Salvage therapy expands highly cytotoxic and metabolically fit resilient CD8+ T cells via ME1 up-regulation.

Patients with advanced cancers who either do not experience initial response to or progress while on immune checkpoint inhibitors (ICIs) receive salvage radiotherapy to reduce tumor burden and tumor-related symptoms. Occasionally, some patients experience substantial global tumor regression with a rebound of cytotoxic CD8+ T cells. We have termed the rebound of cytotoxic CD8+ T cells in response to salvage therapy as T cell resilience and examined the underlying mechanisms of resilience. Resilient T cells are enriched for CX3CR1+ CD8+ T cells with low mitochondrial membrane potential, accumulate less reactive oxygen species (ROS), and express more malic enzyme 1 (ME1). ME1 overexpression enhanced the cytotoxicity and expansion of effector CD8+ T cells partially via the type I interferon pathway. ME1 also increased mitochondrial respiration while maintaining the redox state balance. ME1 increased the cytotoxicity of peripheral lymphocytes from patients with advanced cancers. Thus, preserved resilient T cells in patients rebound after salvage therapy and ME1 enhances their resiliency.

Postmenopausal women's experiences of weight maintenance following a very low energy diet.

Introduction: Very low energy diets (VLEDs) effectively induce substantial weight loss in people with obesity, yet they are rarely used as a first line treatment. There is a belief that such diets do not teach the lifestyle behavior changes needed for long-term weight maintenance. However, little is known about the lived experiences of people who have lost weight on a VLED in the long term. Methods: This study aimed to explore the behaviors and experiences of postmenopausal women who had followed a 4-month VLED (using total meal replacement products [MRPs]), followed by a food-based, moderately energy-restricted diet for an additional 8 months, as part of the TEMPO Diet Trial. Qualitative in-depth semi-structured interviews were conducted with 15 participants at 12 or 24 months (i.e., at 8 or 20 months post diet completion). Transcribed interviews were analyzed thematically using an inductive approach. Results: Undertaking a VLED was reported by participants to confer advantages in weight maintenance that previous weight loss attempts had not been able to do for them. Firstly, the rapid and significant weight loss, in conjunction with ease of use, was motivational and helped instill confidence in the participants. Secondly, the cessation of a normal diet during the VLED was reported by participants to break weight gain-inducing habits, allowing them to abandon unhelpful habits and to introduce in their place more appropriate attitudes toward weight maintenance. Lastly, the new identity, helpful habits and increased self-efficacy around weight loss supported participants during weight maintenance. Additionally, participants reported that ongoing occasional use of MRPs provided a useful and easy new strategy for countering weight regain and supporting their weight maintenance regimen. Conclusion: Among the participants in this qualitative study, most of whom had maintained a loss of over 10% of their baseline body weight at the time of interview, using a VLED in the context of a clinical weight loss trial conferred confidence, motivation and skills for weight maintenance. These findings indicate that VLEDs with clinical support could be successfully leveraged to set up behaviors that will support weight maintenance in the long term.

A Novel PD-L1 Antibody Promotes Antitumor Function of Peripheral Cytotoxic Lymphocytes after Radical Nephrectomy in Patients with Renal Cell Carcinoma.

The intrinsic and acquired resistance to PD-1/PD-L1 immune checkpoint blockade is an important challenge for patients and clinicians because no reliable tool has been developed to predict individualized response to immunotherapy. In this study, we demonstrate the translational relevance of an ex vivo functional assay that measures the tumor cell killing ability of patient-derived CD8 T and NK cells (referred to as "cytotoxic lymphocytes," or CLs) isolated from the peripheral blood of patients with renal cell carcinoma. Patient-derived PBMCs were isolated before and after nephrectomy from patients with renal cell carcinoma. We compared the efficacy of U.S. Food and Drug Administration (FDA)-approved PD-1/PD-L1 inhibitors (pembrolizumab, nivolumab, atezolizumab) and a newly developed PD-L1 inhibitor (H1A Ab) in eliciting cytotoxic function. CL activity was improved at 3 mo after radical nephrectomy compared with baseline, and it was associated with higher circulating levels of tumor-reactive effector CD8 T cells (CD11ahighCX3CR1+GZMB+). Treatment of PBMCs with FDA-approved PD-1/PD-L1 inhibitors enhanced tumor cell killing activity of CLs, but a differential response was observed at the individual-patient level. H1A demonstrated superior efficacy in promoting CL activity compared with FDA-approved PD-1/PD-L1 inhibitors. PBMC immunophenotyping by mass cytometry revealed enrichment of effector CD8 T and NK cells in H1A-treated PBMCs and immunosuppressive regulatory T cells in atezolizumab-treated samples. Our study lays the ground for future investigation of the therapeutic value of H1A as a next-generation immune checkpoint inhibitor and the potential of measuring CTL activity in PBMCs as a tool to predict individual response to immune checkpoint inhibitors in patients with advanced renal cell carcinoma.

