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Internal tandem duplication (ITD) mutation in Fms-like tyrosine kinase 3 gene (FLT3/ITD) represents an unfavorable genetic change in acute myeloid leukemia (AML) and is associated with poor prognosis. Metabolic alterations have been involved in tumor progression and attracted interest as a target for therapeutic intervention. However, few studies analyzed the adaptations of cellular metabolism in the context of FLT3/ITD mutation. Here, we report that FLT3/ITD causes a significant increase in aerobic glycolysis through AKT-mediated upregulation of mitochondrial hexokinase (HK2), and renders the leukemia cells highly dependent on glycolysis and sensitive to pharmacological inhibition of glycolytic activity. Inhibition of glycolysis preferentially causes severe ATP depletion and massive cell death in FLT3/ITD leukemia cells. Glycolytic inhibitors significantly enhances the cytotoxicity induced by FLT3 tyrosine kinase inhibitor sorafenib. Importantly, such combination provides substantial therapeutic benefit in a murine model bearing FLT3/ITD leukemia. Our study suggests that FLT3/ITD mutation promotes Warburg effect, and such metabolic alteration can be exploited to develop effective therapeutic strategy for treatment of AML with FLT3/ITD mutation via metabolic intervention.

Our aim was to explore the patterns of intrinsic capacity (IC) impairments among community-dwelling older adults and the associations of these different patterns with excessive polypharmacy, potentially inappropriate medications, and adverse drug reactions in a nationwide population-based study. A cross-sectional study included older adults from the Taiwan Integrated Care for Older People (ICOPE) program in 2020. The study subjects comprised 38,308 adults aged 65 years and older who participated in the ICOPE Step 1 screening and assessed six domains of IC following the World Health Organization (WHO) ICOPE approach. Latent class analysis was adopted to identify distinct subgroups with different IC impairments patterns. The associations between different IC impairments patterns and unfavorable medication utilization, including excess polypharmacy (EPP), potentially inappropriate medications (PIMs), and adverse drug reactions (ADRs), were assessed by multivariate logistic regression models. Latent class analysis identified five distinct subgroups with different IC impairment patterns: robust (latent class prevalence: 59.4%), visual impairment (17.7%), physio-cognitive decline (PCD) with sensory impairment (12.3%), depression with cognitive impairment (7.7%), and impairments in all domains (2.9%). Compared to the robust group, all other groups were at higher odds for unfavorable medication utilization. The “depression with cognitive impairment” group (EPP: aOR=4.35, 95% CI 3.52–5.39, p<0.01; PIMs: aOR=2.73, 95% CI 2.46–3.02, p<0.01) and the “impairment in all domains” group (EPP: aOR=9.02, 95% CI 7.16–11.37, p<0.01; PIMs: aOR=3.75, 95% CI 3.24–4.34, p<0.01) remained at higher odds for EPP and PIMs after adjustment. We identified five distinct impairment patterns of IC, and each impairment pattern, particularly the “depression with cognitive impairment” and “impairment in all domains”, was associated with higher odds of EPP and PIMs. Further longitudinal and intervention studies are needed to explore long-term outcomes of different impairment pattern and their reversibility.

AbstractObjectiveThe intricate relationship between social determinants, e.g., social frailty, biomarkers and healthy aging remains largely unexplored, despite the potential for social frailty to impact both intrinsic capacity (IC) and functional ability in the aging process. DesignRetrospective longitudinal cohort study. Setting and ParticipantsParticipants aged 50+ years from the Social Environment and Biomarkers of Aging Study (SEBAS) in Taiwan, stratified into three age groups: 50–64, 65–74 and 75+. MeasurementsSocial frailty was defined based on a score derived from four domains: exclusion from general resources, social resources, social activity, and fulfillment of basic social needs. The scores were categorized as score=0 (no social frailty), 1 (social pre-frailty), and 2+ (social frailty). Multivariable logistic regression and Cox proportional hazard models were employed to examine the dose-responsive relationship between social frailty, low IC, functional and psychological health, and mortality. ResultsOf 1015 study participants, 24.9% and 7.9% were classified as social pre-frailty and social frailty, respectively. No significant differences were observed in most biomarkers between those with social frailty and those without. A dose-responsive relationship was found between social frailty and increased risk of low IC (social pre-frailty: aOR 2.20 [95% CI 1.59–3.04]; social frailty: 5.73 [3.39–9.69]). Similar results were found for functional and psychological health. However, no significant association between social frailty and all-cause mortality was found at the 4-year follow-up (social pre-frailty: aHR 1.52 [95% CI 0.94–2.43]; social frailty: 1.59 [0.81–3.09]). ConclusionsThe significant association between social frailty and low IC, functional limitations, cognitive declines, and depressive symptoms underscores the pressing need for research on intervention strategies to enhance healthy aging in the lifespan course.

