Coengineering specificity, safety, and function into T cells for cancer immunotherapy.

Adoptive T-cell transfer (ACT) therapies, including of tumor infiltrating lymphocytes (TILs) and T cells gene-modified to express either a T cell receptor (TCR) or a chimeric antigen receptor (CAR), have demonstrated clinical efficacy for a proportion of patients and cancer-types. The field of ACT has been driven forward by the clinical success of CD19-CAR therapy against various advanced B-cell malignancies, including curative responses for some leukemia patients. However, relapse remains problematic, in particular for lymphoma. Moreover, for a variety of reasons, relative limited efficacy has been demonstrated for ACT of non-hematological solid tumors. Indeed, in addition to pre-infusion challenges including lymphocyte collection and manufacturing, ACT failure can be attributed to several biological processes post-transfer including, (i) inefficient tumor trafficking, infiltration, expansion and retention, (ii) chronic antigen exposure coupled with insufficient costimulation resulting in T-cell exhaustion, (iii) a range of barriers in the tumor microenvironment (TME) mediated by both tumor cells and suppressive immune infiltrate, (iv) tumor antigen heterogeneity and loss, or down-regulation of antigen presentation machinery, (v) gain of tumor intrinsic mechanisms of resistance such as to apoptosis, and (vi) various forms of toxicity and other adverse events in patients. Affinity-optimized TCRs can improve T-cell function and innovative CAR designs as well as gene-modification strategies can be used to coengineer specificity, safety, and function into T cells. Coengineering strategies can be designed not only to directly support the transferred T cells, but also to block suppressive barriers in the TME and harness endogenous innate and adaptive immunity. Here, we review a selection of the remarkable T-cell coengineering strategies, including of tools, receptors, and gene-cargo, that have been developed in recent years to augment tumor control by ACT, more and more of which are advancing to the clinic.

Healthier diet quality and dietary patterns are associated with lower risk of mobility limitation in older men.

PURPOSE: To investigate associations between diet quality, dietary patterns and mobility limitation 15 years later in a population-based sample of older British men. METHODS: We used longitudinal data from 1234 men from the British Regional Heart Study, mean age 66 years at baseline. Mobility limitation was defined as difficulty going up- or downstairs or walking 400 yards as a result of a long-term health problem. Dietary intake was measured using a food frequency questionnaire data from which the Healthy Diet Indicator (HDI), the Elderly Dietary Index (EDI), and three a posteriori dietary patterns were derived. The a posteriori dietary patterns were identified using principal components analysis: (1) high fat/low fibre, (2) prudent and (3) high sugar. RESULTS: Men with greater adherence to the EDI or HDI were less likely to have mobility limitation at follow-up, top vs bottom category odds ratio for the EDI OR 0.50, 95% CI 0.34, 0.75, and for the HDI OR 0.55, 95% CI 0.35, 0.85, after adjusting for age, social class, region of residence, smoking, alcohol consumption and energy intake. Men with a higher score for the high-fat/low-fibre pattern at baseline were more likely to have mobility limitation at follow-up, top vs bottom quartile odds ratio OR 3.28 95% CI 2.05, 5.24. These associations were little changed by adjusting for BMI and physical activity. CONCLUSION: Our study provides evidence that healthier eating patterns could contribute to prevention or delay of mobility limitation in older British men.

Physical frailty in older men: prospective associations with diet quality and patterns.

BACKGROUND: increasing numbers of older adults are living with frailty and its adverse consequences. We investigated relationships between diet quality or patterns and incident physical frailty in older British men and whether any associations were influenced by inflammation. METHODS: prospective study of 945 men from the British Regional Heart Study aged 70-92 years with no prevalent frailty. Incident frailty was assessed by questionnaire after 3 years of follow-up. Frailty was defined as having at least three of: low grip strength, low physical activity, slow walking speed, unintentional weight loss and feeling of low energy, all based on self-report. The Healthy Diet Indicator (HDI) based on WHO dietary guidelines and the Elderly Dietary Index (EDI) based on a Mediterranean-style dietary intake were computed from questionnaire data and three dietary patterns were identified using principal components analysis: prudent, high fat/low fibre and high sugar. RESULTS: men in the highest EDI category and those who followed a prudent diet were less likely to become frail [top vs bottom category odds ratio (OR) (95% CI) 0.49 (0.30, 0.82) and 0.53 (0.30, 0.92) respectively] after adjustment for potential confounders including BMI and prevalent cardiovascular disease. No significant association was seen for the HDI. By contrast those who had a high fat low fibre diet pattern were more likely to become frail [OR (95% CI) 2.54 (1.46, 4.40)]. These associations were not mediated by C-reactive protein (marker of inflammation). CONCLUSIONS: the findings suggest adherence to a Mediterranean-style diet is associated with reduced risk of developing frailty in older people.

