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Background: Genome-wide association studies have identified multiple genetic variants associated with susceptibility to prostate cancer (PrCa). In the two-stage Cancer Genetic Markers of Susceptibility prostate cancer scan, a single-nucleotide polymorphism (SNP), rs10486567, located within intron 2 of JAZF1 gene on chromosome 7p15.2, showed a promising association with PrCa overall (P = 2.14 × 10−6), with a suggestion of stronger association with aggressive disease (P = 1.2 × 10−7).Methods: In the third stage of genome-wide association studies, we genotyped 106 JAZF1 SNPs in 10,286 PrCa cases and 9,135 controls of European ancestry.Results: The strongest association was observed with the initial marker rs10486567, which now achieves genome-wide significance [P = 7.79 × 10−11; ORHET, 1.19 (95% confidence interval, 1.12-1.27); ORHOM, 1.37 (95% confidence interval, 1.20-1.56)]. We did not confirm a previous suggestion of a stronger association of rs10486567 with aggressive disease (P = 1.60 × 10−4 for aggressive cancer, n = 4,597; P = 3.25 × 10−8 for nonaggressive cancer, n = 4,514). Based on a multilocus model with adjustment for rs10486567, no additional independent signals were observed at chromosome 7p15.2. There was no association between PrCa risk and SNPs in JAZF1 previously associated with height (rs849140; P = 0.587), body stature (rs849141, tagged by rs849136; P = 0.171), and risk of type 2 diabetes and systemic lupus erythematosus (rs864745, tagged by rs849142; P = 0.657).Conclusion: rs10486567 remains the most significant marker for PrCa risk within JAZF1 in individuals of European ancestry.Impact: Future studies should identify all variants in high linkage disequilibrium with rs10486567 and evaluate their functional significance for PrCa. Cancer Epidemiol Biomarkers Prev; 19(5); 1349–55. ©2010 AACR.

Background: One of the goals of personalized medicine is to generate individual risk profiles that could identify individuals in the population that exhibit high risk. The discovery of more than two-dozen independent single-nucleotide polymorphism markers in prostate cancer has raised the possibility for such risk stratification. In this study, we evaluated the discriminative and predictive ability for prostate cancer risk models incorporating 25 common prostate cancer genetic markers, family history of prostate cancer, and age.Methods: We fit a series of risk models and estimated their performance in 7,509 prostate cancer cases and 7,652 controls within the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). We also calculated absolute risks based on SEER incidence data.Results: The best risk model (C-statistic = 0.642) included individual genetic markers and family history of prostate cancer. We observed a decreasing trend in discriminative ability with advancing age (P = 0.009), with highest accuracy in men younger than 60 years (C-statistic = 0.679). The absolute ten-year risk for 50-year-old men with a family history ranged from 1.6% (10th percentile of genetic risk) to 6.7% (90th percentile of genetic risk). For men without family history, the risk ranged from 0.8% (10th percentile) to 3.4% (90th percentile).Conclusions: Our results indicate that incorporating genetic information and family history in prostate cancer risk models can be particularly useful for identifying younger men that might benefit from prostate-specific antigen screening.Impact: Although adding genetic risk markers improves model performance, the clinical utility of these genetic risk models is limited. Cancer Epidemiol Biomarkers Prev; 21(3); 437–44. ©2012 AACR.

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Supplementary Table 3 from Refining the Prostate Cancer Genetic Association within the JAZF1 Gene on Chromosome 7p15.2

Supplementary Table 1 from Refining the Prostate Cancer Genetic Association within the JAZF1 Gene on Chromosome 7p15.2

Supplementary Table Legends from Refining the Prostate Cancer Genetic Association within the JAZF1 Gene on Chromosome 7p15.2

Purpose: The global prevalence of overweight remains high; effective strategies that consider patterns of body weight changes to identify periods when adults are susceptible to weight gain are warranted. This systematic review aimed to investigate body weight patterns, and how they were associated with dietary intake and/or dietary behaviours (Prospero CRD42020161977). Methods: Systematic literature search was conducted in the Medline, Embase, and CINAHL databases until November 2020. Observational studies in adults (18 years and over) that reported at least two measurements of weight and dietary intake in a year were included. Risk of bias was conducted using the Evidence Analysis Library by the Academy of Nutrition and Dietetics tool. This review included 16 unique studies after title, abstract, and full-text screening, and findings were narratively synthesised. Results: Of the six studies conducted in the farming populations, five were conducted in countries with two seasons (dry vs. rainy seasons) and all studies observed higher body weight during the dry season (up to 3.1 kg difference between seasons). The remaining study was conducted in a sub-tropical country and did not observe temporal weight patterns. Higher dietary intake was also reported during the dry season in the tropical countries. In non-farming populations (n = 10), temporal patterns were also seen, where higher body weight and adiposity was observed during colder seasons (autumn and winter). However, the opposite was found in a study conducted in Iran, where higher weight was seen in summer. Concurrent with higher body weight, higher energy, fat, carbohydrate and soda consumption, and lower fiber and vegetable intake were observed. Conclusion: Temporal weight and dietary patterns exist, and they were country- and context-specific; these patterns were also related to factors such as activity levels, seasons and occupation. Future interventions should consider temporal patterns in the design and delivery of timely and tailored dietary interventions to promote optimal body weight. Refereed/Peer-reviewed

PURPOSE For patients with metastatic hormone-sensitive prostate cancer, metastatic burden affects outcome. We examined efficacy and safety from the ARASENS trial for subgroups by disease volume and risk. METHODS Patients with metastatic hormone-sensitive prostate cancer were randomly assigned to darolutamide or placebo plus androgen-deprivation therapy and docetaxel. High-volume disease was defined as visceral metastases and/or ≥ 4 bone metastases with ≥ 1 beyond the vertebral column/pelvis. High-risk disease was defined as ≥ 2 risk factors: Gleason score ≥ 8, ≥ 3 bone lesions, and presence of measurable visceral metastases. RESULTS Of 1,305 patients, 1,005 (77%) had high-volume disease and 912 (70%) had high-risk disease. Darolutamide increased overall survival (OS) versus placebo in patients with high-volume (hazard ratio [HR], 0.69; 95% CI, 0.57 to 0.82), high-risk (HR, 0.71; 95% CI, 0.58 to 0.86), and low-risk disease (HR, 0.62; 95% CI, 0.42 to 0.90), and in the smaller low-volume subgroup, the results were also suggestive of survival benefit (HR, 0.68; 95% CI, 0.41 to 1.13). Darolutamide improved clinically relevant secondary end points of time to castration-resistant prostate cancer and subsequent systemic antineoplastic therapy versus placebo in all disease volume and risk subgroups. Adverse events (AEs) were similar between treatment groups across subgroups. Grade 3 or 4 AEs occurred in 64.9% of darolutamide patients versus 64.2% of placebo patients in the high-volume subgroup and 70.1% versus 61.1% in the low-volume subgroup. Among the most common AEs, many were known toxicities related to docetaxel. CONCLUSION In patients with high-volume and high-risk/low-risk metastatic hormone-sensitive prostate cancer, treatment intensification with darolutamide, androgen-deprivation therapy, and docetaxel increased OS with a similar AE profile in the subgroups, consistent with the overall population. [Media: see text]

ObjectiveTo test the efficacy of theTransform-Us!school- and home-based intervention on children’s physical activity (PA), sedentary behaviour (SB) and cardiometabolic risk factor profiles.MethodsA 30-month 2×2 factorial design cluster randomised controlled trial delivered in 20 primary schools (148 Year 3 classes) in Melbourne, Australia (2010–2012), that used pedagogical and environmental strategies to reduce and break up SB, promote PA or a combined approach, compared with usual practice. Primary outcomes (accelerometry data; n=348) were assessed at baseline, 18 and 30 months. Secondary outcomes included body mass index (BMI) and waist circumference (WC) (n=564), blood pressure (BP) (n=537) and biomarkers (minimum n=206). Generalised linear mixed models estimated the interactive effects of the PA and SB interventions on the outcomes. If there was no interaction, the main effects were assessed.ResultsAt 18 months, there were intervention effects on children’s weekday SB (−27 min, 95% CI: −47.3 to −5.3) for the PA intervention, and on children’s average day PA (5.5 min, 95% CI: 0.1 to 10.8) for the SB intervention. At 30 months, there was an intervention effect for children’s average day SB (−33.3 min, 95% CI: −50.6 and −16.0) for the SB intervention. Children’s BMI (PA and SB groups) and systolic BP (combined group) were lower, and diastolic BP (PA group) was higher. There were positive effects on WC at both time points (SB intervention) and mixed effects on blood parameters.ConclusionsTheTransform-Us!PA and SB interventions show promise as a pragmatic approach for reducing children’s SB and adiposity indicators; but achieving substantial increases in PA remains challenging.Trial registrationISRCTN83725066; ACTRN12609000715279.

Background Diabetes mellitus represents a substantial global health challenge, with prevalence rising in low- and middle-income countries (LMICs). Although diabetes is known to follow a socioeconomic gradient, patterns in LMICs are unclear. This study examined associations between education and diabetes, and diabetes self-management behaviours, in six LMICs. Methods Cross-sectional data for 31,780 participants from China, Ghana, India, Mexico, Russia, and South Africa from the World Health Organization Study on Global AGEing and adult health (SAGE) study were used. Participants aged ≥50 years completed face-to-face interviews between 2007 and 2010. Participants self-reported diabetes diagnosis, physical activity, sedentary time, fruit and vegetable consumption, any special diet/program for diabetes, whether they were taking insulin for diabetes and number of years of education. Height, weight, waist, and hip circumference were measured. Country-specific survey-weighted log-binomial regression models were fitted to examine associations between the number of years of education and self-reported diabetes diagnosis (primary analysis). In secondary analyses, among those with a self-reported diabetes diagnosis, generalised linear regression models were fitted to examine associations between education and i) physical activity, ii) sedentary time, iii) fruit and vegetable consumption, iv) special diet for diabetes, v) taking insulin, vi) BMI, vii) waist circumference and viii) hip circumference. Results There was strong evidence of an association between years of education and diabetes diagnosis in Ghana (RR = 1.09, 95% CI: 1.06–1.13) and India (RR = 1.09, 95% CI: 1.07–1.12) only. In India, greater years of education was associated with higher leisure physical activity, fruit and vegetable intake, rates following a special diet or taking insulin, but also higher mean BMI, waist and hip circumference. Relationships between education and self-management behaviours were rarely seen in the other countries. Conclusions Associations between education and diabetes, and behavioural self-management (India only) was more evident in the two least developed (Ghana and India) of the WHO SAGE countries, indicating increasing diabetes diagnosis with greater numbers of years of education. The lack of gradients elsewhere may reflect shifting risk from higher to lower educated populations. While there was some suggestion that self-management behaviours were greater with increased education in India, this was not observed in the other countries.

BACKGROUND People of low socioeconomic position such as those on a low income are disproportionately affected by diabetes, and by unhealthy eating patterns that contribute to poor disease self-management and prognosis. Digitally-delivered interventions have the potential to address some of the barriers to healthy eating experienced by this group. However, little is known about their effectiveness among underserved populations. OBJECTIVE This systematic review was conducted to assess the effectiveness of digitally-delivered interventions for improving nutrition behaviours and nutrition‐related health outcomes among underserved people with type 2 diabetes (T2D). METHODS MEDLINE complete, Global Health, EMBASE, CINAHL complete, Informit Health, IEEE Xplore, Applied science and technology source were searched for digitally-delivered nutrition intervention for disadvantaged people with T2D, published between 1990 and 2022. Two reviewers independently assessed studies for eligibility and determined study quality, using the Cochrane Risk of Bias Assessment Tool. The Behavioural Change Technique Taxonomy V1 (BCTTv1) was used to identify BCTs used in the design of interventions. RESULTS Ten out of 2434 identified records met eligibility criteria and were included, comprising 947 participants. Two digital platforms, web and messaging services (SMS or MMS) were used to deliver interventions. Significant improvements in dietary behaviours were reported in five out of 10 studies, representing improvements in healthier food choices, or increases in dietary knowledge and skills or self-efficacy. Seven studies examined changes in blood glucose level, of which four achieved significant decreases in HbA1C level ranging from 0.3% to 1.8%. The most frequently identified BCTs across all studies were “Instruction on how to perform the behaviour”, “information about health consequences” and “social support”. CONCLUSIONS This review provided some support for the efficacy of digitally-delivered interventions on improving healthy eating behaviours of disadvantaged people with T2D, an essential dietary prerequisite for changes in clinical metabolic parameters. Further research is needed into how underserved people with T2D may benefit more from digital approaches and to find the specific features of effective digital interventions for supporting healthy behaviours amongst disadvantaged populations.

Tumour dependency on specific metabolic signals has been demonstrated and often guided numerous therapeutic approaches. We identify melanoma addiction to the mitochondrial protein glutaryl-CoA dehydrogenase (GCDH), which functions in lysine metabolism and controls protein glutarylation. GCDH knockdown induced cell death programmes in melanoma cells, an activity blocked by inhibition of the upstream lysine catabolism enzyme DHTKD1. The transcription factor NRF2 mediates GCDH-dependent melanoma cell death programmes. Mechanistically, GCDH knockdown induces NRF2 glutarylation, increasing its stability and DNA binding activity, with a concomitant transcriptional upregulation of ATF4, ATF3, DDIT3 and CHAC1, resulting in cell death. In vivo, inducible inactivation of GCDH effectively inhibited melanoma tumour growth. Correspondingly, reduced GCDH expression correlated with improved survival of patients with melanoma. These findings identify melanoma cell addiction to GCDH, limiting apoptotic signalling by controlling NRF2 glutarylation. Inhibiting the GCDH pathway could thus represent a therapeutic approach to treat melanoma.

The introduction of magnetic resonance (MR) linear accelerators (MR-Linac) marks the beginning of a new era in radiotherapy. MR-Linac systems are currently being operated by teams of radiation therapists (RTs), radiation oncology medical physicists (ROMPs) and radiation oncologists (ROs) due to the diverse and complex tasks required to deliver treatment. This is resource-intensive and logistically challenging. RT-led service delivery at the treatment console is paramount to simplify the process and make the best use of this technology for suitable patients with commonly treated anatomical sites. This article will discuss the experiences of our department in developing and implementing an RT-led workflow on the 1.5 T MR-Linac.