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Purpose: (i) Characterize ultra-processed food (UPF) intakes in toddlerhood and mid-childhood, including identifying principal UPF sub-groups and associations with nutrient profile; (ii) explore stability and change in UPF intake between toddlerhood and mid-childhood., Methods: Data were from children in the UK Gemini twin cohort at 21 months (n = 2,591) and 7 years (n = 592) of age. UPF intakes were estimated using diet diaries and Nova classification. Complex samples general linear or logistic regression models were used to explore associations between UPF intake, UPF sub-groups and nutrients, and changes in intake over time., Results: The contribution of UPF to total energy was 46.9% (± 14.7) at 21 months and 59.4% (± 12.5) at 7 years. Principal UPF sub-groups were yogurts, higher-fiber breakfast cereals, and wholegrain breads in toddlerhood, and puddings and sweet cereal products and white breads in mid-childhood. At both ages, mean free sugar and sodium intakes exceeded recommended maximums and higher UPF consumption was associated with consuming more of each nutrient (P < 0.001). UPF intake was negatively associated with fat, saturated fat and protein intake in toddlerhood, and fiber intake in mid-childhood (P < 0.001). Being in the highest UPF intake quintile in toddlerhood was predictive of being in the highest quintile in mid-childhood (OR 9.40, 95%CI 3.94-22.46)., Conclusions: UPF accounted for nearly half of toddlers' energy, increasing to 59% in mid-childhood. Higher UPF consumers had higher intakes of free sugar and sodium. UPF intake in toddlerhood was predictive of mid-childhood intake. Effective policies are needed to reduce UPF intakes in the early years., (© 2024. The Author(s).)

Purpose: People living with and beyond cancer (LWBC) are advised to achieve a body mass index (BMI) within the healthy range (≥ 18.5 and < 25). Not perceiving a need for weight change may be a barrier to achieving a healthy weight. This study aimed to explore factors associated with perceived need for weight change among people LWBC., Methods: Adults diagnosed with breast, prostate, or colorectal cancer were recruited through National Health Service sites in Essex and London. Participants (N = 5835) completed the 'Health and Lifestyle After Cancer' survey, which included a question on perceived need to change weight. Associations between perceived need for weight change and BMI, and perceived need for weight change and health and demographic variables, were analyzed using chi-square tests and logistic regression, respectively., Results: The proportion of participants perceiving a need to lose weight differed according to BMI category: healthy weight (23%), overweight (64%), obese (85%) (P < 0.001). Having overweight or obesity but not perceiving a need to lose weight was associated with being older, male, non-white, not married or cohabiting, and having cancer that had spread, no formal qualifications, no comorbidities, and having received chemotherapy., Conclusions: Perceived need to lose weight is prevalent among people LWBC with obesity and overweight. This group may be interested in weight management support. Demographic and health factors were associated with having obesity or overweight but not perceiving a need to lose weight., Implications for Cancer Survivors: Weight loss interventions for people LWBC are needed. A subset of people LWBC with overweight and obesity may need additional information or motivators to engage with weight management., (© 2023. The Author(s).)

Background: Many people living with and beyond cancer (LWBC) do not meet dietary recommendations. To implement a healthier diet, people LWBC must perceive a need to improve their diet., Methods: Participants included people diagnosed with breast, prostate or colorectal cancer in the UK. Two binary logistic regression models were conducted with perceived need for dietary change as the outcome (need to improve vs. no need). Predictor variables included demographic and clinical characteristics, receipt of dietary advice, and either body mass index (BMI) or adherence to seven relevant World Cancer Research Fund (WCRF) dietary recommendations., Results: The sample included 5835 responses. Only 31% perceived a need to improve their diet. Being younger (odds ratio [OR] 0.95, 95% confidence interval [CI] = 94-0.95), female (OR = 1.33, 95% CI = 1.15-1.53), not of white ethnicity (OR = 1.8, 95% CI = 1.48-2.27), not married/cohabiting (OR = 1.32, 95% CI = 1.16-1.52) and having received dietary advice (OR = 1.36, 95% CI = 1.43-1.86) was associated with an increased odds of perceiving a need to improve diet. This association was also seen for participants with two or more comorbidities (OR = 1.31, 95% CI = 1.09-1.57), those not meeting the recommendations for fruit and vegetables (OR = 0.47, 95% CI = 0.41-0.55), fat (OR = 0.67, 95% CI = 0.58-0.77), and sugar (OR = 0.86, 95% CI = 0.75-0.98) in the dietary components model and those who had a higher BMI (OR = 1.53, 95% CI = 1.32-1.77) in the BMI model., Conclusions: Most of this sample of people LWBC did not perceive a need to improve their diet. More research is needed to understand the reasons for this and to target these reasons in dietary interventions., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Many individuals living with and beyond cancer (LWBC) have ongoing quality of life (QoL) issues, including fatigue. The World Cancer Research Fund (WCRF) provides health behaviour recommendations for people LWBC, and there is some evidence linking adherence to these with improved QoL., Methods: Adults LWBC (specifically breast, colorectal or prostate cancer) completed a survey covering health behaviours (diet, physical activity, alcohol consumption and smoking), fatigue (FACIT-Fatigue Scale, version 4) and a broad measure of QoL (EQ-5D-5L descriptive scale). Participants were categorised as meeting/not meeting WCRF recommendations, using the following cut-offs classified as meeting the guidelines: ≥150 min physical activity/week, fruit and vegetables (≥5 portions/day), fibre (≥30 g fibre per day), free sugar (<5% of total calories from free sugar), fat (<33% total energy), red meat (<500 g/week), processed meat (none), alcohol consumption (<14 units/week) and not a current smoker. Logistic regression analyses explored associations between WCRF adherence and fatigue and QoL issues, controlling for demographic and clinical variables., Results: Among 5835 individuals LWBC (mean age: 67 years, 56% female, 90% white, breast 48%, prostate 32% and colorectal 21%), 22% had severe fatigue and 72% had 1+ issue/s on the EQ-5D-5L. Adhering to physical activity recommendations (odds ratio [OR] = 0.88, confidence interval [CI] = 0.77-0.99), meeting various dietary recommendations (fruit and vegetables OR = 0.79; CI = 0.68-0.91, free sugar OR = 0.85; CI = 0.76-0.96, fat OR = 0.71; CI = 0.62-0.82, red meat OR = 0.65; CI = 0.50-0.85) and not smoking (OR = 0.53, CI = 0.41-0.67) were associated with decreased odds of experiencing severe fatigue. Adhering to physical activity guidelines (OR = 0.71, CI = 0.62-0.82) was also associated with decreased odds of having 1+ QoL issue/s., Conclusions: Adherence to various WCRF recommendations, particularly the recommendation for physical activity, was associated with less fatigue and better QoL in a large UK cohort of people living with and beyond breast, colorectal or prostate cancer. Multi-component interventions designed to support people LWBC to improve health behaviours, in line with the levels recommended by the WCRF, may also improve QoL., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Stress in rabbits (Oryctolagus cuniculus) may influence veterinarians' ability to assess their health and can lead to complications such as gastrointestinal hypomotility and poor anesthetic outcomes. Gabapentin has been used as an anxiolytic in various species, but little information is available on its use in rabbits. To assess the effect of gabapentin on stress in rabbits, 5 female and 3 male New Zealand white rabbits, aged 8-12 months, weighing 3-4.5 kg, were administered a single dose (25 mg/kg) of oral compounded gabapentin. Effects on individual behaviors and selected physiologic parameters were assessed by a blinded observer using a human intruder test and tractability score (summed total 0-8, most to least tractable). Heart and respiratory rate, rectal temperature, body weight, and fecal output were also recorded. Baseline measurements for each rabbit were assessed immediately prior to gabapentin administration, and at 1, 2, and 4 hours post-administration. With this method rabbits acted as their own concurrent control group. Rabbits were assessed at 7 AM, 11 AM, and 3 PM. Data were analyzed as continuous, binary, and continuous nonparametric (P ≤ .05). No significant differences in physiologic parameters were observed between baseline and the post-administration timepoints. Fecal output was reduced similar to baseline measurements. Behaviors pressing down decreased (at 2 and 4 hours; P = .05 and P = .013, respectively) and approaching human increased (at 2 hours; P = .022) post-gabapentin compared to baseline. Tractability scores were improved at the 2-hour timepoint compared to baseline (Friedman P = .0461; Wilcoxon P = .0413). These results suggest gabapentin 25 mg/kg orally decreased reactivity with a peak effect at 2 hours, without significant effects on measured physiologic parameters. Oral gabapentin in rabbits should be considered to reduce stress in the presence of humans and to facilitate handling., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest associated with this manuscript., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Dietary supplements (DSs) are not recommended for the prevention of cancer recurrence. Although DS use is common in individuals living with and beyond cancer, its associations with beliefs about reduced cancer recurrence risk and demographic and health behaviors are unclear., Methods: Adults (18 years old or older) who had been diagnosed with breast, prostate, or colorectal cancer were recruited through National Health Service sites in Essex and London. Participants completed a mailed survey and telephone or online 24-hour dietary recalls (MyFood24). Supplement use was collected during the dietary recalls. Associations between DS use and demographics, health behaviors, and beliefs about DSs and cancer were explored., Results: Nineteen percent of 1049 individuals believed that DSs were important for the reduction of cancer recurrence risk, and 40% of individuals reported DS use. DS use was positively associated with being female (odds ratio [OR], 2.48; confidence interval [CI], 1.72-3.56), meeting 5-a-day fruit and vegetable recommendations (OR, 1.36; CI, 1.02-1.82), and believing that DSs were important for reducing cancer recurrence risk (OR, 3.13; CI, 2.35-4.18). DS use was negatively associated with having obesity (OR, 0.58; CI, 0.38-0.87). The most commonly taken DSs overall were fish oils (taken by 13%). Calcium with or without vitamin D was the most common DS taken by individuals with breast cancer (15%)., Conclusions: DS use by individuals living with and beyond cancer is associated with demographic factors and health behaviors. A belief that DSs reduce the risk of cancer recurrence is common and positively associated with DS use. There is a need for health care professionals to provide advice about DS use and cancer recurrence risk., (© 2021 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

The endothelins and their receptors are best known for their regulation of the vascular system. Their widespread expression in epithelial cells and their overexpression in some tumors has prompted investigation into their ability to regulate cancer progression. In this study, we assessed the mRNA expression of the major endothelin B receptor gene (EDNRB) isoforms and found differences in both mRNA and protein expression in normal breast cells and breast cancer cell lines. Knocking down the EDNRB gene in breast cancer cells altered invasiveness toward endothelin 3 (ET3), and we observed EDNRB isoform-specific regulation of breast cancer cell invasion and cell signaling, as well as isoform- and subtype-specific differences in breast cancer patient survival. The results reported in this study emphasize the importance of the endothelin B receptor in breast cancer. To our knowledge, this study is the first to clarify the differential expression and roles of specific EDNRB isoforms in breast cancer., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Prostate-specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase expressed in a number of tissues. PSMA participates in various biological functions depending on the substrate available in the particular tissue; in the brain, PSMA cleaves the abundant neuropeptide N-acetyl-aspartyl-glutamate to regulate release of key neurotransmitters, while intestinal PSMA cleaves polyglutamated peptides to supply dietary folate. PSMA expression is also progressively upregulated in prostate cancer where it correlates with tumor progression as well as in tumor vasculature, where it regulates angiogenesis. The previous research determined that PSMA cleavage of small peptides generated via matrix metalloprotease-mediated proteolysis of the extracellular matrix protein laminin potently activated endothelial cells, integrin signaling and angiogenesis, although the specific peptide substrates were not identified. Herein, using enzymatic analyses and LC/MS, we unequivocally demonstrate that several laminin-derived peptides containing carboxy-terminal glutamate moieties (LQE, IEE, LNE) are bona fide substrates for PSMA. Subsequently, the peptide products were tested for their effects on angiogenesis in various models. We report that LQ, the dipeptide product of PSMA cleavage of LQE, efficiently activates endothelial cells in vitro and enhances angiogenesis in vivo. Importantly, LQE is not cleaved by an inactive PSMA enzyme containing an active site mutation (E424S). Endothelial cell activation by LQ was dependent on integrin beta-1-induced activation of focal adhesion kinase. These results characterize a novel PSMA substrate, provide a functional rationale for the upregulation of PSMA in cancer cells and tumor vasculature and suggest that inhibition of PSMA could lead to the development of new angiogenic therapies.

