walked for less than 30 min were USD 900 higher than those who walked for more than 60 min. Physical activity among older individuals can reduce LTCI costs, which could provide a rationale for expenditure intervention programs that promote physical activity.

Expression levels of NF-Y target genes changed by CDKN1B correlate with clinical prognosis in multiple cancers.

CDK inhibitors CDKN1B (p27) and CDKN2A (p16) inhibit cell cycle progression. A lower expression level of only p27 has been correlated with poorer prognosis in various types of clinical cancers. The difference may be the result of distinct genes downstream of these CDK inhibitors. Here, we report that NF-Y transcription factor-targeted genes specifically down-regulated by p27 correlate with poor prognosis in multiple tumor types. We performed mRNA expression profiling in HCT116 cells over-expressing either p16 or p27 and identified their regulatory genes. In silico transcription factor prediction indicated that most of the genes specifically down-regulated by p27 are controlled by NF-Y. Under the hypothesis that NF-Y-targeted genes are responsible for poor prognosis, we predicted prognosis in four types of cancer based on genes with the NF-Y motif, and found a significant association between the expression of NF-Y-targeted genes and poor prognosis.