Tracking of serum lipid levels from childhood to adulthood: Systematic review and meta-analysis.

BACKGROUND AND AIMS: The utility of lipid screening in pediatric settings for preventing adult atherosclerotic cardiovascular diseases partly depends on the lifelong tracking of lipid levels. This systematic review aimed to quantify the tracking of lipid levels from childhood and adolescence to adulthood. METHODS: We systematically searched MEDLINE, Embase, Web of Science, and Google Scholar in March 2022. The protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO; ID: CRD42020208859). We included cohort studies that measured tracking of lipids from childhood or adolescence (<18 years) to adulthood (≥18) with correlation or tracking coefficients. We estimated pooled correlation and tracking coefficients using random-effects meta-analysis. Risk of bias was assessed with a review-specific tool. RESULTS: Thirty-three studies of 19 cohorts (11,020 participants) were included. The degree of tracking from childhood and adolescence to adulthood differed among lipids. Tracking was observed for low-density lipoprotein cholesterol (pooled r = 0.55-0.65), total cholesterol (pooled r = 0.51-0.65), high-density lipoprotein cholesterol (pooled r = 0.46-0.57), and triglycerides (pooled r = 0.32-0.40). Only one study included tracking of non-high-density lipoprotein cholesterol (r = 0.42-0.59). Substantial heterogeneity was observed. Study risk of bias was moderate, mostly due to insufficient reporting and singular measurements at baseline and follow-up. CONCLUSIONS: Early-life lipid measurements are important for predicting adult levels. However, further research is needed to understand the tracking of non-high-density lipoprotein cholesterol and the stability of risk classification over time, which may further inform pediatric lipid screening and assessment strategies.

Absolute neutrophil count clinical trial eligibility criteria for pediatric oncology phase I and phase I/II trials by sponsorship.

Normal absolute neutrophil count (ANC) variations, as seen with Duffy-null associated neutrophil count (DANC), are not accounted for in trial eligibility, which may contribute to racial enrollment disparities. We describe ANC eligibility for pediatric oncology phase I/II clinical trials according to primary sponsorship from 2010 to 2023 using ClinicalTrials.gov. Out of 438 trials, 20% were industry-sponsored. Total 17% of trials required ANC ≥1500 cells/µL for enrollment; however, industry-sponsored trials were significantly more likely to require ANC ≥1500 cells/µL than non-industry-sponsored trials (odds ratio 2.53, 95% confidence interval: 1.39-4.62; p < .001). These data suggest laboratory exclusion criteria are one possible mechanism for pediatric clinical trial enrollment disparities.

Brazilin is a natural product inhibitor of the NLRP3 inflammasome.

Excessive or aberrant NLRP3 inflammasome activation has been implicated in the progression and initiation of many inflammatory conditions; however, currently no NLRP3 inflammasome inhibitors have been approved for therapeutic use in the clinic. Here we have identified that the natural product brazilin effectively inhibits both priming and activation of the NLRP3 inflammasome in cultured murine macrophages, a human iPSC microglial cell line and in a mouse model of acute peritoneal inflammation. Through computational modeling, we predict that brazilin can adopt a favorable binding pose within a site of the NLRP3 protein which is essential for its conformational activation. Our results not only encourage further evaluation of brazilin as a therapeutic agent for NLRP3-related inflammatory diseases, but also introduce this small-molecule as a promising scaffold structure for the development of derivative NLRP3 inhibitor compounds.

An extensive disulfide bond network prevents tail contraction in Agrobacterium tumefaciens phage Milano.

A contractile sheath and rigid tube assembly is a widespread apparatus used by bacteriophages, tailocins, and the bacterial type VI secretion system to penetrate cell membranes. In this mechanism, contraction of an external sheath powers the motion of an inner tube through the membrane. The structure, energetics, and mechanism of the machinery imply rigidity and straightness. The contractile tail of Agrobacterium tumefaciens bacteriophage Milano is flexible and bent to varying degrees, which sets it apart from other contractile tail-like systems. Here, we report structures of the Milano tail including the sheath-tube complex, baseplate, and putative receptor-binding proteins. The flexible-to-rigid transformation of the Milano tail upon contraction can be explained by unique electrostatic properties of the tail tube and sheath. All components of the Milano tail, including sheath subunits, are crosslinked by disulfides, some of which must be reduced for contraction to occur. The putative receptor-binding complex of Milano contains a tailspike, a tail fiber, and at least two small proteins that form a garland around the distal ends of the tailspikes and tail fibers. Despite being flagellotropic, Milano lacks thread-like tail filaments that can wrap around the flagellum, and is thus likely to employ a different binding mechanism.

Associations between types and sources of dietary carbohydrates and liver fat: a UK Biobank study.

BACKGROUND AND AIMS: Excess energy intake can lead to metabolic dysfunction-associated steatotic liver disease (MASLD), but the relationship between dietary carbohydrate intake and liver fat content remains unclear. This study aimed to examine the associations between types and sources of dietary carbohydrates and liver fat content. METHODS: UK Biobank participants with no pre-existing diabetes, liver disease or cardiovascular disease reported dietary intake of types and sources of carbohydrates (total carbohydrates, free sugars, non-free sugars, starch from whole grains, starch from refined grains, and fibre) on at least two 24-h dietary assessments. In cross-sectional analyses, (n = 22,973), odds ratios (OR) of high liver fat content (defined as a score of ≥ 36 in the hepatic steatosis index) by quintiles of carbohydrate intakes were estimated using multivariable logistic regression models. In prospective analyses, a second sample (n = 9268) had liver proton density fat fraction (PDFF) measured by magnetic resonance imaging (2014-2020). Multivariable linear regression models estimated geometric means of PDFF (%) by quintiles of carbohydrate intakes. Models were adjusted for demographic and lifestyle confounders, including total energy intake. RESULTS: In the cross-sectional analyses, 6894 cases of high liver fat content were identified. Inverse associations between intakes of fibre (OR of highest vs. lowest quintile 0.46 [95% CI: 0.41-0.52]), non-free sugars (0.63 [0.57-0.70]) and starch from whole grains (0.52 [0.47-0.57]) with liver fat were observed. There were positive associations between starch from refined grains and liver fat (1.33 [1.21-1.46]), but no association with free sugars (p=0.61). In prospective analyses, inverse associations with PDFF (%) were observed for intakes of fibre (- 0.48 geometric mean difference between highest and lowest quintile of intake [- 0.60 to - 0.35]), non-free sugars (- 0.37 [- 0.49 to - 0.25]) and starch from whole grains (- 0.31 [- 0.42 to - 0.19]). Free sugars, but not starch from refined grains, were positively associated with PDFF (0.17 [0.05 to 0.28]). CONCLUSION: This study suggests that different carbohydrate types and sources have varying associations with liver fat, which may be important for MASLD prevention. Non-free sugars, fibre, and starch from whole grains could be protective, while associations with free sugars and starch from refined grains are less clear.

Neck and capsid architecture of the robust Agrobacterium phage Milano.

Large gaps exist in our understanding of how bacteriophages, the most abundant biological entities on Earth, assemble and function. The structure of the "neck" region, where the DNA-filled capsid is connected to the host-recognizing tail remains poorly understood. We describe cryo-EM structures of the neck, the neck-capsid and neck-tail junctions, and capsid of the Agrobacterium phage Milano. The Milano neck 1 protein connects the 12-fold symmetrical neck to a 5-fold vertex of the icosahedral capsid. Comparison of Milano neck 1 homologs leads to four proposed classes, likely evolved from the simplest one in siphophages to more complex ones in myo- and podophages. Milano neck is surrounded by the atypical collar, which covalently crosslinks the tail sheath to neck 1. The Milano capsid is decorated with three types of proteins, a minor capsid protein (mCP) and two linking proteins crosslinking the mCP to the major capsid protein. The extensive network of disulfide bonds within and between neck, collar, capsid and tail provides an exceptional structural stability to Milano.

