Examination of the relationship between participation in salons aimed at care prevention through the promotion of social participation and the subsequent cost of care: A 3-year prospective follow-up study in JAGES.

Many previous studies have found that social participation improves the health and functional maintenance of older people. However, to determine whether promoting social participation can prevent functional decline in the elderly, it is necessary not only to compare the prognosis of those who participate in social activities to those who do not but also to demonstrate that the intervention was effective in promoting social participation. Although the effect of social participation in preventing caregiving has been demonstrated, the key question is whether preventing functional decline through social participation can reduce care costs.

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.

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.

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 (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 ). Compound inhibited all four families of FGFRs in the single-digit nanomolar range and showed high selectivity for over 387 kinases.

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.

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.

[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.

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.

TAS-119, a novel selective Aurora A and TRK inhibitor, exhibits antitumor efficacy in preclinical models with deregulated activation of the Myc, β-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 IC value of 1.

A first-in-human phase 1 and pharmacological study of TAS-119, a novel selective Aurora A kinase inhibitor in patients with advanced solid tumours.

Background: This is a first-in-human study with TAS-119, an Aurora A kinase (AurA) inhibitor.

Methods: Patients with advanced, refractory, solid tumours were enrolled into 5 dose escalation cohorts (70-300 mg BID, 4 days on/3 days off, 3 out of 4 weeks or 4 out of 4 weeks). The expansion part consisted of patients with small-cell lung cancer, HER2-negative breast cancer, MYC-amplified/β-catenin-mutated (MT) tumours or other (basket cohort).

Futibatinib Is a Novel Irreversible FGFR 1-4 Inhibitor That Shows Selective Antitumor Activity against FGFR-Deregulated Tumors.

FGFR signaling is deregulated in many human cancers, and FGFR is considered a valid target in FGFR-deregulated tumors. Here, we examine the preclinical profile of futibatinib (TAS-120; 1-[(3S)-[4-amino-3-[(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3, 4-d] pyrimidin-1-yl]-1-pyrrolidinyl]-2-propen-1-one), a structurally novel, irreversible FGFR1-4 inhibitor. Among a panel of 296 human kinases, futibatinib selectively inhibited FGFR1-4 with IC values of 1.

Aurora A Inhibitor TAS-119 Enhances Antitumor Efficacy of Taxanes and : Preclinical Studies as Guidance for Clinical Development and Trial Design.

TAS-119 is a novel orally active, selective inhibitor of Aurora kinase A identified as a clinical candidate for efficacy testing in combination with taxanes. , TAS-119 enhanced cell growth inhibition of paclitaxel in multiple human cancer cell lines derived from various tissues, including paclitaxel-resistant cell lines. Interestingly, TAS-119 did not enhance paclitaxel antitumor activity in normal lung diploid fibroblast cell lines WI-38 and MRC5.

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.

TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion-Positive Intrahepatic Cholangiocarcinoma.

ATP-competitive fibroblast growth factor receptor (FGFR) kinase inhibitors, including BGJ398 and Debio 1347, show antitumor activity in patients with intrahepatic cholangiocarcinoma (ICC) harboring activating gene fusions. Unfortunately, acquired resistance develops and is often associated with the emergence of secondary kinase domain mutations. Here, we report that the irreversible pan-FGFR inhibitor TAS-120 demonstrated efficacy in 4 patients with 2 fusion-positive ICC who developed resistance to BGJ398 or Debio 1347.

Giving social support to outside family may be a desirable buffer against depressive symptoms in community-dwelling older adults: Japan gerontological evaluation study.

Background: Depression is the leading cause of impaired quality of life and burden upon societies. Social supports can buffer against depressive symptoms effectively. The aim of this study is to determine the type of social support to have a positive relationship with depressive symptoms in healthy population.

Evaluating Chemical CDK Inhibitors as Cell Death Inducers.

The cell cycle of eukaryotic cells is regulated by a family of protein kinases called cyclin-dependent kinases (Cdks). We have reported the identification and biological characterization of a highly potent, small-molecule pan-Cdk inhibitor, which inhibited Cdk1, 2, 4, 5, 6, and 9 with equal potency in the nM range. This compound inhibited multiple events in the cell cycle and induced cell death in human cancer cell lines as well as in peripheral blood or purified resting lymphocytes ex vivo.

[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.

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.

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.

Social participation and the prevention of functional disability in older Japanese: the JAGES cohort study.

Background: We examined the relationship between incident functional disability and social participation from the perspective of number of types of organizations participated in and type of social participation in a prospective cohort study.

Method: The study was based on the Aichi Gerontological Evaluation Study (AGES) Cohort Study data. We followed 13,310 individuals aged 65 years or older for 4 years.

Does social participation improve self-rated health in the older population? A quasi-experimental intervention study.

Social participation has been linked to healthy aging and the maintenance of functional independence in older individuals. However, causality remains tenuous because of the strong possibility of reverse causation (healthy individuals selectively participate in social activities). We describe a quasi-experimental intervention in one municipality of Japan designed to boost social participation as a way of preventing long-term disability in senior citizens through the creation of 'salons' (or community centers).

Participation in sports organizations and the prevention of functional disability in older Japanese: the AGES Cohort Study.

Background: We sought to examine prospectively the difference in the association between incident functional disability and exercise with or without sports organization participation.

Methods: The study was based on the Aichi Gerontological Evaluation Study (AGES) Cohort Study data. In October 2003, self-reported questionnaires were mailed to 29,374 non-disabled Japanese individuals aged 65 years or older.

Social Determinants of Active Aging: Differences in Mortality and the Loss of Healthy Life between Different Income Levels among Older Japanese in the AGES Cohort Study.

We examined the relationship between income, mortality, and loss of years of healthy life in a sample of older persons in Japan. We analyzed 22,829 persons aged 65 or older who were functionally independent at baseline as a part of the Aichi Gerontological Evaluation Study (AGES). Two outcome measures were adopted, mortality and loss of healthy life.