The relationship between clinicopathological features and long-term benefit to trastuzumab-based therapy was evaluated in 164 HER2-positive metastatic breast cancer patients. Treatment duration was associated with hormone receptor status and use of adjuvant trastuzumab; however, with low predictive value. With growing availability of targeted treatments for HER2-positive disease, a major clinical priority is identifying molecular predictors of benefit of anti-HER2 therapies.
The magnitude of benefit of trastuzumab for the treatment of advanced HER2-positive breast cancer varies widely. In this retrospective study, we investigated the clinicopathological features associated with prolonged first-line trastuzumab-based treatment duration.
Patients and Methods
A total of 164 patients diagnosed with advanced HER2-positive breast cancer and treated with first-line trastuzumab-based therapy from 1999 to 2009 were identified. Duration of treatment was classified according to tertiles. Different logistic regression models including age, disease-free interval, number of metastatic sites, visceral disease, hormone receptor, and adjuvant trastuzumab were fitted to investigate associations with benefit of prolonged trastuzumab-based therapies. The predictive value of each model was assessed using C-statistics.
At a median follow-up of 5.8 years (range, 0.7-22.1 years), patients in the short-, intermediate-, and long-term treatment duration groups were given first-line trastuzumab-based therapy for < 7.2 months, 7.2 to 14 months, and > 14 months, respectively. In the multivariate analysis, patients with long-term clinical benefit had a higher likelihood of having hormone receptor-positive tumors (odds ratio [OR]positive vs. negative = 2.39 [95% confidence interval (CI), 1.08-5.31]; P = .032); and a lower likelihood of having received adjuvant trastuzumab (ORadjuvant trastuzumab vs. no adjuvant trastuzumab = 0.30 [95% CI, 0.10-0.96]; P = .043]. C-statistics varied between 0.634 and 0.699.
Long-term benefit of trastuzumab-based therapy is associated with hormone receptor positivity and the absence of previous adjuvant trastuzumab. Nevertheless, clinicopathological features had a low predictive value for prolonged treatment duration. The validation of the current findings and the identification of molecular features associated the magnitude of trastuzumab benefit should be encouraged.
HER2-positive; Outcomes; Treatment Duration
The criteria one uses to reduce accelerometer data can profoundly influence the interpretation of research outcomes. The purpose of this study was to examine the influence of three different interruption periods (i.e., 20, 30, and 60 minutes) on the amount of data retained for analyses and estimates of sedentary time among older adults. Older adults (N=311; Mage=71.1) wore an accelerometer for seven days and reported wear time on an accelerometer log. Accelerometer data were downloaded and scored using 20, 30, and 60-minute interruption periods. Estimates of wear time derived using each interruption period were compared to self-reported wear time, and descriptive statistics were used to compare estimates of sedentary time. Results showed a longer interruption period (i.e., 60 minutes) yields the largest sample size and the closest approximation of self-reported wear time. A short interruption period (i.e., 20 minutes) is likely to underestimate sedentary time among older adults.
The False Hope Syndrome suggests that unrealistic expectations of dieting and weight loss are key constructs in the prediction of behavioral failure and may exacerbate weight cycling. The objective of this study was to determine cross-sectional associations among dieting and thinness expectations and weight cycling history within the framework of the False Hope Syndrome.
Participants were middle-aged (45±12 years) women (n=116) and men (n=98) recruited via worksite intranet distributions. Information on dieting and thinness expectations, weight loss attempts, and weight cycling history was gathered using standard questionnaires.
More women than men reported currently dieting (43% vs. 26%; p<0.01). Moderate [OR=2.54; 95%CI: 1.01–6.45] and higher [OR=2.70; 95%CI: 1.07–6.80] levels of the thinness expectation score were significantly associated with the greater odds of weight cycling, independent of age, sex, BMI, and weight loss attempts.
These data are the first to extend the pervasive and potent influence of thinness expectancy to middle-aged persons and in particular, to men.