Fatigue negatively impacts health outcomes but its association with physical function across the adulthood remains unclear. This study described self-reported fatigue levels across age and sex categories, investigated the associations between fatigue and physical functions, and examined whether age and sex moderated their associations. Cross-sectional design. Community. Nine hundred sixteen participants aged 20–100 years in the observational INSPIRE-T cohort study. Participants were classified into four age categories. Fatigue was assessed using the Patient-Reported Outcomes Measurement Information System (Short Form v1.0 – Fatigue 8a) and physical function was assessed by handgrip strength (HGS, Kg), usual gait speed (UGS, m/s), both 5-repetition (5CR, s) and 30-sec chair rise tests (30sCR, times), isokinetic knee extension strength (IKES, N m), and maximum oxygen consumption (V̇O2 max, ml/kg/min). Multiple linear regressions were performed to examine the associations between fatigue and the physical function outcomes (all square-root-transformed). Interactions of fatigue with age and sex were considered. Fatigue levels were the highest in people 75+ years. Women had a higher fatigue level than men. Fatigue was significantly associated with decreasing performance in UGS, HGS, 5CR, and 30sCR but not in IKES and V̇O2 max. Interaction analyses revealed that fatigue was associated with reduced UGS as people age (Fatigue × age: B = −0.002, 95% confidence interval = −0.003, −0.001). Sex did not moderate the association between fatigue and physical function. Our study indicated that fatigue was negatively associated with several components of physical function. Although sex did not moderate the relationship between fatigue and physical function, the association between fatigue and low UGS was more pronounced with increasing age.

Frailty may in most cases result from two main causes: the aging process (age-related frailty) and diseases (evolving chronic conditions or acute medical illnesses — disease-related frailty). The biological determinants characterizing these two main causes of frailty may be different. The aim of this study is to compare the biological and neuroimaging profile of people without frailty, those with age-related frailty, and subjects with disease-related frailty in community-dwelling older adults. We performed a secondary, cross-sectional analysis from the Multidomain Alzheimer Preventive Trial (MAPT). We included 1199 subjects without frailty throughout the 5-year follow-up, 82 subjects with incident age-related frailty, and 53 with incident disease-related frailty. Available blood biomarkers involved nutritional (eg, vitamin D, omega-3 fatty acids), inflammatory-related (IL-6, TNFR1, GDF15), neurodegenerative (eg, beta-amyloid, neurofilament light chain) and neuroimaging markers (MRI, Amyloid-PET). Although not statistically significant, the results of the unadjusted model showed increasing gradients for inflammatory markers (GDF15, TNFR1) and decreasing gradients for nutritional and neuroimaging markers (omega 3 index, hippocampal volume) from age-related frailty participants to individuals with disease-related frailty. Considering the linear models we observed higher GDF15 values in disease-related frailty group compared to age-related frailty individuals [β = 242.8 (49.5, 436.2)]. We did not find any significant difference between subjects without frailty and those with age-related frailty. Subjects with disease-related frailty compared to subjects without frailty had lower values of DHA [β = −2.42 (−4.76, −0.08)], Omega 3 Index [β = −0.50 (−0.95, −0.06)] and hippocampal volume [β = −0.22 (−0.42,−0.02)]. They also had higher values of GDF15 [β = 246.1 (88.9, 403.4)] and TNFR1 [β = 157.5 (7.8, 307.2)]. Age-related frailty and disease-related frailty may represent different degrees of frailty severity on a biological level. Further research is needed to identify biomarkers potentially able to distinguish these classifications of frailty.

Intrinsic capacity (IC), defined by the World Health Organization's Integrated Care for Older People (ICOPE) framework, is crucial for promoting healthy aging. Understanding the associations between IC impairments and age-related biomarkers can provide insights into the underlying pathophysiological mechanisms and potential interventions. To investigate the associations between IC impairments (ICOPE step 1 and step 2, respectively) and aging-related biomarkers, including inflammatory and cardiometabolic markers, in community-dwelling middle-aged and older adults. Cross-sectional analysis of data from 755 participants (aged 50–64 years, n=212; 65–74 years, n=357; ≥75 years, n=186) enrolled in the Gan-Dau Healthy Longevity Plan, a community-based survey in Taipei City, Taiwan, from 2022. IC impairments assessed by ICOPE Step 1 (screening) and Step 2 (in-depth assessment) across six domains: locomotion, vitality, vision, hearing, cognition, and psychological well-being. Levels of inflammatory biomarkers (albumin, white blood cell count, neutrophils, lymphocytes, monocytes, neutrophil-to-lymphocyte ratio [NLR], lymphocyte-to-monocyte ratio [LMR], platelet-to-lymphocyte ratio [PLR]) and cardiometabolic biomarkers (low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], total cholesterol, fasting glucose, triglycerides, triglyceride-glucose [TyG] index). Of the 755 participants, the mean age was 68.5 years, and 68.2% were women. The proportion of participants with any IC impairment increased with age: 63.2% for those aged 50–64, 65.8% for those aged 65–74, and 74.7% for those aged ≥75 years based on ICOPE Step 1. For ICOPE Step 2, the proportions were 59.9%, 56.9%, and 64.0%, respectively. Impairments in locomotion and cognition were significantly higher in the oldest age group (≥75 years). Adjusted for covariates, IC impairment (ICOPE Step 2) was associated with higher levels of neutrophil count (β = 3.17, p = 0.015) and NLR (β = 0.34, p = 0.021) in those aged 50–64 years, and higher levels of monocyte count in those aged 65–74 years (β = 0.65, p = 0.001) and ≥75 years (β = 0.68, p = 0.037). In conclusion, IC impairments were associated with alterations in specific inflammatory biomarkers, suggesting potential interactions between IC, age, and inflammatory processes. Longitudinal studies are warranted to establish causal relationships and elucidate the underlying mechanisms linking IC impairments, immune dysregulation, and the aging process.

