Fiona R. Saunders

On the natural chemoprevention of cancer.

Cancer is a complex disease to treat and the treatments have not progressed significantly in the last few years. Alternative strategies such as chemoprevention are being investigated. Proof of concept of chemoprevention has been shown with the non-steroidal anti-inflammatory drugs (NSAIDs); however there is significantly more interest in plant and naturally available compounds for chemoprevention. A number of different naturally occurring chemical compounds are reviewed here for their potential benefits and the pathways which they may target, in particular the polyamine pathway.

Hip shape as a predictor of osteoarthritis progression in a prospective population cohort

Hip morphology plays a significant role in the incidence and progression of hip osteoarthritis (OA). We hypothesized that hip shape would also be associated with other key factors and tested this in a longitudinal community‐based cohort combining radiographic, magnetic resonance imaging (MRI), dual‐energy x‐ray absorptiometry (DXA), and clinical data.

Statistical shape modelling of hip and lumbar spine morphology and their relationship in the MRC National Survey of Health and Development

The anatomical shape of bones and joints is important for their proper function but quantifying this, and detecting pathological variations, is difficult to do. Numerical descriptions would also enable correlations between joint shapes to be explored. Statistical shape modelling (SSM) is a method of image analysis employing pattern recognition statistics to describe and quantify such shapes from images; it uses principal components analysis to generate modes of variation describing each image in terms of a set of numerical scores after removing global size variation. We used SSM to quantify the shapes of the hip and the lumbar spine in dual‐energy x‐ray absorptiometry (DXA) images from 1511 individuals in the MRC National Survey of Health and Development at ages 60–64 years. We compared shapes of both joints in men and women and hypothesised that hip and spine shape would be strongly correlated. We also investigated associations with height, weight, body mass index (BMI) and local (hip or lumber spine) bone mineral density. In the hip, all except one of the first 10 modes differed between men and women. Men had a wider femoral neck, smaller neck‐shaft angle, increased presence of osteophytes and a loss of the femoral head/neck curvature compared with women. Women presented with a flattening of the femoral head and greater acetabular coverage of the femoral head. Greater weight was associated with a shorter, wider femoral neck and larger greater and lesser trochanters. Taller height was accompanied by a flattening of the curve between superior head and neck and a larger lesser trochanter. Four of the first eight modes describing lumbar spine shape differed between men and women. Women tended to have a more lordotic spine than men with relatively smaller but caudally increasing anterior‐posterior (a‐p) vertebral diameters. Men were more likely to have a straighter spine with larger vertebral a‐p diameters relative to vertebral height than women, increasing cranially. A weak correlation was found between body weight and a‐p vertebral diameter. No correlations were found between shape modes and height in men, whereas in women there was a weak positive correlation between height and evenness of spinal curvature. Linear relationships between hip and spine shapes were weak and inconsistent in both sexes, thereby offering little support for our hypothesis.

Investigation of the relationship between susceptibility loci for hip osteoarthritis and DXA-derived hip shape in a population based cohort of peri-menopausal women

To examine relationships between known osteoarthritis (OA) susceptibility loci and hip shape in a population‐based cohort of perimenopausal women in order to investigate whether hip shape contributes to OA development.

Associations between body mass index across adult life and hip shapes at age 60 to 64: Evidence from the 1946 British birth cohort

Objective To examine the associations of body mass index (BMI) across adulthood with hip shapes at age 60–64 years. Methods Up to 1633 men and women from the MRC National Survey of Health and Development with repeat measures of BMI across adulthood and posterior-anterior dual-energy X-ray absorptiometry bone mineral density images of the proximal femur recorded at age 60–64 were included in analyses. Statistical shape modelling was applied to quantify independent variations in hip mode (HM), of which the first 6 were examined in relation to: i) BMI at each age of assessment; ii) BMI gain during different phases of adulthood; iii) age first overweight. Results Higher BMI at all ages (i.e. 15 to 60–64) and greater gains in BMI were associated with higher HM2 scores in both sexes (with positive HM2 values representing a shorter femoral neck and a wider and flatter femoral head). Similarly, younger age first overweight was associated with higher HM2 scores but only in men once current BMI was accounted for. In men, higher BMI at all ages was also associated with lower HM4 scores (with negative HM4 values representing a flatter femoral head, a wider neck and smaller neck shaft angle) but no associations with BMI gain or prolonged exposure to high BMI were found. Less consistent evidence of associations was found between BMI and the other four HMs. Conclusion These results suggest that BMI across adulthood may be associated with specific variations in hip shapes in early old age.

Naproxen causes cytotoxicity and induces changes in polyamine metabolism independent of cyclo-oxygenase expression

The ability of the non-steroidal anti-inflammatory drugs (NSAIDs) to prevent colorectal cancer is well established and has been assumed to be mediated through a cyclo-oxygenase (COX) dependent pathway. In this study we demonstrate that naproxen induces cytotoxicity in a COX-2 null human colorectal cancer cell line (HCT-15) and was equipotent in COX expressing cells (DLD-1). Significant decreases in polyamine content (60–45% of control) were observed in both cell lines, with a corresponding increase in the activity of the two major polyamine catabolic enzymes, spermine/spermidine-N1-acetyltransferase (SSAT) and acetylpolyamine oxidase (APAO). Quantitative PCR confirmed a third catabolic enzyme, spermine oxidase (SMO), was also upregulated in both cell lines following exposure to naproxen. These findings indicate that naproxen is capable of inducing changes in polyamine metabolism that could account for its cytotoxicity and possibly also the chemopreventative actions of the NSAIDs, and further confirms a toxicological effect of the NSAIDs independent of COX inhibition.

Body mass index and waist circumference in early adulthood are associated with thoracolumbar spine shape at age 60-64: The Medical Research Council National Survey of Health and Development

This study investigated associations between measures of adiposity from age 36 and spine shape at 60–64 years. Thoracolumbar spine shape was characterised using statistical shape modelling on lateral dual-energy x-ray absorptiometry images of the spine from 1529 participants of the MRC National Survey of Health and Development, acquired at age 60–64. Associations of spine shape modes with: 1) contemporaneous measures of total and central adiposity (body mass index (BMI), waist circumference (WC)) and body composition (android:gynoid fat mass ratio and lean and fat mass indices, calculated as whole body (excluding the head) lean or fat mass (kg) divided by height2 (m)2); 2) changes in total and central adiposity between age 36 and 60–64 and 3) age at onset of overweight, were tested using linear regression models. Four modes described 79% of the total variance in spine shape. In men, greater lean mass index was associated with a larger lordosis whereas greater fat mass index was associated with straighter spines. Greater current BMI was associated with a more uneven curvature in men and with larger anterior-posterior (a-p) vertebral diameters in both sexes. Greater WC and fat mass index were also associated with a-p diameter in both sexes. There was no clear evidence that gains in BMI and WC during earlier stages of adulthood were associated with spine shape but younger onset of overweight was associated with a more uneven spine and greater a-p diameter. In conclusion, sagittal spine shapes had different associations with total and central adiposity; earlier onset of overweight and prior measures of WC were particularly important.

Identification of novel loci associated with hip shape: a meta-analysis of genome-wide association studies

We aimed to report the first genomewide association study (GWAS) meta‐analysis of dual‐energy X‐ray absorptiometry (DXA)‐derived hip shape, which is thought to be related to the risk of both hip osteoarthritis and hip fracture. Ten hip shape modes (HSMs) were derived by statistical shape modeling using SHAPE software, from hip DXA scans in the Avon Longitudinal Study of Parents and Children (ALSPAC; adult females), TwinsUK (mixed sex), Framingham Osteoporosis Study (FOS; mixed), Osteoporotic Fractures in Men study (MrOS), and Study of Osteoporotic Fractures (SOF; females) (total N = 15,934). Associations were adjusted for age, sex, and ancestry. Five genomewide significant (p < 5 × 10−9, adjusted for 10 independent outcomes) single‐nucleotide polymorphisms (SNPs) were associated with HSM1, and three SNPs with HSM2. One SNP, in high linkage disequilibrium with rs2158915 associated with HSM1, was associated with HSM5 at genomewide significance. In a look‐up of previous GWASs, three of the identified SNPs were associated with hip osteoarthritis, one with hip fracture, and five with height. Seven SNPs were within 200 kb of genes involved in endochondral bone formation, namely SOX9, PTHrP, RUNX1, NKX3‐2, FGFR4, DICER1, and HHIP. The SNP adjacent to DICER1 also showed osteoblast cis‐regulatory activity of GSC, in which mutations have previously been reported to cause hip dysplasia. For three of the lead SNPs, SNPs in high LD (r2 > 0.5) were identified, which intersected with open chromatin sites as detected by ATAC‐seq performed on embryonic mouse proximal femora. In conclusion, we identified eight SNPs independently associated with hip shape, most of which were associated with height and/or mapped close to endochondral bone formation genes, consistent with a contribution of processes involved in limb growth to hip shape and pathological sequelae. These findings raise the possibility that genetic studies of hip shape might help in understanding potential pathways involved in hip osteoarthritis and hip fracture.