In women, invasive breast cancer is the second most common cancer and the second cause of cancer-related death. Therefore, identifying novel regulators of breast cancer invasion could lead to additional biomarkers and therapeutic targets. Neprilysin, a cell-surface enzyme that cleaves and inactivates a number of substrates including endothelin-1 (ET1), has been implicated in breast cancer, but whether neprilysin promotes or inhibits breast cancer cell progression and metastasis is unclear. Here, we asked whether neprilysin expression predicts and functionally regulates breast cancer cell invasion. RT-PCR and flow cytometry analysis of MDA-MB-231 and MCF-7 breast cancer cell lines revealed decreased neprilysin expression compared with normal epithelial cells. Expression was also suppressed in invasive ductal carcinoma (IDC) compared with normal tissue. In addition, in vtro invasion assays demonstrated that neprilysin overexpression decreased breast cancer cell invasion, whereas neprilysin suppression augmented invasion. Furthermore, inhibiting neprilysin in MCF-7 breast cancer cells increased ET1 levels significantly, whereas overexpressing neprilysin decreased extracellular-signal related kinase (ERK) activation, indicating that neprilysin negatively regulates ET1-induced activation of mitogen-activated protein kinase (MAPK) signaling. To determine whether neprilysin was epigenetically suppressed in breast cancer, we performed bisulfite conversion analysis of breast cancer cells and clinical tumor samples. We found that the neprilysin promoter was hypermethylated in breast cancer; chemical reversal of methylation in MDA-MB-231 cells reactivated neprilysin expression and inhibited cancer cell invasion. Analysis of cancer databases revealed that neprilysin methylation significantly associates with survival in stage I IDC and estrogen receptor-negative breast cancer subtypes. These results demonstrate that neprilysin negatively regulates the ET axis in breast cancer, and epigenetic suppression of neprilysin in invasive breast cancer cells enables invasion. Together, this implicates neprilysin as an important regulator of breast cancer invasion and clarifies its utility as a potential biomarker for invasive breast cancer.

Prostate specific membrane antigen (PSMA) is a pro-angiogenic cell-surface protease that we previously demonstrated regulates blood vessel formation in a laminin and integrin β1-dependent manner. Here, we examine the principal mechanism of PSMA activation of integrin β1. We show that digesting laminin sequentially with recombinant matrix metalloprotease-2 (MMP-2) and PSMA generates small peptides that enhance endothelial cell adhesion and migration in vitro. We also provide evidence that these laminin peptides activate adhesion via integrin α6β1 and focal adhesion kinase. Using an in vivo Matrigel implant assay, we show that these MMP/PSMA-derived laminin peptides also increase angiogenesis in vivo. Together, our results reveal a novel mechanism of PSMA activation of angiogenesis by processing laminin downstream of MMP-2.

Background & Aims: Measurement of serum iron increase after ingestion of a meal could be an efficient method of comparing post-prandial iron absorption between groups of individuals. We determined whether the rise in post-prandial serum iron is increased in fully treated patients with hereditary haemochromatosis (HFE C282Y+/+; HH) compared to iron deficiency anaemia (IDA), iron-replete heterozygous subjects (HFE C282Y+/-) and iron-replete controls (HFE C282Y-/-)., Methods: Serum iron increase was measured over 4h after a meal containing 13.1 mg non-haem iron., Results: Post-prandial increase in serum iron was similar in treated HH versus IDA (P=0.54), but greater than control subjects (P<0.0001). In five HH patients, using (58)Fe as a tracer, the rate of iron absorption was increased (P<0.05) and serum non-transferrin bound iron showed a tendency to increase (P=0.06). Serum iron curves did not differ for heterozygous subjects and controls (P=0.65)., Conclusions: Using the serum iron method we found a comparable increase in post-prandial iron absorption in treated HH and IDA compared with controls. While post-prandial iron absorption in the group heterozygous for the C282Y mutation was modestly increased relative to controls, this difference was not statistically significant.

CD13/aminopeptidase N is a transmembrane peptidase that is induced in the vasculature of solid tumors and is a potent angiogenic regulator. Here, we demonstrate that CD13 controls endothelial cell invasion in response to the serum peptide bradykinin by facilitating signal transduction at the level of the plasma membrane. Inhibition of CD13 abrogates bradykinin B(2) receptor internalization, leading to the attenuation of downstream events such as bradykinin-induced activation of Cdc42 and filopodia formation, and thus affects endothelial cell motility. Investigation into mechanisms underlying this block led us to focus on B(2)R internalization via membrane-dependent mechanisms. Membrane disruption by depletion of cholesterol or trypsinization halts B(2)R internalization, invasion, and filopodia formation, which can be recovered with addition of cholesterol. However, this functional recovery is severely impaired in the presence of CD13 antagonists, and the distribution of membrane proteins is disordered in treated cells, suggesting a role for CD13 in plasma membrane protein organization. Finally, exogenous expression of wild-type but not mutant CD13 further alters protein distribution, suggesting peptidase activity is required for CD13's regulatory activity. Therefore, CD13 functions as a novel modulator of signal transduction and cell motility via its influence on specific plasma membrane organization, thus regulating angiogenesis.

