Colouration in amphibians as a reflection of nutritional status : the case of tree frogs in Costa Rica

Colouration has been considered a cue for mating success in many species; ornaments in males often are related to carotenoid mobilization towards feathers and/or skin and can signal general health and nutrition status. However, there are several factors that can also link with status, such as physiological blood parameters and body condition, but there is not substantial evidence which supports the existence of these relationships and interactions in anurans. This study evaluated how body score and blood values interact with colouration in free-range Agalychnis callidryas and Agalychnis annae males. We found significant associations between body condition and plasmatic proteins and haematocrit, as well as between body condition and colour values from the chromaticity diagram. We also demonstrated that there is a significant relation between the glucose and plasmatic protein values that were reflected in the ventral colours of the animals, and haematocrit inversely affected most of those colour values. Significant differences were found between species as well as between populations of A. callidryas, suggesting that despite colour variation, there are also biochemical differences within animals from the same species located in different regions. These data provide information on underlying factors for colouration of male tree frogs in nature, provide insights about the dynamics of several nutrients in the amphibian model and how this could affect the reproductive output of the animals

Genetically inferred birthweight, height, and puberty timing and risk of osteosarcoma

INTRODUCTION: Several studies have linked increased risk of osteosarcoma with tall stature, high birthweight, and early puberty, although evidence is inconsistent. We used genetic risk scores (GRS) based on established genetic loci for these traits and evaluated associations between genetically inferred birthweight, height, and puberty timing with osteosarcoma. METHODS: Using genotype data from two genome-wide association studies, totaling 1039 cases and 2923 controls of European ancestry, association analyses were conducted using logistic regression for each study and meta-analyzed to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup analyses were conducted by case diagnosis age, metastasis status, tumor location, tumor histology, and presence of a known pathogenic variant in a cancer susceptibility gene. RESULTS: Genetically inferred higher birthweight was associated with an increased risk of osteosarcoma (OR =1.59, 95% CI 1.07-2.38, P = 0.02). This association was strongest in cases without metastatic disease (OR =2.46, 95% CI 1.44-4.19, P = 9.5 ×10-04). Although there was no overall association between osteosarcoma and genetically inferred taller stature (OR=1.06, 95% CI 0.96-1.17, P = 0.28), the GRS for taller stature was associated with an increased risk of osteosarcoma in 154 cases with a known pathogenic cancer susceptibility gene variant (OR=1.29, 95% CI 1.03-1.63, P = 0.03). There were no significant associations between the GRS for puberty timing and osteosarcoma. CONCLUSION: A genetic propensity to higher birthweight was associated with increased osteosarcoma risk, suggesting that shared genetic factors or biological pathways that affect birthweight may contribute to osteosarcoma pathogenesis

Does supplementation with leucine-enriched protein alone and in combination with fish-oil-derived n–3 PUFA affect muscle mass, strength, physical performance, and muscle protein synthesis in well-nourished older adults? A randomized, double-blind, placebo-controlled trial

peer-reviewedBackground Leucine-enriched protein (LEU-PRO) and long-chain (LC) n–3 (ω–3) PUFAs have each been proposed to improve muscle mass and function in older adults, whereas their combination may be more effective than either alone. Objective The impact of LEU-PRO supplementation alone and combined with LC n–3 PUFAs on appendicular lean mass, strength, physical performance and myofibrillar protein synthesis (MyoPS) was investigated in older adults at risk of sarcopenia. Methods This 24-wk, 3-arm parallel, randomized, double-blind, placebo-controlled trial was conducted in 107 men and women aged ≥65 y with low muscle mass and/or strength. Twice daily, participants consumed a supplement containing either LEU-PRO (3 g leucine, 10 g protein; n = 38), LEU-PRO plus LC n–3 PUFAs (0.8 g EPA, 1.1 g DHA; LEU-PRO+n–3; n = 38), or an isoenergetic control (CON; n = 31). Appendicular lean mass, handgrip strength, leg strength, physical performance, and circulating metabolic and renal function markers were measured pre-, mid-, and postintervention. Integrated rates of MyoPS were assessed in a subcohort (n = 28). Results Neither LEU-PRO nor LEU-PRO+n–3 supplementation affected appendicular lean mass, handgrip strength, knee extension strength, physical performance or MyoPS. However, isometric knee flexion peak torque (treatment effect: −7.1 Nm; 95% CI: −12.5, −1.8 Nm; P < 0.01) was lower postsupplementation in LEU-PRO+n–3 compared with CON. Serum triacylglycerol and total adiponectin concentrations were lower, and HOMA-IR was higher, in LEU-PRO+n–3 compared with CON postsupplementation (all P < 0.05). Estimated glomerular filtration rate was higher and cystatin c was lower in LEU-PRO and LEU-PRO+n–3 postsupplementation compared with CON (all P < 0.05). Conclusions Contrary to our hypothesis, we did not observe a beneficial effect of LEU-PRO supplementation alone or combined with LC n–3 PUFA supplementation on appendicular lean mass, strength, physical performance or MyoPS in older adults at risk of sarcopenia. This trial was registered at clinicaltrials.gov as NCT03429491.Horizon 2020 Framework ProgrammeThis work was supported by the Department of Agriculture, Food and the Marine Food Institutional Research Measure grant entitled NUTRIMAL “Novel Nutritional Solutions for the Prevention of Malnutrition” (grant 14F822), the European Union’s Horizon 2020 Research and Innovation Program under the Marie Skłodowska-Curie Grant Agreement No. 666010, and a Research Fellowship awarded to CHM by the European Society of Clinical Nutrition and Metabolism (ESPEN). HMR was supported by funding from the Joint Programming Initiative Healthy Diet for a Healthy Life (JPI HDHL) EU Food Biomarkers Alliance “FOODBAll” with Science Foundation Ireland (14/JPHDHL/B3076)

