Process evaluation of a sport-for-health intervention to prevent smoking amongst primary school children: SmokeFree Sports

Background: SmokeFree Sports (SFS) was a multi-component sport-for-health intervention aiming at preventing smoking among nine to ten year old primary school children from North West England. The purpose of this study was to evaluate the process and implementation of SFS, examining intervention reach, dose, fidelity, acceptability and sustainability, in order to understand the feasibility and challenges of delivering such interventions and inform interpretations of intervention effectiveness.  Methods: Process measures included: booking logs, 18 focus groups with children (n=95), semi-structured interviews with teachers (n=20) and SFS coaches (n=7), intervention evaluation questionnaires (completed by children, n=1097; teachers, n=50), as well direct observations (by researchers, n=50 observations) and self-evaluations (completed by teachers, n=125) of intervention delivery (e.g. length of sessions, implementation of activities as intended, children's engagement and barriers). Descriptive statistics and thematic analysis were applied to quantitative and qualitative data, respectively.  Results: Overall, SFS reached 30.8% of eligible schools, with 1073 children participating in the intervention (across 32 schools). Thirty-one schools completed the intervention in full. Thirty-three teachers (55% female) and 11 SFS coaches (82% male) attended a bespoke SFS training workshop. Disparities in intervention duration (range=126 to 201 days), uptake (only 25% of classes received optional intervention components in full), and the extent to which core (mean fidelity score of coaching sessions=58%) and optional components (no adaptions made=51% of sessions) were delivered as intended, were apparent. Barriers to intervention delivery included the school setting and children's behaviour and knowledge. SFS was viewed positively (85% and 82% of children and teachers, respectively, rated SFS five out of five) and recommendations to increase school engagement were provided.  Conclusion: SFS was considered acceptable to children, teachers and coaches. Nevertheless, efforts to enhance intervention reach (at the school level), teachers' engagement and sustainability must be considered. Variations in dose and fidelity likely reflect challenges associated with complex intervention delivery within school settings and thus a flexible design may be necessary. This study adds to the limited scientific evidence base surrounding sport-for-health interventions and their implementation, and suggests that such interventions offer a promising tool for engaging children in activities which promote their health

ST6GAL1-mediated aberrant sialylation promotes prostate cancer progression.

Aberrant glycosylation is a universal feature of cancer cells, and cancer-associated glycans have been detected in virtually every cancer type. A common change in tumour cell glycosylation is an increase in α2,6 sialylation of N-glycans, a modification driven by the sialyltransferase ST6GAL1. ST6GAL1 is overexpressed in numerous cancer types, and sialylated glycans are fundamental for tumour growth, metastasis, immune evasion, and drug resistance, but the role of ST6GAL1 in prostate cancer is poorly understood. Here, we analyse matched cancer and normal tissue samples from 200 patients and verify that ST6GAL1 is upregulated in prostate cancer tissue. Using MALDI imaging mass spectrometry (MALDI-IMS), we identify larger branched α2,6 sialylated N-glycans that show specificity to prostate tumour tissue. We also monitored ST6GAL1 in plasma samples from >400 patients and reveal ST6GAL1 levels are significantly increased in the blood of men with prostate cancer. Using both in vitro and in vivo studies, we demonstrate that ST6GAL1 promotes prostate tumour growth and invasion. Our findings show ST6GAL1 introduces α2,6 sialylated N-glycans on prostate cancer cells and raise the possibility that prostate cancer cells can secrete active ST6GAL1 enzyme capable of remodelling glycans on the surface of other cells. Furthermore, we find α2,6 sialylated N-glycans expressed by prostate cancer cells can be targeted using the sialyltransferase inhibitor P-3FAX -Neu5Ac. Our study identifies an important role for ST6GAL1 and α2,6 sialylated N-glycans in prostate cancer progression and highlights the opportunity to inhibit abnormal sialylation for the development of new prostate cancer therapeutics. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland

Upregulation of GALNT7 in prostate cancer modifies O-glycosylation and promotes tumour growth.

Prostate cancer is the most common cancer in men and it is estimated that over 350,000 men worldwide die of prostate cancer every year. There remains an unmet clinical need to improve how clinically significant prostate cancer is diagnosed and develop new treatments for advanced disease. Aberrant glycosylation is a hallmark of cancer implicated in tumour growth, metastasis, and immune evasion. One of the key drivers of aberrant glycosylation is the dysregulated expression of glycosylation enzymes within the cancer cell. Here, we demonstrate using multiple independent clinical cohorts that the glycosyltransferase enzyme GALNT7 is upregulated in prostate cancer tissue. We show GALNT7 can identify men with prostate cancer, using urine and blood samples, with improved diagnostic accuracy than serum PSA alone. We also show that GALNT7 levels remain high in progression to castrate-resistant disease, and using in vitro and in vivo models, reveal that GALNT7 promotes prostate tumour growth. Mechanistically, GALNT7 can modify O-glycosylation in prostate cancer cells and correlates with cell cycle and immune signalling pathways. Our study provides a new biomarker to aid the diagnosis of clinically significant disease and cements GALNT7-mediated O-glycosylation as an important driver of prostate cancer progression

ST6GAL1: A key player in cancer

Aberrant glycosylation is a universal feature of cancer cells and there is now overwhelming evidence that glycans can modulate pathways intrinsic to tumour cell biology. Glycans are important in all of the cancer hallmarks and there is a renewed interest in the glycomic profiling of tumours to improve early diagnosis, determine patient prognosis and identify targets for therapeutic intervention. One of the most widely occurring cancer associated changes in glycosylation is abnormal sialylation which is often accompanied by changes in sialyltransferase activity. Several sialyltransferases are implicated in cancer, but in recent years ST6 β-galactoside α-2,6-sialyltransferase 1 (ST6GAL1) has become increasingly dominant in the literature. ST6GAL1 catalyses the addition of α2,6-linked sialic acids to terminal N-glycans and can modify glycoproteins and/or glycolipids. ST6GAL1 is upregulated in numerous types of cancer (including pancreatic, prostate, breast and ovarian cancer) and can promote growth, survival and metastasis. The present review discusses ST6GAL in relation to the hallmarks of cancer, and highlights its key role in multiple mechanisms intrinsic to tumour cell biology

Synthesis of the Ca2+-mobilizing messengers NAADP and cADPR by intracellular CD38 enzyme in the mouse heart: Role in β-adrenoceptor signaling.

Nicotinic acid adenine dinucleotide phosphate (NAADP) and cyclic ADP-ribose (cADPR) are Ca2+-mobilizing messengers important for modulating cardiac excitation-contraction coupling and pathophysiology. CD38, which belongs to the ADP-ribosyl cyclase family, catalyzes synthesis of both NAADP and cADPR in vitro However, it remains unclear whether this is the main enzyme for their production under physiological conditions. Here we show that membrane fractions from WT but not CD38-/- mouse hearts supported NAADP and cADPR synthesis. Membrane permeabilization of cardiac myocytes with saponin and/or Triton X-100 increased NAADP synthesis, indicating that intracellular CD38 contributes to NAADP production. The permeabilization also permitted immunostaining of CD38, with a striated pattern in WT myocytes, whereas CD38-/- myocytes and nonpermeabilized WT myocytes showed little or no staining, without striation. A component of β-adrenoreceptor signaling in the heart involves NAADP and lysosomes. Accordingly, in the presence of isoproterenol, Ca2+ transients and contraction amplitudes were smaller in CD38-/- myocytes than in the WT. In addition, suppressing lysosomal function with bafilomycin A1 reduced the isoproterenol-induced increase in Ca2+ transients in cardiac myocytes from WT but not CD38-/- mice. Whole hearts isolated from CD38-/- mice and exposed to isoproterenol showed reduced arrhythmias. SAN4825, an ADP-ribosyl cyclase inhibitor that reduces cADPR and NAADP synthesis in mouse membrane fractions, was shown to bind to CD38 in docking simulations and reduced the isoproterenol-induced arrhythmias in WT hearts. These observations support generation of NAADP and cADPR by intracellular CD38, which contributes to effects of β-adrenoreceptor stimulation to increase both Ca2+ transients and the tendency to disturb heart rhythm

Knowledge matters in vocational problem-solving : a cognitive view

While there is increasing emphasis on the idea that vocational education should equip students to think well, very little attention is paid in course design to messages from cognitive research that the quality of people's subject knowledge influences their thinking about problems. The overall aim of the study was to evaluate the usefulness of ideas from cognitive research and from the ‘meta-cognitive movement’ in designing instruction intended to improve students' ability to deal with simple accounting problems. A new ‘cognitive’ approach to teaching an existing basic accounting module was implemented by further education lecturers and evaluated using an experimental/control design. The results indicate that the ‘cognitive’ instruction significantly improved students' scores on non-routine accounting tasks. The authors interpret the results as consistent with their view that the emphasis on understanding and thinking in this study may be more vocationally relevant than is commonly supposed

Sialic acid blockade inhibits the metastatic spread of prostate cancer to bone

Background Bone metastasis is a common consequence of advanced prostate cancer. Bisphosphonates can be used to manage symptoms, but there are currently no curative treatments available. Altered tumour cell glycosylation is a hallmark of cancer and is an important driver of a malignant phenotype. In prostate cancer, the sialyltransferase ST6GAL1 is upregulated, and studies show ST6GAL1-mediated aberrant sialylation of N-glycans promotes prostate tumour growth and disease progression. Methods Here, we monitor ST6GAL1 in tumour and serum samples from men with aggressive prostate cancer and using in vitro and in vivo models we investigate the role of ST6GAL1 in prostate cancer bone metastasis. Findings ST6GAL1 is upregulated in patients with prostate cancer with tumours that have spread to the bone and can promote prostate cancer bone metastasis in vivo. The mechanisms involved are multi-faceted and involve modification of the pre-metastatic niche towards bone resorption to promote the vicious cycle, promoting the development of M2 like macrophages, and the regulation of immunosuppressive sialoglycans. Furthermore, using syngeneic mouse models, we show that inhibiting sialylation can block the spread of prostate tumours to bone. Interpretation Our study identifies an important role for ST6GAL1 and α2-6 sialylated N-glycans in prostate cancer bone metastasis, provides proof-of-concept data to show that inhibiting sialylation can suppress the spread of prostate tumours to bone, and highlights sialic acid blockade as an exciting new strategy to develop new therapies for patients with advanced prostate cancer

Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder.

Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behaviour. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ∼2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, P =  5.87 × 10 -  9; odds ratio (OR) = 1.12) and markers within ERBB2 (rs2517959, P =  4.53 × 10 -  9; OR = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS