Objectives The objective of this study was to examine if, in the general population, physically active adults have less body fat after taking body mass index (BMI) into account. Design A cross-sectional analysis of participants recruited into UK Biobank in 2006–2010. Setting UK Biobank assessment centres throughout the UK. Participants 119 230 men and 140 578 women aged 40–69 years, with complete physical activity information, and without a self-reported long-term illness, disability or infirmity. Exposures Physical activity measured as excess metabolic equivalent (MET)-hours per week, estimated from a combination of walking, and moderate and vigorous physical activity. BMI from measured height and weight. Main outcome measure Body fat percentage estimated from bioimpedance. Results BMI and body fat percentage were highly correlated (r=0.85 in women; r=0.79 in men), and both were inversely associated with physical activity. Compared with <5 excess MET-hours/week at baseline, ≥100 excess MET-hours/week were associated with a 1.1 kg/m 2 lower BMI (27.1 vs 28.2 kg/m 2 ) and 2.8 percentage points lower body fat (23.4% vs 26.3%) in men, and 2.2 kg/m 2 lower BMI (25.6 vs 27.7 kg/m 2 ) and 4.0 percentage points lower body fat (33.9% vs 37.9%) in women. For a given BMI, greater physical activity was associated with lower average body fat percentage (for a BMI of 22.5–24.99 kg/m 2 : 2.0 (95% CI 1.8 to 2.2), percentage points lower body fat in men and 1.8 (95% CI 1.6 to 2.0) percentage points lower body fat in women, comparing ≥100 excess MET-hours per week with <5 excess MET-hours/week). Conclusions In this sample of middle-aged adults, drawn from the general population, physical activity was inversely associated with BMI and body fat percentage. For people with the same BMI, those who were more active had a lower body fat percentage.
UK Biobank provides a unique opportunity to study the association between physical activity and various body composition measures. We examined the relationship between physical activity and both total and central body fat separately for premenopausal and postmenopausal women, since previous studies suggest menopause-related changes in fat accumulation and distribution. We also assessed whether higher overall levels of physical activity were associated with lower fat percentage and absolute mass, for a given body mass index category.
Methods
A total of 40,006 premenopausal and 81,407 postmenopausal generally healthy women aged 39–70 in UK Biobank were included in this cross-sectional study. Self-reported information on frequency and duration of low, moderate, and vigorous physical activity was collected by touchscreen questionnaire. Physical activity was calculated as metabolic equivalent task hours per week (MET-hours/week) and participants were categorised as having low (<10 MET-hours/week), moderate (10–49.9 MET-hours/week), and high (>50 MET-hours/week) levels of physical activity based on International Physical Activity Questionnaire guidelines. Body size was measured by trained technicians. Overall adiposity was assessed by body mass index (BMI) as well as body fat percentage and mass (bioelectrical impedance). Central adiposity was represented using waist circumference, waist-hip ratio, trunk fat mass, and trunk fat percentage. Associations between body composition measures were analysed using multiple linear regression. We adjusted for age at recruitment, educational qualifications, quintiles of Townsend deprivation index, parity, hormone replacement therapy use, and smoking status. Stata 13 (StataCorp LP, Texas, USA) was used for all statistical analyses.
Results
The median (IQR) physical activity was 29.1 MET-hours/week (13.9–54.2) for premenopausal and 31.8 MET-hours/week (15.5–62.0) for postmenopausal women. All measures of total and central adiposity decreased with increasing physical activity. An increase in physical activity from low to moderate or moderate to high was associated with an average 0.94 unit lower BMI (95% CI 0.88–1.01) for premenopausal and 0.82 unit lower BMI (95% CI 0.77–0.86) for postmenopausal women. For a given BMI category, those with a moderate level of physical activity had a lower body fat percentage than those with a low level and the group with the highest level of physical activity had the lowest body fat percentage for a given BMI category.
Conclusion
Both total and central adiposity decrease with increasing levels of physical activity. For a given BMI category, greater physical activity is associated with decreased body and trunk fat mass and percentage.
Body size is an important modifiable risk factor for postmenopausal breast cancer. However, it remains unclear whether direct measures of fat mass are better indicators of risk than anthropometric measures, or whether central adiposity may contribute to risk beyond overall adiposity. We analyzed data from 162,691 postmenopausal women in UK Biobank followed from 2006 to 2014. Body size was measured by trained technicians. Multivariable‐adjusted Cox regression was used to estimate relative risks. Analyses were stratified by age at recruitment, region and socioeconomic status, and adjusted for family history of breast cancer, age at menarche, age at first birth, parity, age at menopause, previous hormone replacement therapy use, smoking, alcohol intake, height, physical activity and ethnicity. We observed 2,913 incident invasive breast cancers during a mean 5.7 years of follow‐up. There was a continuous increase in risk of postmenopausal breast cancer with increasing adiposity, across all measures. The point estimate, comparing women in the top (median 37.6 kg) to bottom (median 17.6 kg) quartile of body fat mass was 1.70 (95% confidence interval 1.52–1.90). The magnitudes of the associations between per SD increase in BMI and body fat mass with breast cancer risk were similar, suggesting impedance measures of fat were not substantially better indicators of risk than anthropometric measures. After adjusting for body fat mass, the associations between anthropometric measures of central adiposity and breast cancer risk were attenuated. The magnitude of risk, across all measures of adiposity, was greater in women who had been postmenopausal for 12 or more years.