Weight cycling; False hope syndrome; Thinness expectations
The area of HER2-positive breast cancer is a rapidly changing field. The use of the humanized monoclonal antibody, trastuzumab, significantly improved the prognosis for patients with HER2-positive breast cancer, however, increasing knowledge regarding mechanisms of resistance to trastuzumab have come to light, prompting research into additional methods to target the HER2 protein. The purpose of this article is to discuss evidence for why continued blockade of the HER2 pathway continues to be important despite progression on trastuzumab, as well as to review additional HER2-targeted therapies and progression in the central nervous system. With the availability of new drugs comes the need to determine the appropriate therapeutic combinations and optimal order in which to deliver these therapies. This review summarizes the practice-changing phase III trials and some supporting phase II data regarding the various targeted HER2 therapies available for patients with advanced HER2-positive breast cancer, proposes order for anti-HER2 therapy in the advanced HER2-positive breast cancer patient, and includes information on future strategies. While other reviews on HER2-targeted therapy are available, this review specifically aims at addressing treatment options after trastuzumab failure in the patient with advanced HER2-positive breast cancer.
Trastuzumab; HER2 therapies; Phase III trials
The current study examined how a randomized one-year aerobic exercise program for healthy older adults would affect serum levels of brain-derived neurotrophic factor (BDNF), insulin-like growth factor type 1 (IGF-1), and vascular endothelial growth factor (VEGF) - putative markers of exercise-induced benefits on brain function. The study also examined whether (a) change in the concentration of these growth factors was associated with alterations in functional connectivity following exercise, and (b) the extent to which pre-intervention growth factor levels were associated with training-related changes in functional connectivity. In 65 participants (mean age = 66.4), we found that although there were no group-level changes in growth factors as a function of the intervention, increased temporal lobe connectivity between the bilateral parahippocampus and the bilateral middle temporal gyrus was associated with increased BDNF, IGF-1, and VEGF for an aerobic walking group but not for a non-aerobic control group, and greater pre-intervention VEGF was associated with greater training-related increases in this functional connection. Results are consistent with animal models of exercise and the brain, but are the first to show in humans that exercise-induced increases in temporal lobe functional connectivity are associated with changes in growth factors and may be augmented by greater baseline VEGF.
exercise; aging; functional connectivity; fMRI; default mode network; aerobic fitness; growth factors
Parents of children with autism spectrum disorders (ASDs) are at risk for higher stress levels than parents of children with other developmental disabilities and typical development. Recent advances in early diagnosis have resulted in younger children being diagnosed with ASDs but factors associated with parent stress in this age group are not well understood.
The present study examined parenting-related stress and psychological distress in mothers of toddlers with ASD, developmental delay without ASD (DD), and typical development. The impact of child problem behavior and daily living skills on parenting-stress and psychological distress were further investigated.
Participants were part of a larger research study on early ASD intervention. Parent self-report of parenting-related stress and psychological distress was utilized.
Parents of toddlers with ASD demonstrated increased parenting-related stress compared with parents of toddlers with DD and typical development. However, psychological distress did not differ significantly between the groups. Child behavior problems, but not daily living skills emerged as a significant predictor of parenting-related stress and psychological distress. This was true for both mothers of children with ASD and DD.
These finding suggest that parents’ abilities to manage and reduce behavior problems is a critical target for interventions for young children with ASD and DD in order to improve child functioning and decrease parenting-related stress.
Autism Spectrum Disorder; parents; distress; toddlers; parenting-stress
Attenuating the physical decline and increases in disability associated with the aging process is an important public health priority. Evidence suggests that regular physical activity participation improves functional performance, such as walking, standing balance, flexibility, and getting up out of a chair, and also plays an important role in the disablement process by providing a protective effect against functional limitations. Whether these effects are direct or indirect has yet to be reliably established. In this review, the authors take the perspective that such relationships are indirect and operate through self-efficacy expectations. They first provide an introduction to social cognitive theory followed by an overview of self-efficacy's reciprocal relationship with physical activity. They then consider the literature that documents the effects of physical activity on functional performance and functional limitations in older adults and the extent to which self-efficacy might mediate these relationships. Furthermore, they also present evidence that suggests that self-efficacy plays a pivotal role in a model in which the protective effects conferred by physical activity on functional limitations operate through functional performance. The article concludes with a brief section making recommendations for the development of strategies within physical activity and rehabilitative programs for maximizing the major sources of efficacy information.