Airway Microbiota and Pathogen Abundance in Age-Stratified Cystic Fibrosis Patients

Bacterial communities in the airways of cystic fibrosis (CF) patients are, as in other ecological niches, influenced by autogenic and allogenic factors. However, our understanding of microbial colonization in younger versus older CF airways and the association with pulmonary function is rudimentary at best. Using a phylogenetic microarray, we examine the airway microbiota in age stratified CF patients ranging from neonates (9 months) to adults (72 years). From a cohort of clinically stable patients, we demonstrate that older CF patients who exhibit poorer pulmonary function possess more uneven, phylogenetically-clustered airway communities, compared to younger patients. Using longitudinal samples collected form a subset of these patients a pattern of initial bacterial community diversification was observed in younger patients compared with a progressive loss of diversity over time in older patients. We describe in detail the distinct bacterial community profiles associated with young and old CF patients with a particular focus on the differences between respective “early” and “late” colonizing organisms. Finally we assess the influence of Cystic Fibrosis Transmembrane Regulator (CFTR) mutation on bacterial abundance and identify genotype-specific communities involving members of the Pseudomonadaceae, Xanthomonadaceae, Moraxellaceae and Enterobacteriaceae amongst others. Data presented here provides insights into the CF airway microbiota, including initial diversification events in younger patients and establishment of specialized communities of pathogens associated with poor pulmonary function in older patient populations

Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer.

Women with epithelial ovarian cancer (EOC) are usually treated with platinum/taxane therapy after cytoreductive surgery but there is considerable inter-individual variation in response. To identify germline single-nucleotide polymorphisms (SNPs) that contribute to variations in individual responses to chemotherapy, we carried out a multi-phase genome-wide association study (GWAS) in 1,244 women diagnosed with serous EOC who were treated with the same first-line chemotherapy, carboplatin and paclitaxel. We identified two SNPs (rs7874043 and rs72700653) in TTC39B (best P=7x10-5, HR=1.90, for rs7874043) associated with progression-free survival (PFS). Functional analyses show that both SNPs lie in a putative regulatory element (PRE) that physically interacts with the promoters of PSIP1, CCDC171 and an alternative promoter of TTC39B. The C allele of rs7874043 is associated with poor PFS and showed increased binding of the Sp1 transcription factor, which is critical for chromatin interactions with PSIP1. Silencing of PSIP1 significantly impaired DNA damage-induced Rad51 nuclear foci and reduced cell viability in ovarian cancer lines. PSIP1 (PC4 and SFRS1 Interacting Protein 1) is known to protect cells from stress-induced apoptosis, and high expression is associated with poor PFS in EOC patients. We therefore suggest that the minor allele of rs7874043 confers poor PFS by increasing PSIP1 expression.This project has been supported by a grant from Cancer Australia. The Mayo Clinic GWAS was supported by R01CA114343 (Haplotype-based genome screen for ovarian cancer loci). The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith. The AOCS was supported by the U.S. Army Medical Research and Materiel Command under DAMD17-01-1-0729, the National Health and Medical Research Council (NHMRC) of Australia (grants 400281, 400413), Cancer Council Victoria, Cancer Council Queensland, Cancer Council New South Wales, Cancer Council South Australia, The Cancer Foundation of Western Australia, and Cancer Council Tasmania. G. Chenevix-Trench is a Senior Principal Research fellow of the NHMRC. Y. Lu is funded by NHMRC grant 496675, S. MacGregor is supported by an NHMRC career development award, S. Edwards and J. French are supported by Fellowships from the National Breast Cancer Foundation (NBCF) Australia. The QIMR Berghofer groups were supported by NHMRC project grants (1051698 to SM and 1058415 to SLE and JDF) and a Weekend to End Women’s Cancer Research Grant (to SLE). A deFazio is funded by the University of Sydney Cancer Research Fund and A deFazio and PR Harnett are funded by the Cancer Institute NSW through the Sydney-West Translational Cancer Research Centre. B. Gao is supported by NHMRC and Cancer Institute NSW scholarship. KBM and MO’R are funded by CR-UK. The Bavarian study (BAV) was supported by ELAN Funds of the University of Erlangen-Nuremberg. HSK would like to thank Ira Schwaab for her tireless work on sample preparation. The Belgian study (BEL) was funded by Nationaal Kankerplan and we would like to thank Gilian Peuteman, Thomas Van Brussel and Dominiek Smeets for technical assistance. The Japanese study (JPN) was funded by a Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare. The International Collaborative Ovarian Neoplasm study (ICON)7 trial team would like to thank the Medical Research Council (MRC) Clinical Trial Unit (CTU) at the University of London (UCL), the ICON7 Translational Research Sub-group, and the University of Leeds for their work on the coordination of samples and data from the ICON7 trial. The LAX study (Women’s Cancer Program) was supported by the American Cancer Society Early Detection Professorship (120950-SIOP-06-258-06-COUN) and Entertainment Industry Foundation. Funding for MALOVA (MAL) was provided by research grant RO1 CA 61107 from the National Cancer Institute, Bethesda, MD; research grant 94 222 52 from the Danish Cancer Society, Copenhagen, Denmark; and the Mermaid I project. The Mayo Clinic study (MAYO) was supported by R01 CA122443, P50 CA136393. The Oregon study (ORE) was funded by the Sherie Hildreth Ovarian Cancer Research Fund and the OHSU Foundation. We would like to thank all members of Scottish Gynaecological Clinical Trials group and the SCOTROC1 investigators. SCOTROC1 (SRO) was funded by Cancer Research UK, and the SCOTROC biological studies were supported by Cancer Research UK (grant C536/A6689). RSH receives support from NIH/NIGMS grant K08GM089941, NIH/NCI grant R21 CA139278, NIH/NIGMS grant UO1GM61393, University of Chicago Cancer Center Support Grant (#P30 CA14599) and Breast Cancer SPORE Career Development Award.This is the final version of the article. It first appeared from Impact Journals via http://dx.doi.org/10.18632/oncotarget.704

Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci

Background: Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription factors (TFs) critical to somatic tumorigenesis. Methods: All 615 TF-target sets from the Molecular Signatures Database were evaluated using gene set enrichment analysis (GSEA) and three GWAS for SOC risk: discovery (2196 cases/4396 controls), replication (7035 cases/21 693 controls; independent from discovery), and combined (9627 cases/30 845 controls; including additional individuals). Results: The PAX8-target gene set was ranked 1/615 in the discovery (PGSEA&lt;0.001; FDR=0.21), 7/615 in the replication (PGSEA=0.004; FDR=0.37), and 1/615 in the combined (PGSEA&lt;0.001; FDR=0.21) studies. Adding other genes reported to interact with PAX8 in the literature to the PAX8-target set and applying an alternative to GSEA, interval enrichment, further confirmed this association (P=0.006). Fifteen of the 157 genes from this expanded PAX8 pathway were near eight loci associated with SOC risk at P&lt;10−5 (including six with P&lt;5 × 10−8). The pathway was also associated with differential gene expression after shRNA-mediated silencing of PAX8 in HeyA8 (PGSEA=0.025) and IGROV1 (PGSEA=0.004) SOC cells and several PAX8 targets near SOC risk loci demonstrated in vitro transcriptomic perturbation. Conclusions: Putative PAX8 target genes are enriched for common SOC risk variants. This finding from our agnostic evaluation is of particular interest given that PAX8 is well-established as a specific marker for the cell of origin of SOC

Development and validation of a targeted gene sequencing panel for application to disparate cancers

Next generation sequencing has revolutionised genomic studies of cancer, having facilitated the development of precision oncology treatments based on a tumour’s molecular profile. We aimed to develop a targeted gene sequencing panel for application to disparate cancer types with particular focus on tumours of the head and neck, plus test for utility in liquid biopsy. The final panel designed through Roche/Nimblegen combined 451 cancer-associated genes (2.01 Mb target region). 136 patient DNA samples were collected for performance and application testing. Panel sensitivity and precision were measured using well-characterised DNA controls (n = 47), and specificity by Sanger sequencing of the Aryl Hydrocarbon Receptor Interacting Protein (AIP) gene in 89 patients. Assessment of liquid biopsy application employed a pool of synthetic circulating tumour DNA (ctDNA). Library preparation and sequencing were conducted on Illumina-based platforms prior to analysis with our accredited (ISO15189) bioinformatics pipeline. We achieved a mean coverage of 395x, with sensitivity and specificity of >99% and precision of >97%. Liquid biopsy revealed detection to 1.25% variant allele frequency. Application to head and neck tumours/cancers resulted in detection of mutations aligned to published databases. In conclusion, we have developed an analytically-validated panel for application to cancers of disparate types with utility in liquid biopsy

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC