Genetic variation in Wnt/β-catenin and ER signalling pathways in female and male elite dancers and its associations with low bone mineral density: a cross-section and longitudinal study.

The association of genetic polymorphisms with low bone mineral density in elite athletes have not been considered previously. The present study found that bone mass phenotypes in elite and pre-elite dancers are related to genetic variants at the Wnt/β-catenin and ER pathways. Some athletes (e.g. gymnasts, dancers, swimmers) are at increased risk for low bone mineral density (BMD) which, if untreated, can lead to osteoporosis. To investigate the association of genetic polymorphisms in the oestrogen receptor (ER) and the Wnt/β-catenin signalling pathways with low BMD in elite and pre-elite dancers (impact sport athletes). The study included three phases: (1) 151 elite and pre-elite dancers were screened for the presence of low BMD and traditional osteoporosis risk factors (low body weight, menstrual disturbances, low energy availability); (2) a genetic association study was conducted in 151 elite and pre-elite dancers and age- and sex- controls; (3) serum sclerostin was measured in 101 pre-elite dancers and age- and sex-matched controls within a 3-year period. Eighty dancers revealed low BMD: 56.3% had at least one traditional osteoporosis risk factor, whereas 28.6% did not display any risk factor (37.2% revealed traditional osteoporosis risk factors, but had normal BMD). Body weight, menstrual disturbances and energy availability did not fully predict bone mass acquisition. Instead, genetic polymorphisms in the ER and Wnt/β-catenin pathways were found to be risk factors for low BMD in elite dancers. Sclerostin was significantly increased in dancers compared to controls during the 3-year follow-up (p < 0.05)

Characterization of the association between 8q24 and colon cancer: gene-environment exploration and meta-analysis

<p>Abstract</p> <p>Background</p> <p>Genome-wide association studies and subsequent replication studies have shown that single nucleotide polymorphisms (SNPs) in the chromosomal region 8q24 are associated with colorectal cancer susceptibility.</p> <p>Methods</p> <p>We examined 11 SNP markers in the 8q24 region between 128.47 and 128.54 Mb, using a total of 1,987 colon cases and 2,339 controls who self-reported as white from two independent, well-characterized study populations. Analysis was performed separately within each study, and combined using random effects meta-analysis. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) and to test for effect modification by known colon cancer risk factors. We also performed a meta-analysis combining our results with previous studies.</p> <p>Results</p> <p>We observed evidence of association for four SNPs in low to high linkage disequilibrium (r²ranging from 0.18 to 0.93) localized in a 16.2 kb region defined by rs10505477 and rs1056368. The combined results for our two studies of colon cancer showed an OR of 1.10 (95% CI: 1.01-1.20, P_trend= 0.023), and a meta-analysis of our results with previously reported studies of colon and colorectal cancer strongly support the association for this SNP (combined OR for rs6983267 = 1.21, 95% CI: 1.18-1.24, p = 5.5 × 10^-44). We did not observe any notable evidence of effect modification by known colon cancer risk factors, and risk did not differ significantly by tumor site or stage.</p> <p>Conclusions</p> <p>Our study confirms the association between polymorphisms on chromosome 8q24 and colon cancer risk and suggests that the susceptibility locus in region 8q24 is not strongly modified by various lifestyle, environmental, and demographic risk factors for colon cancer.</p

Functional Relationship between Skull Form and Feeding Mechanics in Sphenodon, and Implications for Diapsid Skull Development

The vertebrate skull evolved to protect the brain and sense organs, but with the appearance of jaws and associated forces there was a remarkable structural diversification. This suggests that the evolution of skull form may be linked to these forces, but an important area of debate is whether bone in the skull is minimised with respect to these forces, or whether skulls are mechanically “over-designed” and constrained by phylogeny and development. Mechanical analysis of diapsid reptile skulls could shed light on this longstanding debate. Compared to those of mammals, the skulls of many extant and extinct diapsids comprise an open framework of fenestrae (window-like openings) separated by bony struts (e.g., lizards, tuatara, dinosaurs and crocodiles), a cranial form thought to be strongly linked to feeding forces. We investigated this link by utilising the powerful engineering approach of multibody dynamics analysis to predict the physiological forces acting on the skull of the diapsid reptile Sphenodon. We then ran a series of structural finite element analyses to assess the correlation between bone strain and skull form. With comprehensive loading we found that the distribution of peak von Mises strains was particularly uniform throughout the skull, although specific regions were dominated by tensile strains while others were dominated by compressive strains. Our analyses suggest that the frame-like skulls of diapsid reptiles are probably optimally formed (mechanically ideal: sufficient strength with the minimal amount of bone) with respect to functional forces; they are efficient in terms of having minimal bone volume, minimal weight, and also minimal energy demands in maintenance

Array Comparative Genomic Hybridization analysis of resected thymomas on paraffin embedded material

Introduction: Thymomas are rare tumors derived from the thymic epithelial cells. They show heterogeneous biological characteristics and survival outcome. The WHO classification identifies different histotypes with prognostic implications. They range from type A with around 100% 10-year survival to the most aggressive type C with 0% 10 years survival reported. There is very little known of the biology of thymomas and of the genetic alterations present in these tumors. Array comparative genomic hybridization (CGH) is a powerful technique to define compy number abnormalities. Materials and Methods: We selected 60 thymoma samples showing a proportion of cancer cells > 80% from 151 formalin fixed paraffin embedded samples of 134 patients who underwent surgery at Humanitas Hospital, Milan, Italy. The DNA extraction and labeling was performed according to Genomic DNA ULS Labeling Kit (Agilent, Santa Clara, California, USA). We used as reference Human Genomic DNA: Male (Promega, Madison, Wisconsin, USA). Eleven samples were hybridized on Human Genome CGH Array 105A (Agilent) and 29 on SurePrint G3 Human CGH Array 180K (Agilent). Slides were scanned on a laser-based microarray scanner (Agilent). The data were extracted and normalized by Feature Extraction 10.5 (Agilent). We performed data analysis using Nexus 4.0 (Biodiscovery Inc, El Segundo California, USA) by Log Rank segmentation algorithm. We selected for the analysis 40 samples with a Robust Variance Sample QC< 0.2 as recommended. We evaluated aberration of autosomal chromosomes. Common Aberrant Region (CAR) are defined by a imbalance frequencies of 50% in type C and of 35% in the remaining categories. Results: In 40 thymoma samples we identified 12 common aberrant regions: 6 are gains involving 1037 genes and 6 are losses involving 96 genes. These aberrations are present in each histotype. In 9 type A thymoma samples we discovered 11 common aberrant gains (CAG) involving 112 genes and 3 common aberrant losses (CAL) involving 11 genes. For the 11 AB specimens we identified 18 CAG involving 931 genes and 3 CAL involving 56 genes. We evaluated 15 B3 samples presenting 10 CAG involving 1172 genes and 9 CAL involving 389 genes. Five thymic carcinomas showed 20 CAG with 1356 genes and 8 CAL with 540 genes involved. Conclusion: CGH analysis is feasible using FFPE samples commonly stored for diagnosis. The number of genes involved in karyotypic aberration increase from type A to the more aggressive type C. Chromosome imbalance is present in each histotype analyzed

Detection and therapeutic implications of c-Met mutations in small cell lung cancer and neuroendocrine tumors

We evaluated the mutation status of c-Met in small cell lung cancer (SCLC) and neuroendocrine tumors (NET), for which relatively limited therapeutic targets have been explored

Estrogen receptor alpha regulates area-adjusted bone mineral content in late pubertal girls

Context: Whether the action of estrogen in skeletal development depends on estrogen receptor alpha as encoded by the ESR1 gene is unknown. Objectives: The aim of this study was to establish whether the gain in area-adjusted bone mineral content (ABMC) in girls occurs in late puberty and to examine whether the magnitude of this gain is related to ESR1 polymorphisms. Design: We conducted a cross-sectional analysis. Setting: The study involved the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based prospective study. Participants: Participants included 3097 11-yr-olds with DNA samples, dual x-ray absorptiometry measurements, and pubertal stage information. Outcomes: Outcome measures included separate prespecified analyses in boys and girls of the relationship between ABMC derived from total body dual x-ray absorptiometry scans and Tanner stage and of the interaction between ABMC, Tanner stage, and ESR1 polymorphisms. Results: Total body less head and spinal ABMC were higher in girls in Tanner stages 4 and 5, compared with those in Tanner stages 1, 2, and 3. In contrast, height increased throughout puberty. No differences were observed in ABMC according to Tanner stage in boys. For rs2234693 (PvuII) and rs9340799 (XbaI) polymorphisms, differences in spinal ABMC in late puberty were 2-fold greater in girls who were homozygous for the C and G alleles, respectively (P = 0.001). For rs7757956, the difference in total body less head ABMC in late puberty was 50% less in individuals homozygous or heterozygous for the A allele (P = 0.006). Conclusions: Gains in ABMC in late pubertal girls are strongly associated with ESR1 polymorphisms, suggesting that estrogen contributes to this process via an estrogen receptor alpha-dependent pathway