physical activity; aging; self-efficacy; function; limitations; social cognitive theory
Intubation is a risk factor for nosocomial sinusitis in adult intensive care patients. Sinusitis in intubated adults can be an occult cause of fever. In children nasal intubation may be associated with a greater risk of sinusitis. No pediatric study has determined the incidence of nosocomial sinusitis in the pediatric intensive care unit (PICU) setting. We hypothesized that within a subset of patients who had head CT imaging: (1) the incidence of sinusitis in PICU patients exceeds the incidence in non-PICU patients; (2) the incidence of sinusitis is greater in PICU patients with a tube (nasotracheal, nasogastric, orotracheal, or orogastric); and (3) nasal tubes confer an increased risk for sinusitis compared to oral tubes.
Retrospective chart review
Independent not-for-profit pediatric healthcare system
PICU and non-PICU (inpatients hospitalized on medical-surgical wards) patients referred for head CT
Measurements and Main Results
CT images were evaluated for the presence of a tube and sinusitis. Images were scored using the Lund-MacKay (LM) staging system. Sinusitis was defined as a LM score >3.5. 596 patients were studied; 395 (66.3%) PICU. 197 (50%) PICU versus 69 (34.3%) non-PICU patients had sinusitis (p <0.001). 108/147 (73.5%) PICU patients with a tube present had sinusitis versus 88/248 (35.9%) of those without a tube present (p <0.001). There was no significant difference in sinusitis based on tube location (p=0.218). Younger age or the presence of a tube increased the probability of sinusitis (p <0.001).
Almost 50% of our PICU patients imaged for reasons other than evaluation for sinus disease had evidence of sinusitis. This finding raises the concern that sinusitis in PICU patients is common and likely should be considered in the differential diagnosis of fever in PICU patients.
Sinusitis; PICU; Lund-Mackay; endotracheal tube; nasotracheal tube
The purpose of this study was to determine a profile for predicting attrition among older adults involved in a 12-month exercise program.
The parent study was a single-blinded randomized controlled trial. The study took place between 2006 and 2009 within a university setting. Older adults (N = 179) completed baseline assessments of functional performance and psychosocial measures. Participants who relinquished their consent to participate were considered “dropouts” and those remaining were classified as “completers.”
A discriminant function analysis differentiated dropouts (n = 35) from completers (n = 144) at likelihood much better than chance (72% accurate overall) across four measures: frequency of forgetting, barriers self-efficacy scale, balance, and stair performance. Study dropouts exhibited a higher frequency of forgetting, lower efficacy for overcoming barriers to exercise, poorer single leg balance, and longer times to walk down stairs.
The results provide an initial validation of a profile for discriminating between “dropouts” and “completers,” one that may have considerable utility for screening older adults prior to study entry.
exercise; attrition; dropout; older adults
As the result of a recent national shortage in paclitaxel, some patients who were receiving or scheduled to receive weekly paclitaxel were converted to every 3-week (q3w) docetaxel with granulocyte colony-stimulating factor support. Our institution noted higher than expected incidence of severe skin toxicity events attributable to docetaxel during the shortage period among our breast cancer patients. In this report, we summarize the clinical course of the first five cases, review the literature surrounding docetaxel-induced skin toxicity, and offer possible prevention and treatment strategies to improve docetaxel tolerability.
The observation period for this case series was August 1 through October 21, 2011. All patients treated with docetaxel were identified from our electronic medical record. Operable stage I–III breast cancer patients who received ≥1 dose of docetaxel monotherapy at 75–100 mg/m2 q3w were included in this study. The cases of grade 3–4 docetaxel-induced skin toxicities identified by the treating oncologists were then contacted and signed an informed consent through an Institutional Review Board-approved protocol.
Thirty-four patients met the inclusion criteria. Five patients (14.7 %) experienced grade 3 skin toxicity events attributable to docetaxel, a significantly higher rate than previously reported for docetaxel dosed at 75–100 mg/m2.
Docetaxel-induced dermatologic toxicity is well characterized; nonetheless, its etiology is largely unknown and evidence-based prevention and management strategies are lacking. This report shows that the use of docetaxel 75–100 mg/m2 q3w subsequent to dose-dense doxorubicin and cyclophosphamide regimen can lead to unacceptable rate of severe skin toxicity.
Taxane; Hand–foot syndrome; Breast cancer; Chemotherapy toxicity
The discovery of amplification of human epidermal growth factor receptor 2 (HER2), a member of the epidermal growth factor receptor family, was an important milestone in our understanding of the biology of breast cancers. This heralded the discovery of trastuzumab, a humanized monoclonal antibody targeting HER2. Trastuzumab is the foundation of treatment of HER2-positive breast cancers, demonstrating dramatic responses in patients with metastatic disease. Unfortunately, most tumors will inevitably develop resistance to trastuzumab, necessitating the need for alternate HER2-directed therapeutic approaches. Recent advances in our understanding of the interaction between HER2 and other members of the epidermal growth factor receptor family have led to identification of newer agents, resulting in the expansion of the clinical armamentarium of available agents for the treatment of HER2-positive tumors. In this article, we review the molecular biology of the ERbb receptor family, the use of HER2-targeted agents in early and advanced breast cancer, and the next-generation anti-HER2 agents that are currently in clinical evaluation.
HER2; trastuzumab; breast cancer; pertuzumab; T-DM1
To cross-validate the psychometric properties of the abbreviated Late-Life Function and Disability Instrument (LL-FDI), a measure of perceived functional limitations and disability.
Baseline and 12-month follow-up assessments conducted across the course of a 12-month exercise program.
University research community.
Older healthy adults (N=179; mean ± SD age, 66.43±5.67y) at baseline; 145 were retained at follow-up.
Main Outcome Measures
LL-FDI and functional performance measures.
Factor analyses confirmed the factor structure of the abbreviated LL-FDI, and all subscales met minimal criteria for temporal invariance. Significant correlations also were found between functional limitations subscales and an array of physical function performance measures, supporting the scale’s construct validity.
The abbreviated LL-FDI with some modifications appears to be temporally invariant in community-dwelling older adults. Additionally, moderate relationships between functional limitations and functional performance provide further support for these being conceptually distinct constructs.
Geriatrics; Longitudinal studies; Psychometrics; Rehabilitation
Trastuzumab is associated with improvements in overall survival (OS) among patients with HER2-positive metastatic breast cancer (MBC); however disease course and patterns of care in individual patients are highly variable.
113 HER2-positive patients diagnosed with MBC from 1999 to 2005 who received trastuzumab-based therapy were retrospectively identified to allow for a minimum of 5 years of follow-up time. Median OS and median duration of therapy were determined using Kaplan–Meier methodology and group comparisons were based on the log-rank test. Hazard ratios (HR) were obtained using a Cox proportional hazards model.
Median OS was 3.5 years (95% CI 3.0–4.4) from time of initiation of first therapy in the metastatic setting. On univariate analysis, central nervous system (CNS) disease at first recurrence was associated with a shorter OS compared with liver and/or lung metastases or other sites (CNS: 1.9 years CI 0.1–5.9, liver/lung: 3.2 years CI 2.5–4.2, other: 4.6 years CI 2.7–8.0; p = 0.05), however, this was not predictive of survival outcome in multivariate analysis. CNS metastases developed in 62 (55%) patients by the time of death or last follow-up. Median duration of therapy was similar up to 6 lines of treatment, and ranged from 5.2 months to 7.2 months.
The natural history of HER2-positive MBC has evolved with trastuzumab-based therapy with median OS now exceeding 3 years. CNS disease is a major problem with continued risk of CNS progression over time. Patients demonstrate clinical benefit to multiple lines of HER2-directed therapy.