Objective: To develop an algorithm to predict the percentage non-heme iron absorption based on the foods contained in a meal (wholemeal cereal, tea, cheese, etc.). Existing algorithms use food constituents (phytate, polyphenols, calcium, etc.), which can be difficult to obtain., Design: A meta-analysis of published studies using erythrocyte incorporation of radio-isotopic iron to measure non-heme iron absorption., Methods: A database was compiled and foods were categorized into food groups likely to modify non-heme iron absorption. Absorption data were then adjusted to a common iron status and a weighted multiple regression was performed., Results: Data from 53 research papers (3,942 individual meals) were used to produce an algorithm to predict non-heme iron absorption (R(2) =0.22, P < 0.0001)., Conclusions: The percentage non-heme iron absorption can be predicted from information on the types of foods contained in a meal with similar efficacy to that of food-constituent-based algorithms (R(2) = 0.16, P= 0.0001).

Erythrocyte incorporation of isotopic iron (Fe) is the standard method for assessing iron bioavailability, but the process is expensive, technically difficult, and gives no information on the kinetics of absorption. The main objective of this study was to validate serum Fe curves as measures of dietary iron absorption because previous work demonstrated that serum iron curves can be generated with iron doses as low as 5-20 mg and that up to 20 mg iron can be added to meals without affecting relative absorption. In 3 studies, groups (n = 10, 10, 21) of Fe-deficient, mildly anemic women consumed meals of varying calculated Fe bioavailability, with and without added ferric chloride (10 mg Fe). Blood samples were collected at baseline and every 30 min for 4 h after the meal. Serum Fe concentrations were measured. Areas under the serum Fe curves and peak concentrations were used in different models to estimate Fe absorption and uptake. In 21 subjects, (58)Fe-enriched ferric chloride was added to the meals, and blood was taken 2 wk later to calculate red cell isotope incorporation. The addition of 10 mg Fe to test meals produced measurable serum iron curves even when the meal Fe bioavailability was low. Serum Fe curves were highly reproducible and were affected as expected by food composition. Even the single measurement at the estimated time of peak iron concentration was correlated significantly with erythrocyte incorporation of (58)Fe (r = 0.72, P < 0.0001). Hence the extent and rate of absorption of nonheme iron from meals, rather than in individuals, can be investigated with such subjects without the need for isotopes.

The transmembrane peptidase prostate-specific membrane antigen (PSMA) is universally upregulated in the vasculature of solid tumors, but its functional role in tumor angiogenesis has not been investigated. Here we show that angiogenesis is severely impaired in PSMA-null animals and that this angiogenic defect occurs at the level of endothelial cell invasion through the extracellular matrix barrier. Because proteolytic degradation of the extracellular matrix is a critical component of endothelial invasion in angiogenesis, it is logical to assume that PSMA participates in matrix degradation. However, we demonstrate a novel and more complex role for PSMA in angiogenesis, where it is a principal component of a regulatory loop that is tightly modulating laminin-specific integrin signaling and GTPase-dependent, p21-activated kinase 1 (PAK-1) activity. We show that PSMA inhibition, knockdown, or deficiency decreases endothelial cell invasion in vitro via integrin and PAK, thus abrogating angiogenesis. Interestingly, the neutralization of beta(1) or the inactivation of PAK increases PSMA activity, suggesting that they negatively regulate PSMA. This negative regulation is mediated by the cytoskeleton as the disruption of interactions between the PSMA cytoplasmic tail and the anchor protein filamin A decreases PSMA activity, integrin function, and PAK activation. Finally, the inhibition of PAK activation enhances the PSMA/filamin A interaction and, thus, boosts PSMA activity. These data imply that PSMA participates in an autoregulatory loop, wherein active PSMA facilitates integrin signaling and PAK activation, leading to both productive invasion and downregulation of integrin beta(1) signaling via reduced PSMA activity. Therefore, we have identified a novel role for PSMA as a true molecular interface, integrating both extracellular and intracellular signals during angiogenesis.