'Get Healthy!' physical activity and healthy eating intervention for adults with intellectual disability: results from the feasibility pilot.

BACKGROUND: People with intellectual disabilities (ID) experience high rates of lifestyle related morbidities, in part due to lack of access to tailored health promotion programmes. This study aimed to assess the feasibility and preliminary efficacy of a tailored healthy lifestyle intervention, Get Healthy! METHODS: Get Healthy! is a 12-week physical activity and healthy eating programme designed to address lifestyle-related risks for adults with mild-moderate ID. The feasibility pilot was designed to assess subjective participant experience and programme feasibility across: recruitment and screening, retention, session attendance and engagement, adverse events, and practicality and reliability of outcome procedures. Exploratory programme efficacy was assessed across the following measures: anthropometry (body mass index, weight, waist circumference), cardiovascular fitness, physical strength, dietary intake, healthy literacy, and quality of life. RESULTS: Six participants with moderate ID and two carer participants completed the feasibility trial, representing a 100% retention rate. Qualitative data indicated the programme was well received. Participants with ID attended 75% of sessions offered and displayed a high level of engagement in sessions attended (91% mean engagement score). While most data collection procedures were feasible to implement, several measures were either not feasible for our participants, or required a higher level of support to implement than was provided in the existing trial protocol. Participants with ID displayed decreases in mean waist circumference between baseline and endpoint (95% CI: - 3.20, - 0.17 cm) and some improvements in measures of cardiovascular fitness and physical strength. No changes in weight, body mass index, or objectively measured knowledge of nutrition and exercise or quality of life were detected from baseline to programme endpoint. Dietary intake results were mixed. DISCUSSION: The Get Healthy! programme was feasible to implement and well received by participants with moderate ID and their carers. Exploratory efficacy data indicates the programme has potential to positively impact important cardiometabolic risk factors such as waist circumference, cardiovascular fitness, and physical strength. Several of the proposed data collection instruments will require modification or replacement prior to use in a sufficiently powered efficacy trial. TRIAL REGISTRATION: ACTRN: ACTRN12618000349246. Registered March 8th 2018-retrospectively registered, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374497 UTN: U1111-1209-3132.

A Novel Humanized PD-1/PD-L1 Mouse Model Permits Direct Comparison of Antitumor Immunity Generated by Food and Drug Administration-Approved PD-1 and PD-L1 Inhibitors.

Seven different anti-PD-1 and PD-L1 mAbs are now widely used in the United States to treat a variety of cancer types, but no clinical trials have compared them directly. Furthermore, because many of these Abs do not cross-react between mouse and human proteins, no preclinical models exist in which to consider these types of questions. Thus, we produced humanized PD-1 and PD-L1 mice in which the extracellular domains of both mouse PD-1 and PD-L1 were replaced with the corresponding human sequences. Using this new model, we sought to compare the strength of the immune response generated by Food and Drug Administration-approved Abs. To do this, we performed an in vivo T cell priming assay in which anti-PD-1/L1 therapies were given at the time of T cell priming against surrogate tumor Ag (OVA), followed by subsequent B16-OVA tumor challenge. Surprisingly, both control and Ab-treated mice formed an equally robust OVA-specific T cell response at the time of priming. Despite this, anti-PD-1/L1-treated mice exhibited significantly better tumor rejection versus controls, with avelumab generating the best protection. To determine what could be mediating this, we identified the increased production of CX3CR1+PD-1+CD8+ cytotoxic T cells in the avelumab-treated mice, the same phenotype of effector T cells known to increase in clinical responders to PD-1/L1 therapy. Thus, our model permits the direct comparison of Food and Drug Administration-approved anti-PD-1/L1 mAbs and further correlates successful tumor rejection with the level of CX3CR1+PD-1+CD8 + T cells, making this model a critical tool for optimizing and better utilizing anti-PD-1/L1 therapeutics.

Cancer-targeted photoimmunotherapy induces antitumor immunity and can be augmented by anti-PD-1 therapy for durable anticancer responses in an immunologically active murine tumor model.

The complex immunosuppressive nature of solid tumor microenvironments poses a significant challenge to generating efficacious and durable anticancer responses. Photoimmunotherapy is a cancer treatment strategy by which an antibody is conjugated with a non-toxic light-activatable dye. Following administration of the conjugate and binding to the target tumor, subsequent local laser illumination activates the dye, resulting in highly specific target cell membrane disruption. Here we demonstrate that photoimmunotherapy treatment elicited tumor necrosis, thus inducing immunogenic cell death characterized by the release of damage-associated molecular patterns (DAMPs). Photoimmunotherapy-killed tumor cells activated dendritic cells (DC), leading to the production of proinflammatory cytokines, T cell stimulation, priming antigen-specific T cells, and durable memory T cell responses, which led complete responder mice to effectively reject new tumors upon rechallenge. PD-1 blockade in combination with photoimmunotherapy enhanced overall anticancer efficacy, including against anti-PD-1-resistant tumors. The combination treatment also elicited abscopal anticancer activity, as observed by reduction of distal, non-illuminated tumors, further demonstrating the ability of photoimmunotherapy to harness local and peripheral T cell responses. With this work we therefore delineate the immune mechanisms of action for photoimmunotherapy and demonstrate the potential for cancer-targeted photoimmunotherapy to be combined with other immunotherapy approaches for augmented, durable anticancer efficacy. Moreover, we demonstrate responses utilizing various immunocompetent mouse models, as well as in vitro data from human cells, suggesting broad translational potential.

Dietary or supplemental intake of antioxidants and the risk of mortality in older people: A systematic review.

PURPOSE: Antioxidants have a protective role in the prevention of cancer, cardiovascular disease and all-cause mortality. The association between dietary or supplemental intake of various antioxidants and all-cause mortality or cause-specific mortality among older populations is inconclusive. This systematic review aimed to systematically evaluate whether higher dietary or supplemental intake of antioxidants can lower the risk of all-cause mortality or cause-specific mortality in the older population. METHODS: Five electronic databases were searched to identify studies that evaluated the effects of dietary or supplemental intake of antioxidants on cause-specific or all-cause mortality in the older population aged ≥65 years. The overall quality of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. Twenty-two longitudinal, prospective observational studies and randomised controlled trial (RCT) studies involving 1 090 844 cases of cause-specific and all-cause mortality were included. The overall quality of studies was high with a low risk of bias. RESULT: Of the 22 studies, 16 were observational studies and 6 were RCTs. The overall quality of evidence for observational studies and RCTs were rated down as low (due to very serious risk of bias and indirectness) and moderate (due to unable to rule out publication bias), respectively. Nine studies showed significant decreases, four found significant increases and nine reported no association between antioxidant intake and risk of mortality. CONCLUSION: There was inconclusive evidence on the associations between dietary or supplemental intake of antioxidants and mortality in the older population. More clinical trials are required to confirm the associations.

Sex differences in gene expression patterns associated with the APOE4 allele.

Background: The APOE gene encodes apolipoprotein ε (ApoE), a protein that associates with lipids to form lipoproteins that package and traffic cholesterol and lipids through the bloodstream. There are at least three different alleles of the APOE gene: APOE2, APOE3, and APOE4. The APOE4 allele increases an individual's risk for developing late-onset Alzheimer disease (AD) in a dose-dependent manner. Sex differences have been reported for AD susceptibility, age of onset, and symptom progression, with females being more affected than males. Methods: In this study, we use a systems biology approach to examine gene expression patterns in the brains of aged female and male individuals who are positive for the APOE4 allele in order to identify possible sex-related differences that may be relevant to AD. Results: Based on correlation analysis, we identified a large number of genes with an expression pattern similar to that of APOE in APOE4-positive individuals. The number of these genes was much higher in APOE4-positive females than in APOE4-positive males, who in turn had more of such genes than APOE4-negative control groups. Our findings also indicate a significant sex* genotype interaction for the CNTNAP2 gene, a member of the neurexin family and a significant interaction for brain area*sex* genotype for PSEN2, a risk factor gene for AD.  Conclusions: Profiling of these genes using Gene Ontology (GO) term classification, pathway enrichment, and differential expression analysis supports the idea of a transcriptional role of APOE with respect to sex differences and AD.

Effectiveness and Behavioral Mechanisms of Social Media Interventions for Positive Nutrition Behaviors in Adolescents: A Systematic Review.

PURPOSE: To determine the effectiveness of social media-based interventions in promoting positive changes in nutrition behaviors amongst adolescents, and identify the behavior change technique(s) (BCT(s)) that were used in effective interventions. METHODS: MEDLINE, Embase, PsycINFO, Cinahl, and Cochrane library were systematically searched. Eligible studies included: participants aged 13-18 years; use of one or more social media platform(s) in the intervention; a comparison group not exposed to the social media-based intervention; nutrition- and diet-related behavior outcome(s); and an experimental study design. BCTs were identified using a behavior change taxonomy. Quality and risk of bias assessments were also conducted. RESULTS: Seven eligible interventions were included, varying from internet-only programs to in-person programs with internet or website-based component(s). Studies used relatively outdated forms of social media such as purpose-built discussion boards or chat rooms rather than commercial social media interfaces (e.g. Facebook). Five of the seven interventions demonstrated improvements in at least one nutrition behavior. The most common improvement was for fruit or vegetable intake, and two of four studies showed improvements for sugar-sweetened beverage consumption. The most common BCT used was social support, followed by demonstration of behavior, self-monitoring, goal setting, and feedback. CONCLUSIONS: The current evidence base is equivocal with respect to changing overall dietary behaviors, as increasing intakes of desirable food groups were more successful than decreasing unfavorable food habits. Further research using better quality interventions, full description of the BCTs, long-term follow-up, and popular contemporary social media platforms to build the evidence base are required.

'Get Healthy!' A physical activity and nutrition program for older adults with intellectual disability: pilot study protocol.

BACKGROUND: Older adults with intellectual disability have high rates of lifestyle-related illness yet remain poorly engaged in physical activity and nutrition interventions. There is a need to clarify what types of healthy lifestyle interventions are feasible and effective to implement in this population and how outcome measures can best be tracked. This paper describes the pilot feasibility study protocol for implementing a 12-week physical activity and healthy eating program, 'Get Healthy!' with older adults with intellectual disability. METHODS: The primary study aims are to assess the feasibility of implementing and monitoring the 'Get Healthy!' program with adults with mild to moderate intellectual disability, aged 40 years and over, and their carers. Secondary study aims are to assess the impact of the intervention across the following parametres: body mass index, waist circumference, cardiovascular fitness, physical activity (amount and intensity) and sedentary behaviours, resting blood pressure, functional strength/capacity, dietary intake (energy intake, food group consumption and diet quality), dietary and physical activity knowledge, and quality of life. Between 8 and 10 participants in total will be recruited into the 12-week program that will be run in metropolitan NSW, Australia. A combination of objective and subjective measures will be used to assess program feasibility and impact at set timepoints (baseline, mid and end-program). DISCUSSION: Results from the feasibility pilot will be used to refine the study methodology and 'Get Healthy!' program content for future use in a sufficiently powered trial. Findings may be of interest to a broad range of disability and allied health workers engaged in supporting and monitoring healthy lifestyle change in adults with intellectual disability. TRIAL REGISTRATION: ACTRN: ACTRN12618000349246. Registered March 8, 2018- Retrospectively registered, UTN: U1111-1209-3132.

Recruitment Strategies for a Randomised Controlled Trial Comparing Fast Versus Slow Weight Loss in Postmenopausal Women with Obesity-The TEMPO Diet Trial.

Current research around effective recruitment strategies for clinical trials of dietary obesity treatments have largely focused on younger adults, and thus may not be applicable to older populations. The TEMPO Diet Trial (Type of Energy Manipulation for Promoting optimal metabolic health and body composition in Obesity) is a randomised controlled trial comparing the long-term effects of fast versus slow weight loss on body composition and cardio-metabolic health in postmenopausal women with obesity. This paper addresses the recruitment strategies used to enrol participants into this trial and evaluates their relative effectiveness. 101 post-menopausal women aged 45⁻65 years, with a body mass index of 30⁻40 kg/m² were recruited and randomised to either fast or slow weight loss. Multiple strategies were used to recruit participants. The total time cost (labour) and monetary cost per randomised participant from each recruitment strategy was estimated, with lower values indicating greater cost-effectiveness and higher values indicating poorer cost-effectiveness. The most cost-effective recruitment strategy was word of mouth, followed (at equal second place) by free publicity on TV and radio, and printed advertorials, albeit these avenues only yielded 26/101 participants. Intermediate cost-effective recruitment strategies were flyer distribution at community events, hospitals and a local tertiary education campus, internet-based strategies, and clinical trial databases and intranets, which recruited a further 40/101 participants. The least cost-effective recruitment strategy was flyer distribution to local health service centres and residential mailboxes, and referrals from healthcare professionals were not effective. Recruiting for clinical trials involving postmenopausal women could benefit from a combination of recruitment strategies, with an emphasis on word of mouth and free publicity via radio, TV, and print media, as well as strategic placement of flyers, supplemented with internet-based strategies, databases and intranets if a greater yield of participants is needed.

Less Waste on Waist Measurements: Determination of Optimal Waist Circumference Measurement Site to Predict Visceral Adipose Tissue in Postmenopausal Women with Obesity.

With obesity being a leading cause of preventable death, it is vital to understand how best to identify individuals with greater risk of metabolic disease, especially those with high visceral adipose tissue (VAT). This study aimed to determine whether three commonly used waist circumference (WC) measurement sites could provide accurate estimations of VAT, as determined by magnetic resonance imaging (MRI), which is a gold standard for measuring VAT, in postmenopausal women with obesity. VAT volume was measured by MRI of the total abdomen in 97 women aged 57.7 ± 0.4 years (mean ± SEM), mean body mass index 34.5 ± 0.2 kg/m². WC was measured at the midpoint between the lowest rib and the iliac crest (WCmid), the narrowest point of the torso (WCnarrow), and at the level of the umbilicus (WCumbilicus). WC differed significantly according to measurement site, with WCnarrow (102.1 ± 0.7 cm) < WCmid (108.3 ± 0.7 cm) < WCumbilicus (115.7 ± 0.8 cm) (p < 0.001). WCmid, WCnarrow and WCumbilicus were all significantly correlated with VAT, as measured by MRI (r = 0.581, 0.563 and 0.390, respectively; p < 0.001 for all), but the relationships between WCmid or WCnarrow and VAT determined by MRI were stronger than for WCumbilicus. Measurement of either WCmid or WCnarrow provides valid estimates of VAT in postmenopausal women with obesity, with WCnarrow being favoured in light of its greater ease and speed of measurement in this population.

Accuracy of hands v. household measures as portion size estimation aids.