Breast cancer; Central nervous system; HER2 Metastases; Trastuzumab
Increasingly, clinical trials incorporate translational research questions aimed at identifying biomarkers of response or resistance to agents under investigation. Biomarker assays can require tissue samples to be collected through a research biopsy before therapy, during treatment, or at the time of tumor progression. Such biopsy samples will generally not provide a direct benefit to the patient and, given the risks associated with any surgical procedure, ethical concerns have been raised when the participant’s enrollment on a clinical trial depends on their consent to undergo a research biopsy. In this Perspectives article, we present the rationale for mandatory research biopsies and offer suggestions for standardization to ensure that high-quality, patient-centered, clinical trials continue to be designed with scientific and ethical rigor.
The Flexibility, Toning, and Balance (FlexToBa™) Trial is a two-armed randomized controlled trial which will contrast the effects of a DVD-delivered, home-based, physical activity intervention and a Healthy Aging attention control condition on physical activity, functional performance, functional limitations, and quality of life in low active, older adults. This innovative trial will recruit 300 participants across central Illinois who will be randomized into the intervention arm or control arm of the study. The intervention will last 6 months with a 6 month follow-up. Assessments at baseline, post intervention and follow-up will include physical activity (self-report and accelerometry), a battery of functional performance measures, functional limitations, quality of life, and an array of psychological health measures. In addition, measures of external validity will be included to determine public health significance of a successful outcome. Participants will engage in a progressive series of activities focusing on flexibility, strengthening, and balance exercises which are demonstrated by a trained exercise leader and age-appropriate models on a series of DVDs. Delivery of the intervention has its basis in social cognitive theory. The specific aims of the trial are (a) to determine the effects of the DVD-delivered FlexToBa™ program on physical activity, functional performance, functional limitations, and quality of life, (b) to examine the mediators of the relationships between physical activity and functional limitations and quality of life, (c) to assess external validity indicators relative to the intervention, and (d) to determine differential effects of the intervention on psychosocial health measures.
Physical activity; older adults; functional limitations; functional performance; quality of life
This study examines differential trajectories of exercise-related self-efficacy beliefs across a 12-month randomized controlled exercise trial.
Previously inactive older adults (N = 144; M age = 66.5) were randomly assigned to one of two exercise conditions (walking, flexibility-toning-balance) and completed measures of barriers self-efficacy (BARSE), exercise self-efficacy (EXSE), and self-efficacy for walking (SEW) across a 12-month period. Changes in efficacy were examined according to efficacy type and inter-individual differences. Latent growth curve modeling was employed to (a) examine average levels and change in each type of efficacy for the collapsed sample and by intervention condition, and (b) explore subpopulations (i.e., latent classes) within the sample that differ in their baseline efficacy and trajectory.
Analyses revealed two negative trends in BARSE and EXSE at predicted transition points, in addition to a positive linear trend in SEW. Two subgroups with unique baseline efficacy and trajectory profiles were also identified.
These results shed new light on the relationship between exercise and self-efficacy in older adults, and highlight the need for strategies for increasing and maintaining efficacy within interventions, namely targeting participants who start with a disadvantage (lower efficacy) and integrating efficacy-boosting strategies for all participants prior to program end.
exercise; self-efficacy; trajectories of change; aging
The purpose of this study was to extend our earlier work to determine the extent to which cardiorespiratory fitness is associated with the frequency of memory problems via its effects on the hippocampus and spatial working memory. We hypothesized that age, sex, education, body composition, and physical activity were direct determinants of fitness which, in turn, influenced frequency of forgetting indirectly through hippocampal volume and spatial working memory.
We conducted assessments of hippocampal volume, spatial working memory, frequency of forgetting, BMI, physical activity, demographic characteristics, and cardiorespiratory fitness in 158 older adults (M age = 66.49). Path analyses within a covariance modeling framework were used to examine relationships among these constructs.
Sex, age, BMI, and education were all significant determinants of cardiorespiratory fitness. The hypothesized path models testing the effects of fitness on frequency of forgetting through hippocampal volume and accuracy and speed of spatial working memory all fit the data well.
Our findings suggest that older adults with higher levels of fitness show greater preservation of hippocampal volume which, in turn, is associated with more accurate and faster spatial memory and fewer episodes of forgetting. Given the proportion of older adults reporting memory problems, it is necessary to determine whether improvements in fitness brought about by physical activity interventions can result in subsequent attenuation of memory problems or potentially improvements in memory.
Frequency of Forgetting; Hippocampus Volume; Cardiorespiratory Fitness; Spatial Memory; Older Adults
Self-efficacy and the use of self-regulatory strategies are consistently associated with physical activity behavior. Similarly, behavioral inhibition and cognitive resource allocation, indices of executive control function, have also been associated with this health behavior.
The purpose of this study was to examine the hypothesis that self-efficacy mediates the relationship between self-regulatory processes, such as executive function, and sustained exercise behavior.
Older adults (N = 177, mean age = 66.44 years) completed measures of executive function, self-reported use of self-regulatory strategies and self-efficacy prior to and during the first month of a 12-month exercise intervention. Percentage of exercise classes attended over the following 11 months was used to represent adherence. Data were collected from 2007 to 2010 and analyzed in 2010–2011. Structural equation models were tested examining the effect of executive function and strategy use on adherence via efficacy.
As hypothesized, results showed significant direct effects of two elements of executive function and of strategy use on self-efficacy and of efficacy on adherence. In addition, there were significant indirect effects of strategy use and executive function on adherence via self-efficacy.
Higher levels of executive function and use of self-regulatory strategies at the start of an exercise program enhance beliefs in exercise capabilities, which in turn leads to greater adherence.
This 12-month, 2 arm, single blind randomized controlled exercise trial examined relationships among changes in multidimensional self-esteem as a function of intervention mode (i.e., walking vs. flexibility-toning-balance). Data were collected on three equidistant occasions (baseline, 6 and 12 months). One-hundred seventy-nine older adults (Mage = 66.38) began the study and 145 completed assessments at all time points. Participants completed measures of physical and global self-esteem as well as demographic information. There were no significant group differences at baseline on these demographic indicators or esteem variables. Data were analyzed using linear and parallel process growth modeling procedures. Results supported the position that across both groups, domain-level (i.e., physical self-worth) was dependent upon sub-domain-level (i.e., perceived attractiveness, strength, and condition) esteem change. Furthermore, greater improvements were observed in the flexibility-toning-balance group, in terms of perceived strength and attractiveness esteem, compared to the walking group. Our findings support theoretically-based predictions and extend the literature showing unique psychological responses conditional on specific types of physical activities.
Self perceptions; Physical activity; Growth models; Modes of exercise
The basal ganglia play a central role in regulating the response selection abilities that are critical for mental flexibility. In neocortical areas, higher cardiorespiratory fitness levels are associated with increased gray matter volume, and these volumetric differences mediate enhanced cognitive performance in a variety of tasks. Here we examine whether cardiorespiratory fitness correlates with the volume of the subcortical nuclei that make up the basal ganglia and whether this relationship predicts cognitive flexibility in older adults. Structural MRI was used to determine the volume of the basal ganglia nuclei in a group of older, neurologically healthy individuals (mean age 66 years, N = 179). Measures of cardiorespiratory fitness (VO2max), cognitive flexibility (task switching), and attentional control (flanker task) were also collected. Higher fitness levels were correlated with higher accuracy rates in the Task Switching paradigm. In addition, the volume of the caudate nucleus, putamen, and globus pallidus positively correlated with Task Switching accuracy. Nested regression modeling revealed that caudate nucleus volume was a significant mediator of the relationship between cardiorespiratory fitness, and task switching performance. These findings indicate that higher cardiorespiratory fitness predicts better cognitive flexibility in older adults through greater grey matter volume in the dorsal striatum.