Gap junction channels, which are made of connexins, are critical for intercellular communication, a function that may be disrupted in a variety of diseases. We studied the consequences of two cataract-associated mutations at adjacent positions at the first extracellular boundary in human connexin50 (Cx50), W45S and G46V. Both of these mutants formed gap junctional plaques when they were expressed in HeLa cells, suggesting that they trafficked to the plasma membrane properly. However, their functional properties differed. Dual two-microelectrode voltage-clamp studies showed that W45S did not form functional intercellular channels in paired Xenopus oocytes or hemichannel currents in single oocytes. When W45S was coexpressed with wild-type Cx50, the mutant acted as a dominant negative inhibitor of wild-type function. In contrast, G46V formed both functional gap junctional channels and hemichannels. G46V exhibited greatly enhanced currents compared with wild-type Cx50 in the presence of physiological calcium concentrations. This increase in hemichannel activity persisted when G46V was coexpressed with wild-type lens connexins, consistent with a dominant gain of hemichannel function for G46V. These data suggest that although these two mutations are in adjacent amino acids, they have very different effects on connexin function and cause disease by different mechanisms: W45S inhibits gap junctional channel function; G46V reduces cell viability by forming open hemichannels.
Body size and physical activity are important modifiable risk factors for breast cancer. However, many previous studies are limited by the use of body mass index (BMI), which is unable to distinguish between fat and lean mass. Questions also remain over the role of vigorous compared to lower intensity physical activity in relation to breast cancer risk. We investigate the associations between BMI, body fat percentage, waist-to-hip ratio, waist-to-height ratio, total and vigorous physical activity and both premenopausal and postmenopausal breast cancer.
Methods
We analysed data from 48,713 premenopausal and 127,850 postmenopausal women in UK Biobank followed prospectively from 2006 through 2012. We observed 443 premenopausal and 1,422 postmenopausal incident invasive breast cancers during a mean 3.84 years of follow-up. Body size was measured by trained technicians. Self-reported frequency and duration of walking, moderate, and vigorous physical activity was collected by touchscreen questionnaire and calculated as metabolic equivalent task hours per week (MET-hrs/wk). Multivariable-adjusted Cox regression was used. Current users of hormone replacement therapy (HRT) were excluded. All analyses were stratified by age, region, and socioeconomic status and adjusted for family history of breast cancer, previous HRT use, height, parity, age at first birth, smoking, age at menarche, alcohol intake frequency, and age at menopause (for postmenopausal women only). Stata 13 (StataCorp LP, Texas, USA) was used for all statistical analyses.
Results
All measures of adiposity were positively associated with increased breast cancer risk in postmenopausal but not premenopausal women. Compared with postmenopausal women in the lowest quartile of body fat percentage (16.8–32.9%; median, 29.6%), women in the highest quartile (41.9–54.3%; 44.8%) had an increased risk of breast cancer (HR, 1.47; 95% confidence interval, 1.24–1.74; ptrend < 0.001). Vigorous physical activity was associated with lower breast cancer risk in postmenopausal but not premenopausal women. Postmenopausal women who participated in an average of 17.5 MET-h/week of vigorous physical activity had a 15% lower risk of breast cancer (HR 0.85; 0.74–0.98; ptrend = 0.025) which was attenuated after adjusting for body fat percentage (HR 0.88, 0.77–1.02, ptrend = 0.084). Higher levels of total physical activity were associated with non-statistically significant breast cancer risk reductions in all women.
Conclusion
Postmenopausal breast cancer risk is strongly associated with greater adiposity. Although greater vigorous physical activity is protective against postmenopausal breast cancer, adjusting for body fat percentage attenuated the association. Longer follow-up is needed to clarify associations, particularly in premenopausal women. In future analyses, we plan to subdivide cancers by hormone receptor status.
The treatment for recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) with immune checkpoint inhibitors (anti-PD1) with or without chemotherapy has led to an improvement in survival. Yet, despite this therapeutic advancement, only 15%-19% of patients remain alive at four years, highlighting the poor survival and unmet need for improved therapies for this patient population. Some of the key evolving novel therapeutics beyond anti-PD1 in R/M HNSCC have included therapeutic vaccine therapies, bispecific antibodies/fusion proteins and multitargeted kinase inhibitors, and antibody-drug conjugates (ADCs). Multiple concurrent investigations of novel therapeutics for patients with R/M HNSCC beyond anti-PD(L)1 inhibition are currently underway with some promising early results. Beyond immune checkpoint inhibition, novel immunotherapeutic strategies including therapeutic vaccines ranging from targeting human papillomavirus-specific epitopes to personalized neoantigen vaccines are ongoing with some early efficacy signals and large, randomized trials. Other novel weapons including bispecific antibodies, fusion proteins, and multitargeted kinase inhibitors leverage multiple concurrent targets and modulation of the tumor microenvironment to harness antitumor immunity and inhibition of protumorigenic signaling pathways with emerging promising results. Finally, as with other solid tumors, ADCs remain a promising therapeutic intervention either alone or in combination with immunotherapy for patients with R/M HNSCC. With early enthusiasm across novel therapies in R/M HNSCC, results of larger randomized trials in R/M HNSCC are eagerly awaited.
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