Electrowetting has recently been explored as a mechanism for moving small amounts of fluids in confined spaces. We propose a diffuse-interface model for drop motion, due to electrowetting, in a Hele-Shaw geometry. In the limit of small interface thickness, asymptotic analysis shows that the model is equivalent to Hele-Shaw flow with a voltage-modified Young–Laplace boundary condition on the free surface. We show that details of the contact angle significantly affect the time scale of motion in the model. We measure receding and advancing contact angles in the experiments and derive their influence through a reduced-order model. These measurements suggest a range of time scales in the Hele-Shaw model which include those observed in the experiment. The shape dynamics and topology changes in the model agree well with the experiment, down to the length scale of the diffuse-interface thickness.

The impact of the column number of ellipsoidal dimples on a highly-loaded compressor cascade (NACA65-K48) under design conditions was investigated by using a numerical simulation method. Ellipsoidal dimples with a thickness of 0.2 mm were located at the position of chord length ranging from 10% to 36%. The span-wise interval was 5.0 mm. The performance and flow field structures of cascades with 1 to 5 ellipsoidal dimpled columns were compared, and the results showed that the turbulent kinetic energy intensity near the wall was enhanced and the fluid separation resistance was consequently improved. The total pressure loss was reduced by all modified ellipsoidal dimples. In addition, the separation bubble of the suction side was broken or weakened, the corner separation was improved, and the influence range of the passage vortex was reduced. Moreover, the improvement effect of cascade performance parameters initially increased with the increase in the number of dimple columns and then reduced as the number of columns was further increased. The reductions in the total pressure loss of the cascade were 0.59%, 1.47%, 1.69%, 1.91%, and 1.73% for column numbers 1 to 5, respectively.

An inexact two-stage fuzzy-stochastic programming (ITFSP) method is developed for water resources management under uncertainty. Fuzzy sets theory is introduced to represent various punishment policies under different water availability conditions. As an extension of conventional two-stage stochastic programming (TSP) method, two special characteristics of the proposed approach make it unique compared with existing approaches. One is it could handle flexible penalty rates, which are much reasonable for both of the authorities and users, and have seldom been considered in the TSP framework. The other is uncertain information expressed as discrete intervals and probability distribution functions can be effectively reflected in the optimization processes and solutions. After formulating the model, a hypothetical case is employed for demonstrating its applicability under two scenarios, where the inflow is divided into four and eight intervals, respectively. The results indicate that reasonable solutions have been obtained. They provide desired allocation patterns with maximized system benefit under two feasibility levels. The solutions present as stable intervals with different risk levels in violating the water demands, and can be used for generating decision alternatives. Comparisons of the solution from the ITFSP with that from the ITSP (inexact two-stage stochastic programming) and TSP approach are also undertaken. It shows that the ITFSP could produce more system benefit than existing methods and deal with flexible penalty policies for better water management and utilization.

As a theoretical basis for improvement of Eucalyptus urophylla in China, the genetic diversity and structure for advanced generation breeding populations were evaluated, and the changes of genetic diversity between improved generation and their parental generation were compared. The genotyping was performed on families sampled from advanced generation with 16 neutral microsatellite loci. The testing of Hardy-Weinberg equilibrium showed significant heterozygote deficits in two improved generation breeding populations. The expected heterozygosity of the 3rd generation was very close to that of the 2nd generation breeding population, indicating no heterozygosity had been lost, and the genetic diversity was consistent in two improved populations supported by Shannon’s information index. Wright’s fixed index of two advanced generations also indicated significant heterozygote in advanced generation breeding populations, compared with their parental generation. Most of the molecular variation was explained by the source of the families, both in two advanced generations, using analysis of molecular variances (AMOVA). The advanced generation breeding population of E. urophylla had a high level of genetic diversity after heavy artificial selection, consistently, and with no significant difference among generations.