Accurate estimation of food portion size is critical in dietary studies. Hands are potentially useful as portion size estimation aids; however, their accuracy has not been tested. The aim of the present study was to test the accuracy of a novel portion size estimation method using the width of the fingers as a 'ruler' to measure the dimensions of foods ('finger width method'), as well as fists and thumb or finger tips. These hand measures were also compared with household measures (cups and spoons). A total of sixty-seven participants (70 % female; age 32·7 (sd 13·7) years; BMI 23·2 (sd  3·5) kg/m(2)) attended a 1·5 h session in which they estimated the portion sizes of forty-two pre-weighed foods and liquids. Hand measurements were used in conjunction with geometric formulas to convert estimations to volumes. Volumes determined with hand and household methods were converted to estimated weights using density factors. Estimated weights were compared with true weights, and the percentage difference from the true weight was used to compare accuracy between the hand and household methods. Of geometrically shaped foods and liquids estimated with the finger width method, 80 % were within ±25 % of the true weight of the food, and 13 % were within ±10 %, in contrast to 29 % of those estimated with the household method being within ±25 % of the true weight of the food, and 8 % being within ±10 %. For foods that closely resemble a geometric shape, the finger width method provides a novel and acceptably accurate method of estimating portion size.

Does Diet-Induced Weight Loss Lead to Bone Loss in Overweight or Obese Adults? A Systematic Review and Meta-Analysis of Clinical Trials.

Diet-induced weight loss has been suggested to be harmful to bone health. We conducted a systematic review and meta-analysis (using a random-effects model) to quantify the effect of diet-induced weight loss on bone. We included 41 publications involving overweight or obese but otherwise healthy adults who followed a dietary weight-loss intervention. The primary outcomes examined were changes from baseline in total hip, lumbar spine, and total body bone mineral density (BMD), as assessed by dual-energy X-ray absorptiometry (DXA). Secondary outcomes were markers of bone turnover. Diet-induced weight loss was associated with significant decreases of 0.010 to 0.015 g/cm(2) in total hip BMD for interventions of 6, 12, or 24 (but not 3) months' duration (95% confidence intervals [CIs], -0.014 to -0.005, -0.021 to -0.008, and -0.024 to -0.000 g/cm(2), at 6, 12, and 24 months, respectively). There was, however, no statistically significant effect of diet-induced weight loss on lumbar spine or whole-body BMD for interventions of 3 to 24 months' duration, except for a significant decrease in total body BMD (-0.011 g/cm(2); 95% CI, -0.018 to -0.003 g/cm(2)) after 6 months. Although no statistically significant changes occurred in serum concentrations of N-terminal propeptide of type I procollagen (P1NP), interventions of 2 or 3 months in duration (but not of 6, 12, or 24 months' duration) induced significant increases in serum concentrations of osteocalcin (0.26 nmol/L; 95% CI, 0.13 to 0.39 nmol/L), C-terminal telopeptide of type I collagen (CTX) (4.72 nmol/L; 95% CI, 2.12 to 7.30 nmol/L) or N-terminal telopeptide of type I collagen (NTX) (3.70 nmol/L; 95% CI, 0.90 to 6.50 nmol/L bone collagen equivalents [BCEs]), indicating an early effect of diet-induced weight loss to promote bone breakdown. These data show that in overweight and obese individuals, a single diet-induced weight-loss intervention induces a small decrease in total hip BMD, but not lumbar spine BMD. This decrease is small in comparison to known metabolic benefits of losing excess weight.

The neuropeptide Y-ergic system: potential therapeutic target against bone loss with obesity treatments.

Obesity is no longer considered to provide protection against osteoporosis. Moreover, treatments for obesity are now suspected of reducing bone mass. With the escalating incidence of obesity, combined with increases in the frequency, duration and intensity of interventions used to combat it, we face a potential increase in health burden due to osteoporotic fractures. The neuropeptide Y-ergic system offers a potential target for the prevention and anabolic treatment of bone loss in obesity, due to its dual role in the regulation of energy homeostasis and bone mass. Although the strongest stimulation of bone mass by this system appears to occur via indirect hypothalamic pathways involving Y2 receptors (one of the five types of receptors for neuropeptide Y), Y1 receptors on osteoblasts (bone-forming cells) induce direct effects to enhance bone mass. This latter pathway may offer a suitable target for anti-osteoporotic treatment while also minimizing the risk of adverse side effects.