Associations of intakes of total protein, protein from dairy sources, and dietary calcium with risks of colorectal, breast, and prostate cancer: a prospective analysis in UK Biobank.

BACKGROUND: Evidence concerning intakes of protein or sources of dairy protein and risks of colorectal, breast, and prostate cancers is inconclusive. METHODS: Using a subsample of UK Biobank participants who completed ≥2 (maximum of 5) 24-h dietary assessments, we estimated intakes of total protein, protein from total dairy products, milk, and cheese, and dietary calcium in 114,217 participants. Hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using multivariable-adjusted Cox regression. RESULTS: After a median of 9.4 years of follow-up, 1193 colorectal, 2024 female breast, and 2422 prostate cancer cases were identified. There were inverse associations of total dairy protein, protein from milk, and dietary calcium intakes with colorectal cancer incidence (HRQ4 vs Q1:0.80, 95% CI: 0.67-0.94; 0.79, 0.67-0.94; 0.71, 0.58-0.86, respectively). We also observed positive associations of milk protein and dietary calcium with prostate cancer risk (HRQ4 vs Q1:1.12, 1.00-1.26 and 1.16, 1.01-1.33, respectively). No significant associations were observed between intake of dairy protein and breast cancer risk. When insulin-like growth factor-I concentrations measured at recruitment were added to the multivariable-adjusted models, associations remained largely unchanged. Analyses were also similar when looking at total grams of dairy products, milk, and cheese. CONCLUSION: Further research is needed to understand the mechanisms underlying the relationships of dairy products with cancer risk and the potential roles of dietary protein and calcium.

Increased dietary fiber is associated with weight loss among Full Plate Living program participants.

Introduction: Prior studies have demonstrated that an intake of foods rich in dietary fiber is associated with a favorable impact on health status and body weight. However, the association between fiber intake and weight loss has not been well-studied in employer settings. This research aimed to assess the relationship between dietary fiber and weight loss among individuals participating in the Full Plate Living (FPL) program. Methods: The 16-week plant-predominant fiber-rich eating program was delivered to 72 employers, primarily in the Southwest U.S., over 3 years (2017-2019). Participants received weekly video lessons, FPL materials, and additional online resources. A retrospective analysis of repeated measures was conducted using participant data obtained from 4,477 participants, of which 2,792 (62.5%) reduced body weight. Analysis of variance with post hoc analysis was used to assess the statistical significance of the changes between baseline and follow-up measures of dietary fiber intake in each of the food categories, specifically the relationship between changes in individual and combined (composite) daily servings of fruits, vegetables, whole grains, beans, and nuts on body weight measures among three groups at follow-up: those who lost, maintained, or gained weight. Multilevel modeling was used to test the hypothesis that increased intake of fiber was associated with greater weight loss. Results: The mean weight loss for the weight loss group was 3.28 kg. As compared to the two other groups, the intake of whole fiber-rich foods at follow-up was significantly higher among the weight loss group with fruits (2.45 servings), vegetables (2.99 servings), beans (1.03 servings), and total fiber composites (9.07 servings; P < 0.001). A significant increase in servings of grains was also noted (P < 0.05). Multilevel modeling demonstrated that a higher total fiber composite (Model 1), as well as higher intakes of either vegetables or fruits (Model 2), resulted in greater weight loss. Discussion: Our findings indicate that the FPL program can be a part of a lifestyle medicine approach to healthy eating and weight loss. Delivering the program in clinical, community, and workplace settings can increase its reach as an effective and low-cost offering.

Prospective Analysis Reveals Associations between Carbohydrate Intakes, Genetic Predictors of Short-Chain Fatty Acid Synthesis, and Colorectal Cancer Risk.

Whole grain and fiber intakes may decrease the risk of colorectal cancer. The interplay between host genetic factors, colonization of specific bacteria, production of short-chain fatty acids (SCFA), and intake of whole grains and fiber could alter the protective role of carbohydrates against colorectal cancer. Here, we assessed intakes of types and sources of carbohydrates in 114,217 UK Biobank participants with detailed dietary data (2-5 24-hour dietary assessments), and a host polygenic score (PGS) was applied to categorize participants as high or low for intraluminal microbial SCFA production, namely, butyrate and propionate. Multivariable Cox proportional hazards models were used to determine the associations of carbohydrates and SCFA with colorectal cancer incidence. During a median follow-up of 9.4 years, 1,193 participants were diagnosed with colorectal cancer. Risk was inversely associated with intakes of non-free sugar and whole grain fiber. Evidence of heterogeneity was observed by the butyrate PGS; consuming higher amounts of whole grain starch was only associated with a lower risk of colorectal cancer in those with predicted high SCFA production. Similarly, in additional analyses utilizing the larger UK Biobank cohort (N = 343,621) with less detailed dietary assessment, only individuals with a high genetically predicted butyrate production had a lower risk of colorectal cancer per 5 g/day intake of bread and cereal fiber. This study suggests that colorectal cancer risk varies by intake of carbohydrate types and sources, and the impact of whole grain intake may be modified by SCFA production. SIGNIFICANCE: Prospective population-level analyses provide evidence supporting the importance of butyrate production in reduction of colorectal cancer risk by whole grain consumption.

Associations between types and sources of dietary carbohydrates and cardiovascular disease risk: a prospective cohort study of UK Biobank participants.

BACKGROUND: Recent studies have reported that the associations between dietary carbohydrates and cardiovascular disease (CVD) may depend on the quality, rather than the quantity, of carbohydrates consumed. This study aimed to assess the associations between types and sources of dietary carbohydrates and CVD incidence. A secondary aim was to examine the associations of carbohydrate intakes with triglycerides within lipoprotein subclasses. METHODS: A total of 110,497 UK Biobank participants with ≥ two (maximum five) 24-h dietary assessments who were free from CVD and diabetes at baseline were included. Multivariable-adjusted Cox regressions were used to estimate risks of incident total CVD (4188 cases), ischaemic heart disease (IHD; 3138) and stroke (1124) by carbohydrate intakes over a median follow-up time of 9.4 years, and the effect of modelled dietary substitutions. The associations of carbohydrate intakes with plasma triglycerides within lipoprotein subclasses as measured by nuclear magnetic resonance (NMR) spectroscopy were examined in 26,095 participants with baseline NMR spectroscopy measurements. RESULTS: Total carbohydrate intake was not associated with CVD outcomes. Free sugar intake was positively associated with total CVD (HR; 95% CI per 5% of energy, 1.07;1.03-1.10), IHD (1.06;1.02-1.10), and stroke (1.10;1.04-1.17). Fibre intake was inversely associated with total CVD (HR; 95% CI per 5 g/d, 0.96;0.93-0.99). Modelled isoenergetic substitution of 5% of energy from refined grain starch with wholegrain starch was inversely associated with total CVD (0.94;0.91-0.98) and IHD (0.94;0.90-0.98), and substitution of free sugars with non-free sugars was inversely associated with total CVD (0.95;0.92-0.98) and stroke (0.91;0.86-0.97). Free sugar intake was positively associated with triglycerides within all lipoproteins. CONCLUSIONS: Higher free sugar intake was associated with higher CVD incidence and higher triglyceride concentrations within all lipoproteins. Higher fibre intake and replacement of refined grain starch and free sugars with wholegrain starch and non-free sugars, respectively, may be protective for incident CVD.

A Study of the Reliability, Validity, and Physiological Changes of Sit-to-Stand Tests in People With Heart Failure.

PURPOSE: The objective of this study was to describe the psychometric properties and physiological response of the five times sit-to-stand (STST-5) and 60-sec sit-to-stand test (STST-60) in adults with heart failure (HF). METHODS: People with HF enrolled in a 12-wk exercise rehabilitation program completed two STST-5 and two STST-60 as part of their usual baseline and follow-up assessments. Test-retest reliability, validity, and responsiveness of the two STSTs were described. Results were correlated with the 6-min walk test (6MWT) and timed up and go test (TUGT), and rating of perceived exertion and physiological responses were compared between all tests. Feasibility was also reported according to the presence of adverse events and adherence to the protocol. RESULTS: Forty-nine adults with HF participated in this study. Intraclass correlation coefficients of the STST-5 and STST-60 were 0.91 (95% CI, 0.78-0.96) and 0.96 (95% CI, 0.93-0.98), respectively. The STST-60 was strongly associated with both the 6MWT ( r = 0.76) and the TUGT ( rs =-0.77). The STST-5 was strongly associated with the TUGT ( rs = 0.79) and moderately associated with the 6MWT ( rs =-0.70). Rating of perceived exertion and lower limb fatigue were greater in the STST-60 than in the 6MWT ( P < .001) or STST-5 ( P < .001). Adverse events occurred in five participants undertaking the STST-60 and one participant undertaking the STST-5. CONCLUSIONS: The STST-5 and STST-60 are reliable and valid measures of functional exercise capacity in people with HF.

Health Benefits of a 16-Week Whole Food, High Fiber, Plant Predominant Diet among U.S. Employees.

PURPOSE: To assess improvements in eating behaviors and health measures among adults participating in a whole food plant predominant diet, Full Plate Living (FPL) program. DESIGN: Retrospective, post hoc analysis of self-reported 16-week pre-post participant data obtained over a 3 year program period (2017-19). SETTING: Wellness offering for employees in Southwest U.S. SUBJECTS: Of 6,820 enrollees, 4,477 completed the program, further segmented by generational cohorts. INTERVENTION: FPL program materials and weekly online video lessons. MEASURES: Baseline and follow-up measures included eating behaviors, self-perceived health status and energy, body weight, and confidence in healthy eating and weight loss. ANALYSIS: Paired t-tests were used to examine changes in eating behaviors and health measures. Mixed-effects models were used to examine whether changes among generational cohorts differed. RESULTS: Significant pre-post improvements were demonstrated for all measures, including servings of fruits (1.54 to 2.34), vegetables (2.05 to 2.87), beans (.63 to .99), and weight loss (3.5) (P < .001). Self-perceived health and energy values, and confidence in making healthy food choices and losing weight improved (P < .001). Improvements were observed across generational cohorts (P < .001). CONCLUSION: The FPL healthy eating approach has a beneficial impact on health measures across generational cohorts, and may be an effective addition to lifestyle medicine and corporate wellness offerings. Longer-term program evaluation is warranted.

Associations between food group intakes and circulating insulin-like growth factor-I in the UK Biobank: a cross-sectional analysis.

PURPOSE: Circulating insulin-like growth factor-I (IGF-I) concentrations have been positively associated with risk of several common cancers and inversely associated with risk of bone fractures. Intakes of some foods have been associated with increased circulating IGF-I concentrations; however, evidence remains inconclusive. Our aim was to assess cross-sectional associations of food group intakes with circulating IGF-I concentrations in the UK Biobank. METHODS: At recruitment, the UK Biobank participants reported their intake of commonly consumed foods. From these questions, intakes of total vegetables, fresh fruit, red meat, processed meat, poultry, oily fish, non-oily fish, and cheese were estimated. Serum IGF-I concentrations were measured in blood samples collected at recruitment. After exclusions, a total of 438,453 participants were included in this study. Multivariable linear regression was used to assess the associations of food group intakes with circulating IGF-I concentrations. RESULTS: Compared to never consumers, participants who reported consuming oily fish or non-oily fish ≥ 2 times/week had 1.25 nmol/L (95% confidence interval:1.19-1.31) and 1.16 nmol/L (1.08-1.24) higher IGF-I concentrations, respectively. Participants who reported consuming poultry ≥ 2 times/week had 0.87 nmol/L (0.80-0.94) higher IGF-I concentrations than those who reported never consuming poultry. There were no strong associations between other food groups and IGF-I concentrations. CONCLUSIONS: We found positive associations between oily and non-oily fish intake and circulating IGF-I concentrations. A weaker positive association of IGF-I with poultry intake was also observed. Further research is needed to understand the mechanisms which might explain these associations.

Promoting food literacy in primary school classrooms through the HealthLit4Kids Program in Australia.

Food literacy (FL) refers to the knowledge, skills, and behaviours associated with healthy eating. Schools are recognised as an important setting for FL promotion during childhood. HealthLit4Kids is an Australian primary school intervention that engages students, families, and educators to promote health literacy. This study aimed to assess the promotion of FL, a subtype of health literacy, in primary school classrooms across five schools. Teachers planned and implemented classroom activities over a 12-month period. Researchers examined lesson plans created by teachers and 'artefacts' (e.g. drawings, models) created by students during activities. Most classroom activities considered the nutritional knowledge and interpersonal communication skills associated with healthy eating, whereas fewer activities addressed students' ability to critically analyse and apply information relating to food. The FL themes considered most frequently in classroom activities were 'food and health choices', 'knowledge', and 'skills and behaviour'. Whereas the FL themes considered less frequently were 'food systems', 'emotion', and 'culture'. The delivery of classroom activities was supported by the integration of other curriculum areas (e.g. The Arts and English). Future studies are required to understand how school-based interventions can promote the areas of FL that were less frequently addressed in this intervention in the classroom and beyond.

Evaluation of the New Individual Fatty Acid Dataset for UK Biobank: Analysis of Intakes and Sources in 207,997 Participants.

The Oxford WebQ is an online 24 h dietary assessment tool used by several large prospective studies. This study describes the creation of the new individual fatty acid (FA) dataset for the Oxford WebQ and reports intakes and sources of dietary individual FAs in the UK Biobank. Participants who completed ≥1 (maximum of five) 24 h dietary assessments were included (n = 207,997). Nutrient intakes were obtained from the average of all completed 24 h dietary assessments. Nutrient data from the UK McCance and Widdowson's The Composition of Foods and the US Department of Agriculture food composition tables were used to calculate intakes of 21 individual FAs. The individual FA dataset included 10 saturated fatty acids (SFAs), 4 monounsaturated fatty acids (MUFAs), and 7 polyunsaturated fatty acids (PUFAs; including alpha-linolenic (18:3), eicosapentaenoic (20:5), and docosahexaenoic (22:6) acids). Palmitic (16:0; mean ± standard deviation (SD): 13.5 ± 5.7 g/d) and stearic (18:0; 5.2 ± 2.5) acids were the main contributors to SFAs, and the main sources of these were cereals and cereal products (mostly desserts/cakes/pastries), milk and milk products (mostly cheese and milk), and meat and meat products. Oleic acid (18:1; 24.2 ± 9.8) was the main MUFA, derived mainly from cereals and cereal products, and meat and meat products. Linoleic acid (18:2; 9.7 ± 4.3) was the main PUFA, derived mostly from cereals and cereal products, and vegetables (including potatoes) and vegetable dishes. The individual FA dataset for the Oxford WebQ will allow future investigations on individual FAs and disease risk.

Intra-S phase checkpoint kinase Chk1 dissociates replication proteins Treslin and TopBP1 through multiple mechanisms during replication stress.

Replication stress impedes DNA polymerase progression causing activation of the ataxia telangiectasia and Rad3-related signaling pathway, which promotes the intra-S phase checkpoint activity through phosphorylation of checkpoint kinase 1 (Chk1). Chk1 suppresses replication origin firing, in part, by disrupting the interaction between the preinitiation complex components Treslin and TopBP1, an interaction that is mediated by TopBP1 BRCT domain-binding to two cyclin-dependent kinase (CDK) phosphorylation sites, T968 and S1000, in Treslin. Two nonexclusive models for how Chk1 regulates the Treslin-TopBP1 interaction have been proposed in the literature: in one model, these proteins dissociate due to a Chk1-induced decrease in CDK activity that reduces phosphorylation of the Treslin sites that bind TopBP1 and in the second model, Chk1 directly phosphorylates Treslin, resulting in dissociation of TopBP1. However, these models have not been formally examined. We show here that Treslin T968 phosphorylation was decreased in a Chk1-dependent manner, while Treslin S1000 phosphorylation was unchanged, demonstrating that T968 and S1000 are differentially regulated. However, CDK2-mediated phosphorylation alone did not fully account for Chk1 regulation of the Treslin-TopBP1 interaction. We also identified additional Chk1 phosphorylation sites on Treslin that contributed to disruption of the Treslin-TopBP1 interaction, including S1114. Finally, we showed that both of the proposed mechanisms regulate origin firing in cancer cell line models undergoing replication stress, with the relative roles of each mechanism varying among cell lines. This study demonstrates that Chk1 regulates Treslin through multiple mechanisms to promote efficient dissociation of Treslin and TopBP1 and furthers our understanding of Treslin regulation during the intra-S phase checkpoint.

Risk of cancer in regular and low meat-eaters, fish-eaters, and vegetarians: a prospective analysis of UK Biobank participants.

BACKGROUND: Following a vegetarian diet has become increasingly popular and some evidence suggests that being vegetarian may be associated with a lower risk of cancer overall. However, for specific cancer sites, the evidence is limited. Our aim was to assess the associations of vegetarian and non-vegetarian diets with risks of all cancer, colorectal cancer, postmenopausal breast cancer, and prostate cancer and to explore the role of potential mediators between these associations. METHODS: We conducted a prospective analysis of 472,377 UK Biobank participants who were free from cancer at recruitment. Participants were categorised into regular meat-eaters (n = 247,571), low meat-eaters (n = 205,385), fish-eaters (n = 10,696), and vegetarians (n = 8685) based on dietary questions completed at recruitment. Multivariable-adjusted Cox regressions were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for all cancer incidence and separate cancer sites across diet groups. RESULTS: After an average follow-up of 11.4 years, 54,961 incident cancers were identified, including 5882 colorectal, 7537 postmenopausal breast, and 9501 prostate cancers. Compared with regular meat-eaters, being a low meat-eater, fish-eater, or vegetarian were all associated with a lower risk of all cancer (HR: 0.98, 95% CI: 0.96-1.00; 0.90, 0.84-0.96; 0.86, 0.80-0.93, respectively). Being a low meat-eater was associated with a lower risk of colorectal cancer in comparison to regular meat-eaters (0.91, 0.86-0.96); however, there was heterogeneity in this association by sex (p = 0.007), with an inverse association across diet groups in men, but not in women. Vegetarian postmenopausal women had a lower risk of breast cancer (0.82, 0.68-0.99), which was attenuated and non-significant after adjusting for body mass index (BMI; 0.87, 0.72-1.05); in mediation analyses, BMI was found to possibly mediate the observed association. In men, being a fish-eater or a vegetarian was associated with a lower risk of prostate cancer (0.80, 0.65-0.99 and 0.69, 0.54-0.89, respectively). CONCLUSION: The lower risk of colorectal cancer in low meat-eaters is consistent with previous evidence suggesting an adverse impact of meat intake. The lower risk of postmenopausal breast cancer in vegetarian women may be explained by their lower BMI. It is not clear whether the other differences observed for all cancers and for prostate cancer reflect any causal relationships or are due to other factors such as residual confounding or differences in cancer detection.

A randomised multiple baseline case series of a novel imagery rescripting protocol for intrusive trauma memories in people with psychosis.

BACKGROUND AND OBJECTIVES: There has been limited investigation of therapies targeting trauma-related psychological mechanisms hypothesised to play a role in post-traumatic and psychosis symptoms. Imagery rescripting (ImRs) is a therapeutic technique which involves transforming images, such as episodic memories, to modify associated distressing beliefs. This study is the first ImRs study for psychosis to incorporate experimental controls. We used a novel ImRs protocol, targeting present-focused, self-referential distressing meanings associated with intrusive trauma memories. A multiple baseline case series design investigated whether the protocol was feasible, safe, acceptable and effective. METHODS: 12 participants with a psychosis diagnosis and intrusive trauma memories were assessed and randomised to a monitoring period (one, two or three weeks), followed by three ImRs sessions (over three weeks), a further two-week monitoring period with a post-therapy assessment a week after completing therapy. Memory phenomenology was assessed daily during monitoring. Post-traumatic stress symptoms and wellbeing were assessed pre and post therapy. RESULTS: ImRs was feasible, safe and rated as highly acceptable. No participants dropped-out of the brief, targeted intervention. There were moderate effects on the frequency, distress, controllability and appraisals of trauma memories. Notably, ten participants showed reliable change, and seven clinically significant change, in post-traumatic stress symptoms. LIMITATIONS: Assessments were not blinded and impact on psychosis was not examined. CONCLUSIONS: The study indicates that a brief, novel ImRs protocol targeting present-focused, self-referential meanings is a promising intervention for intrusive trauma memories. Future research should investigate its integration into trauma-focused therapy for psychosis and impact on psychosis severity.

Repurposing Ceritinib Induces DNA Damage and Enhances PARP Inhibitor Responses in High-Grade Serous Ovarian Carcinoma.

PARP inhibitors (PARPi) have activity in homologous recombination (HR) repair-deficient, high-grade serous ovarian cancers (HGSOC). However, even responsive tumors develop PARPi resistance, highlighting the need to delay or prevent the appearance of PARPi resistance. Here, we showed that the ALK kinase inhibitor ceritinib synergizes with PARPis by inhibiting complex I of the mitochondrial electron transport chain, which increases production of reactive oxygen species (ROS) and subsequent induction of oxidative DNA damage that is repaired in a PARP-dependent manner. In addition, combined treatment with ceritinib and PARPi synergized in HGSOC cell lines irrespective of HR status, and a combination of ceritinib with the PARPi olaparib induced tumor regression more effectively than olaparib alone in HGSOC patient-derived xenograft (PDX) models. Notably, the ceritinib and olaparib combination was most effective in PDX models with preexisting PARPi sensitivity and was well tolerated. These findings unveil suppression of mitochondrial respiration, accumulation of ROS, and subsequent induction of DNA damage as novel effects of ceritinib. They also suggest that the ceritinib and PARPi combination warrants further investigation as a means to enhance PARPi activity in HGSOC, particularly in tumors with preexisting HR defects. SIGNIFICANCE: The kinase inhibitor ceritinib synergizes with PARPi to induce tumor regression in ovarian cancer models, suggesting that ceritinib combined with PARPi may be an effective strategy for treating ovarian cancer.

Associations of circulating insulin-like growth factor-I with intake of dietary proteins and other macronutrients.

BACKGROUND & AIMS: Circulating insulin-like growth factor-I (IGF-I) is associated with the risk of several cancers. Dietary protein intake, particularly dairy protein, may increase circulating IGF-I; however, associations with different protein sources, other macronutrients, and fibre are inconclusive. To investigate the associations between intake of protein, macronutrients and their sources, fibre, and alcohol with serum IGF-I concentrations. METHODS: A total of 11,815 participants from UK Biobank who completed ≥4 24-h dietary assessments and had serum IGF-I concentrations measured at baseline were included. Multivariable linear regression was used to assess the cross-sectional associations of macronutrient and fibre intake with circulating IGF-I concentrations. RESULTS: Circulating IGF-I concentrations were positively associated with intake of total protein (per 2.5% higher energy intake: 0.56 nmol/L (95% confidence interval: 0.47, 0.66)), milk protein: 1.20 nmol/L (0.90, 1.51), and yogurt protein: 1.33 nmol/L (0.79, 1.86), but not with cheese protein: -0.07 nmol/L (-0.40, 0.25). IGF-I concentrations were also positively associated with intake of fibre (per 5 g/day higher intake: 0.46 nmol/L (0.35, 0.57)) and starch from wholegrains (Q5 vs. Q1: 1.08 nmol/L (0.77, 1.39)), and inversely associated with alcohol consumption (>40 g/day vs <1 g/day: -1.36 nmol/L (-1.00, -1.71)). CONCLUSIONS: These results show differing associations with IGF-I concentrations depending on the source of dairy protein, with positive associations with milk and yogurt protein intake but no association with cheese protein. The positive association of fibre and starch from wholegrains with IGF-I warrants further investigation.