Jessica D. Bihuniak

Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses

Activated T cells engage aerobic glycolysis and anabolic metabolism for growth, proliferation, and effector functions. We propose that a glucose-poor tumor microenvironment limits aerobic glycolysis in tumor-infiltrating T cells, which suppresses tumoricidal effector functions. We discovered a new role for the glycolytic metabolite phosphoenolpyruvate (PEP) in sustaining T cell receptor-mediated Ca(2+)-NFAT signaling and effector functions by repressing sarco/ER Ca(2+)-ATPase (SERCA) activity. Tumor-specific CD4 and CD8 T cells could be metabolically reprogrammed by increasing PEP production through overexpression of phosphoenolpyruvate carboxykinase 1 (PCK1), which bolstered effector functions. Moreover, PCK1-overexpressing T cells restricted tumor growth and prolonged the survival of melanoma-bearing mice. This study uncovers new metabolic checkpoints for T cell activity and demonstrates that metabolic reprogramming of tumor-reactive T cells can enhance anti-tumor T cell responses, illuminating new forms of immunotherapy.

Adequate dietary protein is associated with better physical performance among post-menopausal women 60-90 years

Objectives: ObjectivesSarcopenia, the involuntary loss of skeletal muscle with age, affects up to onequarter of older adults. Evidence indicates a positive association between dietary protein intake and lean muscle mass and strength among older persons, but information on dietary proteins effect on physical performance in older adults has received less attention.DesignCross-sectional observational analysis of the relationship of dietary protein on body composition and physical performance.SettingClinical research center.Participants387 healthy women aged 60–90 years (mean 72.7 ± 7.0 y).MeasurementsMeasures included body composition (fat-free mass, appendicular skeletal mass and fat mass) via dual x-ray absorptiometry (DXA), physical performance (Physical Performance Test [PPT] and Short Physical Performance Battery [SPPB]), handgrip strength, Physical Activity Scale in the Elderly (PASE), quality of life measure (SF-8), falls, fractures, nutrient and macromolecule intake (four-day food record). Independent samples t-tests determined mean differences between the above or below RDA protein groups.Statistical AnalysisAnalysis of covariance was used to control for body mass index (BMI) between groups when assessing physical performance, physical activity and health-related quality of life.ResultsThe subjects consumed an average of 72.2 g protein/day representing 1.1 g protein/kg body weight/day. Subjects were categorized as below the recommended daily allowance (RDA) for protein (defined as less than 0.8 g protein/kg) or at or above the RDA (equal to or higher than 0.8 g protein/kg). Ninety-seven subjects (25%) were in the low protein group, and 290 (75%) were in the higher protein group. Women in the higher protein group had lower body mass, including fat and lean mass, and fat-to-lean ratio than those in the lower-protein group (p <0.001). Composite scores of upper and lower extremity strength were impaired in the group with low protein intake; SPPB score was 9.9±1.9 compared to 10.6±1.6 in those with higher protein intake and PPT was 19.8± 2.9 compared to 20.9±2.1 in the low and higher protein groups, respectively. The results were attenuated by correction for BMI, but remained significant. The physical component of the SF-8 was also lower in the low protein group but did not remain significant when controlling for BMI. No significant differences were found in hand grip strength or reported physical activity.ConclusionHealthy, older postmenopausal women consumed, on average, 1.1 g/kg/d protein, although 25% consumed less than the RDA. Those in the low protein group had higher body fat and fat-to-lean ratio than those who consumed the higher protein diet. Upper and lower extremity function was impaired in those who consumed a low protein diet compared to those with a higher protein intake. Protein intake should be considered when evaluating the multi-factorial loss of physical function in older women.

The Effect of the Traditional Mediterranean-Style Diet on Metabolic Risk Factors: A Meta-Analysis

The Mediterranean-style diet (MedSD) has gained attention for its positive effects on health outcomes, including metabolic risk factors. However, it is unknown as to which components of MedSD interventions are most beneficial in reducing risk. The objective of this meta-analysis was to obtain effect sizes for metabolic risk factors and explain the variability across the current literature based on study design, sample, and diet characteristics. Six electronic databases were searched from inception until 9 February 2016. Data from 29 studies (N = 4133) were included. There were significant effects in favor of the MedSD for waist circumference, triglycerides, blood glucose, systolic blood pressure, and diastolic blood pressure (d+ = −0.54; d+ = −0.46; d+ = −0.50; d+ = −0.72; d+ = −0.94, respectively). The MedSD was significantly beneficial when the intervention was longer in duration, was conducted in Europe, used a behavioral technique, and was conducted using small groups. The traditional MedSD had significant beneficial effects on five of the six metabolic risk factors. Results from this study provide support for population specific dietary guideline for metabolic risk reduction.

The effect of a whey protein supplement on bone mass in older Caucasian adults

CONTEXT It has been assumed that the increase in urine calcium (Ca) that accompanies an increase in dietary protein was due to increased bone resorption. However, studies using stable Ca isotopes have found that dietary protein increases Ca absorption without increasing bone resorption. OBJECTIVE The objective of the study was to investigate the impact of a moderately high protein diet on bone mineral density (BMD). DESIGN This was a randomized, double-blind, placebo-controlled trial of protein supplementation daily for 18 months. SETTING The study was conducted at two institutional research centers. PARTICIPANTS Two hundred eight older women and men with a body mass index between 19 and 32 kg/m(2) and a self-reported protein intake between 0.6 and 1.0 g/kg participated in the study. INTERVENTION Subjects were asked to incorporate either a 45-g whey protein or isocaloric maltodextrin supplement into their usual diet for 18 months. MAIN OUTCOME MEASURE BMD by dual-energy x-ray absorptiometry, body composition, and markers of skeletal and mineral metabolism were measured at baseline and at 9 and 18 months. RESULTS There were no significant differences between groups for changes in L-spine BMD (primary outcome) or the other skeletal sites of interest. Truncal lean mass was significantly higher in the protein group at 18 months (P = .048). C-terminal telopeptide (P = .0414), IGF-1 (P = .0054), and urinary urea (P < .001) were also higher in the protein group at the end of the study period. There was no difference in estimated glomerular filtration rate at 18 months. CONCLUSION Our data suggest that protein supplementation above the recommended dietary allowance (0.8 g/kg) may preserve fat-free mass without adversely affecting skeletal health or renal function in healthy older adults.

Methodologic quality of meta-analyses and systematic reviews on the Mediterranean diet and cardiovascular disease outcomes: a review

BACKGROUND Several systematic reviews/meta-analyses published within the past 10 y have examined the associations of Mediterranean-style diets (MedSDs) on cardiovascular disease (CVD) risk. However, these reviews have not been evaluated for satisfying contemporary methodologic quality standards. OBJECTIVE This study evaluated the quality of recent systematic reviews/meta-analyses on MedSD and CVD risk outcomes by using an established methodologic quality scale. The relation between review quality and impact per publication value of the journal in which the article had been published was also evaluated. DESIGN To assess compliance with current standards, we applied a modified version of the Assessment of Multiple Systematic Reviews (AMSTARMedSD) quality scale to systematic reviews/meta-analyses retrieved from electronic databases that had met our selection criteria: 1) used systematic or meta-analytic procedures to review the literature, 2) examined MedSD trials, and 3) had MedSD interventions independently or combined with other interventions. RESULTS Reviews completely satisfied from 8% to 75% of the AMSTARMedSD items (mean ± SD: 31.2% ± 19.4%), with those published in higher-impact journals having greater quality scores. At a minimum, 60% of the 24 reviews did not disclose full search details or apply appropriate statistical methods to combine study findings. Only 5 of the reviews included participant or study characteristics in their analyses, and none evaluated MedSD diet characteristics. CONCLUSIONS These data suggest that current meta-analyses/systematic reviews evaluating the effect of MedSD on CVD risk do not fully comply with contemporary methodologic quality standards. As a result, there are more research questions to answer to enhance our understanding of how MedSD affects CVD risk or how these effects may be modified by the participant or MedSD characteristics. To clarify the associations between MedSD and CVD risk, future meta-analyses and systematic reviews should not only follow methodologic quality standards but also include more statistical modeling results when data allow.

Dietary Protein-Induced Increases in Urinary Calcium Are Accompanied by Similar Increases in Urinary Nitrogen and Urinary Urea: A Controlled Clinical Trial

To determine the usefulness of urinary urea as an index of dietary protein intake, 10 postmenopausal women were enrolled in and completed a randomized, double-blind, cross-over feeding trial from September 2008 to May 2010 that compared 10 days of a 45-g whey supplement with 10 days of a 45-g maltodextrin control. Urinary nitrogen, urinary calcium, urinary urea, and bone turnover markers were measured at days 0, 7, and 10. Paired sample t tests, Pearsons correlation statistic, and simple linear regression were used to assess differences between treatments and associations among urinary metabolites. Urinary nitrogen/urinary creatinine rose from 12.3±1.7 g/g (99.6±13.8 mmol/mmol) to 16.8±2.2 g/g (135.5±17.8 mmol/mmol) with whey supplementation, but did not change with maltodextrin. Whey supplementation caused urinary calcium to rise by 4.76±1.84 mg (1.19±0.46 mmol) without a change in bone turnover markers. Because our goal was to estimate protein intake from urinary nitrogen/urinary creatinine, we used our data to develop the following equation: protein intake (g/day)=71.221+1.719×(urinary nitrogen, g)/creatinine, g) (R=0.46, R(2)=0.21). As a more rapid and less costly alternative to urinary nitrogen/urinary creatinine, we next determined whether urinary urea could predict protein intake and found that protein intake (g/day)=63.844+1.11×(urinary urea, g/creatinine, g) (R=0.58, R(2)=0.34). These data indicate that urinary urea/urinary creatinine is at least as good a marker of dietary protein intake as urinary nitrogen and is easier to quantitate in nutrition intervention trials.

Social networks and social norms are associated with obesity treatment outcomes.

To examine whether overweight social network members and normative influence for obesity are associated with weight loss outcomes during obesity treatment.

Supplementing a Low-Protein Diet with Dibasic Amino Acids Increases Urinary Calcium Excretion in Young Women

Increasing dietary protein within a physiologic range stimulates intestinal calcium absorption, but it is not known if specific amino acids or dietary protein as a whole are responsible for this effect. Therefore, we selectively supplemented a low-protein (0.7 g/kg) diet with either the calcium-sensing receptor-activating amino acids (CaSR-AAAs) L-tryptophan, L-phenylalanine, and L-histidine, or the dibasic amino acids (DAAs) L-arginine and L-lysine, to achieve intakes comparable to the content of a high-protein diet (2.1 g/kg) and measured intestinal calcium absorption. Fourteen young women took part in a placebo-controlled, double-blind, crossover feeding trial in which each participant ingested a 6-d low-protein diet supplemented with CaSR-AAAs, DAAs, or methylcellulose capsules (control) after an 11-d adjustment period. All participants ingested all 3 diets in random order. Intestinal calcium absorption was measured between days 5 and 6 using dual-stable calcium isotopes ((42)Ca, (43)Ca, and (44)Ca). There was no difference in calcium absorption between the diet supplemented with CaSR-AAAs (22.9 ± 2.0%) and the control diet (22.3 ± 1.4%) (P = 0.64). However, calcium absorption tended to be greater during the DAA supplementation period (25.2 ± 1.4%) compared with the control diet period (22.3 ± 1.4%) (P < 0.10). Larger and longer clinical trials are needed to clarify the possible benefit of arginine and lysine on calcium absorption.

The effects of dietary protein and amino acids on skeletal metabolism

Dietary protein is required for optimal skeletal growth and maturation. Although Recommended Dietary Allowances (RDAs) exist for global dietary protein intake, the level and sources of dietary protein that are optimal for skeletal health over the life continuum have not been established. This is partly due to the difficulty in quantifying the effects of variable levels of a nutrients intake over a lifetime as well as the complex nature of the relationships between dietary protein and calcium economy. Areas of current uncertainty include the precise source and amount of dietary protein required for optimal skeletal accretion and maintenance of skeletal mass, as well as the site-specific effects of dietary protein. The cellular and molecular mechanisms that underpin the actions of dietary protein on mineral metabolism and skeletal homeostasis remain unclear. This review attempts to summarize recent data bearing on these questions.

Adherence to a Mediterranean-Style Diet and Its Influence on Cardiovascular Risk Factors in Postmenopausal Women

BACKGROUND A Mediterranean-style diet (MedSD) is associated with positive health outcomes, particularly reduced risk of cardiovascular disease. It is of interest to assess the feasibility of adherence to a MedSD in a subset of older adults in the United States. OBJECTIVE To assess the efficacy of implementing a MedSD intervention in a subset of postmenopausal women living in the United States, and to detect the influence of this dietary pattern on blood lipid levels. DESIGN A partial feeding, nutrition counseling, pilot study with a one-group longitudinal design. PARTICIPANTS Sixteen healthy, postmenopausal, American women living in suburban communities in Farmington, CT, with a mean±standard deviation age of 77±6.8 years and a body mass index of 26.1±3.1. INTERVENTION Participants were counseled by a registered dietitian nutritionist on how to follow a MedSD, which included increased sources of n-3 polyunsaturated fatty acids, fruits, and vegetables, and decreased saturated fat, n-6 polyunsaturated fatty acids, and simple sugars for 12 weeks. To maintain isocaloric conditions, participants were asked to substitute sources of saturated fat and refined carbohydrates for extra virgin olive oil (3 T/day), walnuts (1.5 oz/day), and fatty fish (3 to 5 servings/wk), which were provided at 3-week intervals. MAIN OUTCOME MEASURES Dietary adherence measures included the Mediterranean Diet Score, 3-day diet records, and serum fatty acid and lipid profiles. STATISTICAL ANALYSES Mixed model longitudinal analyses were conducted to assess changes over time (Weeks 0, 12, and 24) in the outcome variables. RESULTS Mediterranean Diet Score increased by 8.9 points (P<0.001) after the MedSD phase. Dietary sugar decreased by 10.8 g (P<0.05), total dietary n-3 increased by 1.6 g (P<0.01), total dietary n-6 increased by 5.5 g (P<0.01), and dietary n-6:n3 ratio decreased by 3.6 units (P<0.01). In serum, 22:6 (n-3), 20:5 (n-3), and 18:3 (n-3) increased (P<0.001, P<0.01, and P<0.001, respectively), and 14:0, 16:0, 17:0, 20:4 (n-6), 22:4 (n-6) declined after the intervention (P<0.01, P<0.001, P<0.01, P<0.01, and P<0.001, respectively), which support a change in dietary intake toward a MedSD. Serum high-density lipoprotein cholesterol levels increased by 3.8 mg/dL (0.098 mmol/L) (P<0.05) and serum triglyceride levels decreased by 11.6 mg/dL (0.131 mmol/L) (P<0.10). CONCLUSIONS A pilot study of a 12-week MedSD intervention with counseling from a registered dietitian nutritionist can favorably influence the dietary pattern and lipid profile of postmenopausal women living in the United States.