There is increasing evidence that cardiorespiratory fitness (CRF) is associated with brain structure and function, and improvements in CRF through exercise training have been associated with neural and cognitive functioning in older adults. The objectives of this study were to validate the use of a non-exercise estimate of CRF, and to examine its association with cognitive function, brain structure and subjective memory complaints. Low active, older adults (N = 86; M age= 65.14) completed a physician-supervised maximal exercise test, a 1-mile timed walk, several measures of cognitive function, and a 3 Tesla structural MRI. Fitness was also calculated from an equation derived by (Jurca et al., 2005) based on age, sex, body mass index, resting heart rate, and self-reported physical activity level. Analyses indicated that all three measures of CRF were significantly correlated with one another. In addition, measures of cognitive function, hippocampus volume, and memory complaints were significantly correlated with each measure of fitness. These findings have implications for using a low-risk, low-cost, non-exercise estimate of CRF in determining fitness associations with brain structure and cognitive function in older adults. As such, this measure may have utility for larger population based studies. Further validation is required, as is determination of whether such relationships hold over the course of exercise interventions.
Equation-derived CRF; cognitive function; hippocampus; older adults
The purpose of this study was to validate the Physical Activity Enjoyment Scale (PACES) in a sample of older adults. Participants within two different exercise groups were assessed at two time points, 6 months apart. Group and longitudinal invariance was established for a novel, 8-item version of the PACES. The shortened, psychometrically sound measure provides researchers and practitioners an expedited and reliable instrument for assessing the enjoyment of physical activity.
Research has shown the human brain is organized into separable functional networks during rest and varied states of cognition, and that aging is associated with specific network dysfunctions. The present study used functional magnetic resonance imaging (fMRI) to examine low-frequency (0.008 < f < 0.08 Hz) coherence of cognitively relevant and sensory brain networks in older adults who participated in a 1-year intervention trial, comparing the effects of aerobic and non-aerobic fitness training on brain function and cognition. Results showed that aerobic training improved the aging brain's resting functional efficiency in higher-level cognitive networks. One year of walking increased functional connectivity between aspects of the frontal, posterior, and temporal cortices within the Default Mode Network and a Frontal Executive Network, two brain networks central to brain dysfunction in aging. Length of training was also an important factor. Effects in favor of the walking group were observed only after 12 months of training, compared to non-significant trends after 6 months. A non-aerobic stretching and toning group also showed increased functional connectivity in the DMN after 6 months and in a Frontal Parietal Network after 12 months, possibly reflecting experience-dependent plasticity. Finally, we found that changes in functional connectivity were behaviorally relevant. Increased functional connectivity was associated with greater improvement in executive function. Therefore the study provides the first evidence for exercise-induced functional plasticity in large-scale brain systems in the aging brain, using functional connectivity techniques, and offers new insight into the role of aerobic fitness in attenuating age-related brain dysfunction.
exercise; aging; functional connectivity; fMRI; default mode network; executive function; aerobic fitness
DNA replication in eukaryotic cells is tightly controlled by a licensing mechanism, ensuring that each origin fires once and only once per cell cycle. We demonstrate that the ataxia telangiectasia and Rad3 related (ATR)–mediated S phase checkpoint acts as a surveillance mechanism to prevent rereplication. Thus, disruption of licensing control will not induce significant rereplication in mammalian cells when the ATR checkpoint is intact. We also demonstrate that single-stranded DNA (ssDNA) is the initial signal that activates the checkpoint when licensing control is compromised in mammalian cells. We demonstrate that uncontrolled DNA unwinding by minichromosome maintenance proteins upon Cdt1 overexpression is an important mechanism that leads to ssDNA accumulation and checkpoint activation. Furthermore, we show that replication protein A 2 and retinoblastoma protein are both downstream targets for ATR that are important for the inhibition of DNA rereplication. We reveal the molecular mechanisms by which the ATR-mediated S phase checkpoint pathway prevents DNA rereplication and thus significantly improve our understanding of how rereplication is prevented in mammalian cells.