Objectively measured physical activity, sedentary behaviour and all-cause mortality in older men: does volume of activity matter more than pattern of accumulation?

OBJECTIVES: To understand how device-measured sedentary behaviour and physical activity are related to all-cause mortality in older men, an age group with high levels of inactivity and sedentary behaviour. METHODS: Prospective population-based cohort study of men recruited from 24 UK General Practices in 1978-1980. In 2010-2012, 3137 surviving men were invited to a follow-up, 1655 (aged 71-92 years) agreed. Nurses measured height and weight, men completed health and demographic questionnaires and wore an ActiGraph GT3x accelerometer. All-cause mortality was collected through National Health Service central registers up to 1 June 2016. RESULTS: After median 5.0 years' follow-up, 194 deaths occurred in 1181 men without pre-existing cardiovascular disease. For each additional 30 min in sedentary behaviour, or light physical activity (LIPA), or 10 min in moderate to vigorous physical activity (MVPA), HRs for mortality were 1.17 (95% CI 1.10 to 1.25), 0.83 (95% CI 0.77 to 0.90) and 0.90 (95% CI 0.84 to 0.96), respectively. Adjustments for confounders did not meaningfully change estimates. Only LIPA remained significant on mutual adjustment for all intensities. The HR for accumulating 150 min MVPA/week in sporadic minutes (achieved by 66% of men) was 0.59 (95% CI 0.43 to 0.81) and 0.58 (95% CI 0.33 to 1.00) for accumulating 150 min MVPA/week in bouts lasting ≥10 min (achieved by 16% of men). Sedentary breaks were not associated with mortality. CONCLUSIONS: In older men, all activities (of light intensity upwards) were beneficial and accumulation of activity in bouts ≥10 min did not appear important beyond total volume of activity. Findings can inform physical activity guidelines for older adults.

Association Between 20-Year Trajectories of Nonoccupational Physical Activity From Midlife to Old Age and Biomarkers of Cardiovascular Disease: A 20-Year Longitudinal Study of British Men.

The trajectories of physical activity (PA) from midlife into old age and their associations with established and novel cardiovascular disease (CVD) risk factors in later life remain unclear. This study examined associations between 20-year nonoccupational PA trajectories and a range of CVD biomarkers at ages 60-79 years. We used data from a sample of 3,331 men (mean baseline age = 50.2 ± 5.8 years) recruited in 1978-1980, with follow-up after 12, 16, and 20 years, reporting habitual nonoccupational PA at each wave. At the 20-year follow-up, surviving men attended a physical examination and provided a fasting blood sample. Group-based trajectory modeling was used to identify trajectories. Adjusted regression analyses examined the association between trajectory-group membership and several cardiometabolic, cardiac, and inflammatory markers at follow-up. Three distinct 20-year trajectories were identified: low/decreasing (21.3%), light/stable (51.8%), and moderate/increasing (27.0%). Compared with the low/decreasing group, membership in the light/stable and moderate/increasing trajectory groups was associated with a more favorable cardiometabolic profile and lower levels of inflammation and endothelial dysfunction. Although following a moderate-increasing PA trajectory was most favorable, more modest but sustained doses of PA into old age may be sufficient to lower CVD risk.

Trajectories of self-reported physical activity and predictors during the transition to old age: a 20-year cohort study of British men.

BACKGROUND: Maintenance of physical activity (PA) during later life is associated with optimal health; however, the long-term trajectories of PA into old age and their predictors have not been extensively researched using latent class methods. This study aimed to identify trajectories of self-reported PA and their predictors in men transitioning from midlife to old age. METHODS: 7735 men (aged 40-59 years) recruited in 1978-80 were followed up after 12, 16 and 20 years, reporting PA, health status, lifestyle behaviours and socio-demographic characteristics. Group-based trajectory modelling identified the trajectories of PA and associations with time-stable and time-varying covariates. We considered a range of sociodemographic and health and lifestyle factors as potential covariates. RESULTS: 4952 men (mean baseline age 49.1 ± 5.6 years) providing PA data at ≥3 time points were included in analyses. Three distinct 20-year trajectories were identified: low decreasing (24.6%, n = 1218), light stable (51.1%, n = 2530) and moderate increasing (24.3%, n = 1204). Being older, having a manual occupation, having never married or had children, residing in the midlands or North of England, suffering from a range of health conditions, being a smoker/ex-smoker and never consuming breakfast cereal or alcohol were independently associated with reduced odds of belonging to the moderate increasing trajectory group compared to the low decreasing group. Of the time-varying covariates considered, leaving employment was associated with a decrease in PA in the low decreasing group (ß -0.306, p < 0.001) but an increase in the light stable (ß 0.324, p < 0.001) and moderate increasing groups (ß 0.847, p < 0.001). Developing cardiovascular-related conditions was associated with a decrease in PA in the low decreasing (ß -0.408, p < 0.001) and light stable groups (ß -0.118, p < 0.001) but no association was observed in the moderate increasing group (ß -0.060, p = 0.313). CONCLUSIONS: Three distinct trajectories of PA were identified in men transitioning from midlife to old age, of which nearly a quarter had persistently low levels of PA. Promotion efforts may need to focus attention prior to middle age and consider a number of sociodemographic, health and lifestyle factors to sustain PA into old age. The effects of retirement and development of cardiovascular disease may vary according to PA trajectories.

Objectively measured physical activity and kidney function in older men; a cross-sectional population-based study.

Background: kidney function declines in older adults and physical activity levels are low. We investigated whether higher levels of physical activity and lower levels of sedentary behaviour were associated with lower odds of low kidney function in older men. Methods: cross-sectional study of 1,352 men from the British Regional Heart Study, mean (standard deviation) age 78.5 (4.6) year. Physical activity and sedentary behaviour were measured using Actigraph GT3X accelerometers. Kidney function was measured by estimated Glomerular filtration rate (eGFR) using the chronic kidney disease-EPI creatinine-cystatin equation. Associations between physical (in)activity and kidney function were investigated using regression models. Results: higher levels of physical activity and lower levels of sedentary behaviour were associated with reduced odds ratios (ORs) for lower eGFR (<45 versus ≥45 ml/min per 1.73 m2) after adjustment for covariates. Each additional 1,000 steps, 30 min of light physical activity and 10 min of moderate/vigorous physical activity per day were associated with a lower odds (95% confidence interval (CI)) of a low eGFR; OR 0.81 (0.73, 0.91), OR 0.87 (0.78, 0.97) and OR 0.84 (0.76, 0.92), respectively. Each additional 30 min of sedentary behaviour per day was associated with a higher odds of a low eGFR (1.16 95% CI 1.06, 1.27). Associations between moderate/vigorous physical activity and lower kidney function persisted after adjustment for light physical activity or sedentary behaviour. Conclusion: physical activity is associated with kidney function in older men and could be of public health importance in this group who are at increased risk of poor kidney function and low physical activity. More evidence is needed on whether the association is causal.

Medical students' perceived educational needs to prevent and treat childhood obesity.

BACKGROUND: Medical schools are challenged to incorporate more prevention-based education into curricula, offering an opportunity to revisit approaches to nutrition education. The objective of this study was to explore United States (US) medical students' understanding of childhood obesity, specifically barriers to childhood obesity prevention and treatment and students' perceived educational deficits. METHODS: The research team conducted phone interviews with 78 3rd- and 4th-year medical students, representing 25 different medical schools across the US. Using a semi-structured interview guide, researchers asked students to describe the etiology of childhood obesity and reflect on where they acquired knowledge of the etiology and what additional resources they would need to treat obese children. Using a phenomenological approach to analysis, researchers identified five dominant emergent themes. RESULTS: Student-perceived barriers to childhood obesity prevention and treatment in clinical care included student-centered (e.g., lack of knowledge), patient-centered (e.g., lack of access), and healthcare system-centered barriers (e.g., limited time). Students requested more applicable nutrition information and counseling skills relevant to preventing and treating childhood obesity; however, they tended to identify others (e.g., parents, schools), rather than themselves, when asked to describe how childhood obesity should be prevented or treated. DISCUSSION: To provide students with an understanding of their role in preventing and treating childhood obesity, US medical schools need to provide students with childhood obesity-specific and general nutrition education. To build their self-efficacy in nutrition counseling, schools can use a combination of observation and practice led by skilled physicians and other healthcare providers. Increasing students' self-efficacy through training may help them overcome perceived barriers to childhood obesity prevention and treatment.

Validity of questionnaire-based assessment of sedentary behaviour and physical activity in a population-based cohort of older men; comparisons with objectively measured physical activity data.

BACKGROUND: Older adults are the most inactive age group and self-reporting of activities may be complicated by age-related reductions in structured activities and misclassification or recall biases. We investigate the validity of simple questionnaires about sedentary behaviour (SB), (including the widely used proxy television (TV) viewing), and physical activity (PA) in comparison with objective measures. METHODS: Community dwelling men aged 71-93 years, from a UK population-based cohort wore a GT3X accelerometer over the right hip for 7 days and self-completed a questionnaire including information about SB (TV, reading, computer use and car use) and PA (leisure and sporting domains). RESULTS: 1566/3137 surviving men (mean age 79 years) attended. 1377 ambulatory men provided questionnaire and accelerometer data. Questionnaires under-estimated mean daily sedentary time; 317 minutes total SB (TV, computer use, reading or driving), 176 minutes (TV) vs 619 minutes (objectively measured). Correlations between objective measures and self-reports were 0.18 (total SB) and 0.17 (TV), both P < 0.001. Objective SB levels were similar across the lowest three quartiles of self-reported SB but raised in the highest quartile. Correlations between steps/day or moderate to vigorous PA with self-reported total PA were both 0.49, P < 0.001 and measured PA levels were progressively higher at higher levels of self-reported PA. CONCLUSIONS: Among older men, simple SB questions performed poorly for identifying total SB time, although simple PA questions were associated with a graded increase with objectively measured PA. Future studies of health effects of SB in older men would benefit from objective measures of SB.

Does duration of physical activity bouts matter for adiposity and metabolic syndrome? A cross-sectional study of older British men.

BACKGROUND: Older adults have low physical activity(PA) and high sedentary behaviour(SB) levels. We investigate how total volume and specific patterns of moderate to vigorous PA(MVPA), light PA(LPA) and SB are related to adiposity and metabolic syndrome (MS). Then, with reference to physical activity guidelines which encourage MVPA in bouts > =10 min and avoiding "long" sedentary bouts, we investigate whether accumulating PA and SB in bouts of different defined durations are differently associated with these outcomes. METHODS: Cross-sectional study of men (71-91 years) recruited in UK primary care centres. Nurses made physical measures (weight, height, bio-impedance, blood pressure) and took fasting blood samples. 1528/3137 (49%) surviving men had ≥3 valid days (≥600 min) accelerometer data. 450 men with pre-existing chronic disease were excluded. 1009/1078 (93.6%) had complete covariate data. RESULTS: Men (n = 1009, mean age 78.5(SD 4.7) years) spent 612(SD 83), 202(SD 64) and 42(SD 33) minutes in SB, LIPA and MVPA respectively. Each additional 30 min/day of SB and MVPA were associated with 0.32 (95% CI 0.23, 0.40)Kg/m(2) higher Body Mass Index (BMI) and -0.72(-0.93, -0.51) lower BMI Kg/m(2) respectively. Patterns for waist circumference (WC), fat mass index (FMI), fasting insulin and MS were similar. MVPA in bouts lasting <10 min or ≥10 min duration were not associated differently with outcomes. In models adjusted for total MVPA, each minute accumulated in SB bouts lasting 1-15 min was associated with lower BMI -0.012 kg/m(2), WC -0.029 cm, and OR 0.989 for MS (all p < 0.05), and coefficients for LPA bouts 1-9 min were very similar in separate models adjusted for total MVPA. Minutes accumulated in SB bouts 1-15 min and LPA bouts 1-9 min were correlated, r = 0.62. CONCLUSIONS: Objectively measured MVPA, LPA and SB were all associated with lower adiposity and metabolic risk. The beneficial associations of LPA are encouraging for older adults for whom initiating MVPA and maintaining bouts lasting ≥10 min may be particularly challenging. Findings that short bouts of LPA (1-9 min) and SB (1-15 min), but that all MVPA, not just MVPA accumulated in bouts ≥10 min were associated with lower adiposity and better metabolic health could help refine older adult PA guidelines.

Cross-sectional associations of objectively measured physical activity and sedentary time with sarcopenia and sarcopenic obesity in older men.

This study investigated associations between objectively measured physical activity (PA) with sarcopenia and sarcopenic obesity in older British men. Participants were men aged 70-92years (n=1286) recruited from UK Primary Care Centres. Outcomes included (i) sarcopenia, defined as low muscle mass (lowest two fifths of the mid-upper arm muscle circumference distribution) accompanied by low muscular strength (hand grip strength <30kg) or low physical performance (gait speed≤0.8m/s); (ii) severe sarcopenia, required all three conditions; (iii) sarcopenic obesity defined as sarcopenia or severe sarcopenia and a waist circumference of >102cm. Independent variables included time spent in PA intensities measured by GT3x accelerometers, worn during one week in 2010-12. Multinomial regression models were used for cross-sectional analyses relating PA and sarcopenia. In total, 14.2% (n=183) of men had sarcopenia and a further 5.4% (n=70) had severe sarcopenia. 25.3% of sarcopenic or severely sarcopenic men were obese. Each extra 30min per day of moderate-to-vigorous PA (MVPA) was associated with a reduced risk of severe sarcopenia (relative risk [RR] 0.53, 95% confidence interval [CI] 0.30, 0.93) and sarcopenic obesity (RR 0.47 [95% CI 0.27, 0.84]). Light PA (LPA) and sedentary breaks were marginally associated with a reduced risk of sarcopenic obesity. Sedentary time was marginally associated with an increased risk of sarcopenic obesity independent of MVPA (RR 1.18 [95% CI 0.99, 1.40]). MVPA may reduce the risk of severe sarcopenia and sarcopenic obesity among older men. Reducing sedentary time and increasing LPA and sedentary breaks may also protect against sarcopenic obesity.

Objectively measured physical activity, sedentary time and subclinical vascular disease: Cross-sectional study in older British men.

Low physical activity (PA) and high levels of sedentary time (ST) are associated with higher cardiovascular disease (CVD) risk among older people. However, their independent contribution and importance of duration of PA and ST bouts remain unclear. We investigated associations between objectively measured PA, ST and non-invasive vascular measures, markers of CVD risk. Cross-sectional study of 1216 men from the British Regional Heart Study, mean age 78.5years, measured in 2010-2012. Carotid intima thickness (CIMT), distensibility coefficient (DC) and plaque presence were measured using ultrasound; pulse wave velocity (cfPWV) and augmentation index (AIx) using a Vicorder. PA and ST were measured using hip-worn ActiGraph GT3X accelerometers. After adjusting for covariates, each additional 1000 steps per day was associated with a 0.038m/s lower cfPWV (95% CI=-0.076, 0.0003), 0.095 10(-3) kPa(-1) higher DC (95% CI=0.006, 0.185), 0.26% lower AIx (95% CI=-0.40, -0.12) and a 0.005mm lower CIMT (95% CI=-0.008, -0.001). Moderate and vigorous PA (MVPA) was associated with lower AIx and CIMT, light PA (LPA) with lower cfPWV and CIMT and ST with higher cfPWV, AIx and CIMT and lower DC. LPA and ST were highly correlated (r=-0.62). The independence of MVPA and ST or MVPA and LPA was inconsistent across vascular measures. Bout lengths for both PA and ST were not associated with vascular measures. In our cross-sectional study of older men, all PA regardless of intensity or bout duration was beneficially associated with vascular measures, as was lower ST. LPA was particularly relevant for cfPWV and CIMT.

Diurnal patterns of objectively measured physical activity and sedentary behaviour in older men.

BACKGROUND: Physical activity (PA) levels among older adults are generally low and sedentary behaviour (SB) very common; increasing PA and reducing SB levels could have appreciable health benefits. Quantifying PA and SB patterns through the day could help in defining strategies for change. We examined within day variations in PA and SB and whether these varied by demographic factors and health status. METHODS: Men aged 71-91 years participating in an established UK population-based cohort study were invited to wear a GT3x Actigraph accelerometer over the hip for one week in 2010-12. Percentages of time spent in sedentary (SB, <100 counts per minute [CPM]); in light (LIPA, 100-1040 CPM) and in moderate to vigorous PA (MVPA, >1040 CPM) were derived. Multilevel models were used to estimate the associations between demographic factors and health status and SB, LIPA and MVPA. RESULTS: 1455 of 3137 men invited (46.4 %) participated and provided adequate data. Men spent 73 % of the day in SB, 23 % in LIPA and 4.5 % in MVPA (619, 197 and 39 min per day respectively). The percentage of time spent in MVPA was highest in the morning, peaking at 10-11 am (8.4 %), and then declining until the evening, with the exception of a small increase at 2-3 pm. LIPA followed a similar pattern. Conversely, SB levels were lowest in the morning and increased throughout the day, peaking at 9 pm (88 %). Men who were older, did not use active transport, had mobility limitations, were obese, depressed, had more chronic health conditions, and were smokers had lower levels of MVPA. The impacts of older age, obesity, mobility limitations and chronic diseases on LIPA, MVPA and SB were more marked in the morning than in the afternoon and evening. CONCLUSIONS: Levels of MVPA and LIPA are highest in the morning (peak at 10-11 am) and decrease during the day. SB increases through the course of the day to peak in the evening. Interventions to encourage older men to be physically active may need to take account of current PA patterns, aiming to prolong active morning bouts of PA and/or reducing SB in the afternoon and evening hours.

How are falls and fear of falling associated with objectively measured physical activity in a cohort of community-dwelling older men?

BACKGROUND: Falls affect approximately one third of community-dwelling older adults each year and have serious health and social consequences. Fear of falling (FOF) (lack of confidence in maintaining balance during normal activities) affects many older adults, irrespective of whether they have actually experienced falls. Both falls and fear of falls may result in restrictions of physical activity, which in turn have health consequences. To date the relation between (i) falls and (ii) fear of falling with physical activity have not been investigated using objectively measured activity data which permits examination of different intensities of activity and sedentary behaviour. METHODS: Cross-sectional study of 1680 men aged 71-92 years recruited from primary care practices who were part of an on-going population-based cohort. Men reported falls history in previous 12 months, FOF, health status and demographic characteristics. Men wore a GT3x accelerometer over the hip for 7 days. RESULTS: Among the 12% of men who had recurrent falls, daily activity levels were lower than among non-fallers; 942 (95% CI 503, 1381) fewer steps/day, 12(95% CI 2, 22) minutes less in light activity, 10(95% CI 5, 15) minutes less in moderate to vigorous PA [MVPA] and 22(95% CI 9, 35) minutes more in sedentary behaviour. 16% (n = 254) of men reported FOF, of whom 52% (n = 133) had fallen in the past year. Physical activity deficits were even greater in the men who reported that they were fearful of falling than in men who had fallen. Men who were fearful of falling took 1766(95% CI 1391, 2142) fewer steps/day than men who were not fearful, and spent 27(95% CI 18, 36) minutes less in light PA, 18(95% CI 13, 22) minutes less in MVPA, and 45(95% CI 34, 56) minutes more in sedentary behaviour. The significant differences in activity levels between (i) fallers and non-fallers and (ii) men who were fearful of falling or not fearful, were mediated by similar variables; lower exercise self-efficacy, fewer excursions from home and more mobility difficulties. CONCLUSIONS: Falls and in particular fear of falling are important barriers to older people gaining health benefits of walking and MVPA. Future studies should assess the longitudinal associations between falls and physical activity.

Adherence to physical activity guidelines in older adults, using objectively measured physical activity in a population-based study.

BACKGROUND: Physical activity (PA) levels in older adults decline with age. The prevalence and correlates of adherence to current UK PA guidelines in older adults has not been studied using objectively measured PA, which can examine precisely whether PA is carried out in bouts of specified length and intensity. METHODS: Free living men and women aged 70-93 years from 25 towns in the United Kingdom, participating in parallel on-going population based cohort studies were invited (by post) to wear a GT3x accelerometer over the hip for one week in 2010-12. Adherence to UK PA guidelines was defined as ≥150 minutes/week of moderate or vigorous PA (MVPA) in bouts of ≥10 minutes; the effect of different intensities and durations were examined. RESULTS: 1593 men and 857 women participated (responses 51% and 29% respectively). 15% men and 10% women achieved ≥150 minutes/week of MVPA (defined as >1040 cpm) in bouts lasting ≥10 minutes. With MVPA defined as >1952 cpm, prevalences were 7% and 3% respectively. Those adhering to guidelines were younger, had fewer chronic health conditions, less depression, less severe mobility limitations, but higher exercise self-efficacy and exercise outcomes expectations. They rated their local environment more highly for social activities and leisure facilities, having somewhere nice to go for a walk and feeling safe after dark, They left the house on more days per week, were more likely to use active transport (cycle or walk) and to walk a dog regularly. CONCLUSIONS: Few older adults attain current PA guidelines. Health promotion to extend the duration of moderate-intensity activity episodes to 10 minutes or more could yield important health gains among older adults. However future studies will need to clarify whether attaining guideline amounts of PA in spells lasting 10 minutes or more is critical for reducing chronic disease risks as well as improving cardiometabolic risk factors.

Targeting the activated microenvironment with endosialin (CD248)-directed CAR-T cells ablates perivascular cells to impair tumor growth and metastasis.

BACKGROUND: Targeting of solid cancers with chimeric antigen receptor (CAR)-T cells is limited by the lack of suitable tumor-specific antigens and the immunosuppressive, desmoplastic tumor microenvironment that impedes CAR-T cell infiltration, activity and persistence. We hypothesized that targeting the endosialin (CD248) receptor, strongly expressed by tumor-associated pericytes and perivascular cancer-associated fibroblasts, would circumvent these challenges and offer an exciting antigen for CAR-T cell therapy due to the close proximity of target cells to the tumor vasculature, the limited endosialin expression in normal tissues and the lack of phenotype observed in endosialin knockout mice. METHODS: We generated endosialin-directed E3K CAR-T cells from three immunocompetent mouse strains, BALB/c, FVB/N and C57BL/6. E3K CAR-T cell composition (CD4+/CD8+ ratio), activity in vitro against endosialin+ and endosialin- cells, and expansion and activity in vivo in syngeneic tumor models as well as in tumor-naive healthy and wounded mice and tumor-bearing endosialin knockout mice was assessed. RESULTS: E3K CAR-T cells were active in vitro against both mouse and human endosialin+, but not endosialin-, cells. Adoptively transferred E3K CAR-T cells exhibited no activity in endosialin knockout mice, tumor-naive endosialin wildtype mice or in wound healing models, demonstrating an absence of off-target and on-target/off-tumor activity. By contrast, adoptive transfer of E3K CAR-T cells into BALB/c, FVB/N or C57BL/6 mice bearing syngeneic breast or lung cancer lines depleted target cells in the tumor stroma resulting in increased tumor necrosis, reduced tumor growth and a substantial impairment in metastatic outgrowth. CONCLUSIONS: Together these data highlight endosialin as a viable antigen for CAR-T cell therapy and that targeting stromal cells closely associated with the tumor vasculature avoids CAR-T cells having to navigate the harsh immunosuppressive tumor microenvironment. Further, the ability of E3K CAR-T cells to recognize and target both mouse and human endosialin+ cells makes a humanized and optimized E3K CAR a promising candidate for clinical development applicable to a broad range of solid tumor types.

Position of the Society for Nutrition Education and Behavior: Nutrition Educator Competencies for Promoting Healthy Individuals, Communities, and Food Systems: Rationale and Application.

It is the position of the Society for Nutrition Education and Behavior that to improve the health of individuals, communities, and food systems, it is essential that nutrition educators meet each of 6 content competencies (basic food and nutrition knowledge, nutrition across the life cycle, food science, physical activity, food and nutrition policy, and agricultural production and food systems) and 4 process competencies (behavior and education theory; nutrition education program design, implementation and evaluation; written, oral, and social media communication; and nutrition education research methods). These competencies reflect the breadth of the nutrition education field and are grounded in peer-reviewed research. The rationale and evidence base for these competencies are presented. They are designed for educational institutions to plan curricula and programs; public, private, and nonprofit organizations for training; individuals for professional development; and policymakers and advocates to inform strong, comprehensive nutrition education policy.

A lentiviral vector for the production of T cells with an inducible transgene and a constitutively expressed tumour-targeting receptor.

Vectors that facilitate the engineering of T cells that can better harness endogenous immunity and overcome suppressive barriers in the tumour microenvironment would help improve the safety and efficacy of T-cell therapies for more patients. Here we report the design, production and applicability, in T-cell engineering, of a lentiviral vector leveraging an antisense configuration and comprising a promoter driving the constitutive expression of a tumour-directed receptor and a second promoter enabling the efficient activation-inducible expression of a genetic payload. The vector allows for the delivery of a variety of genes to human T cells, as we show for interleukin-2 and a microRNA-based short hairpin RNA for the knockdown of the gene coding for haematopoietic progenitor kinase 1, a negative regulator of T-cell-receptor signalling. We also show that a gene encoded under an activation-inducible promoter is specifically expressed by tumour-redirected T cells on encountering a target antigen in the tumour microenvironment. The single two-gene-encoding vector can be produced at high titres under an optimized protocol adaptable to good manufacturing practices.

Trajectories of physical activity from midlife to old age and associations with subsequent cardiovascular disease and all-cause mortality.

INTRODUCTION: It is well established that physical activity (PA) protects against mortality and morbidity, but how long-term patterns of PA are associated with mortality and cardiovascular disease (CVD) remains unclear. METHODS: 3231 men recruited to the British Regional Heart Study, a prospective cohort study, reported usual PA levels at baseline in 1978-1980 (aged 40-59 years) and at 12-year, 16-year and 20-year follow ups. Twenty-year trajectories of PA, spanning from 1978/1980 to 2000, were identified using group-based trajectory modelling. Men were subsequently followed up until 30 June 2016 for mortality through National Health Service central registers and for non-fatal CVD events through primary and secondary care records. Data analyses were conducted in 2019. RESULTS: Three PA trajectories were identified: low/decreasing (22.7%), light/stable (51.0%) and moderate/increasing (26.3%). Over a median follow-up of 16.4 years, there were 1735 deaths. Compared with the low/decreasing group, membership of the light/stable (HR 0.83, 95% CI 0.74 to 0.94) and moderate/increasing (HR 0.76, 95% CI 0.66 to 0.88) groups was associated with a lower risk of all-cause mortality. Similar associations were observed for CVD mortality, major coronary heart disease and all CVD events. Associations were only partially explained by a range of confounders. Sensitivity analyses suggested that survival benefits were largely driven by most recent/current PA. CONCLUSIONS: A dose-response relationship was observed, with higher levels of PA from midlife to old age associated with additional benefits. However, even fairly modest and sustained PA was protective and may be more achievable for the most inactive.

Twenty-Year Trajectories of Physical Activity Types from Midlife to Old Age.

PURPOSE: Correlates of physical activity (PA) vary according to type. However, predictors of long-term patterns of PA types into old age are unknown. This study aimed to identify 20-yr trajectories of PA types into old age and their predictors. METHODS: Seven thousand seven hundred thirty-five men (age, 40-59 yr) recruited from UK towns in 1978 to 1980 were followed up after 12, 16, and 20 yr. Men reported participation in sport/exercise, recreational activity and walking, health status, lifestyle behaviors and socio-demographic characteristics. Group-based trajectory modeling identified the trajectories of PA types and associations with time-stable and time-varying covariates. RESULTS: Men with ≥3 measures of sport/exercise (n = 5116), recreational activity (n = 5085) and walking (n = 5106) respectively were included in analyses. Three trajectory groups were identified for sport/exercise, four for recreational activity and three for walking. Poor health, obesity and smoking were associated with reduced odds of following a more favorable trajectory for all PA types. A range of socioeconomic, regional and lifestyle factors were also associated with PA trajectories but the magnitude and direction were specific to PA type. For example, men with manual occupations were less likely to follow a favorable sport/exercise trajectory but more likely to follow an increasing walking trajectory compared to men with nonmanual occupations. Retirement was associated with increased PA but this was largely due to increased sport/exercise participation. CONCLUSIONS: Physical activity trajectories from middle to old age vary by activity type. The predictors of these trajectories and effects of major life events, such as retirement, are also specific to the type of PA.