The interaction between cancer cells and microenvironment has a critical role in tumor development and progression. Although microRNAs regulate all the major biological mechanisms, their influence on ...tumor microenvironment is largely unexplored. Here, we investigate the role of microRNAs in the tumor-supportive capacity of stromal cells. We demonstrated that miR-15 and miR-16 are downregulated in fibroblasts surrounding the prostate tumors of the majority of 23 patients analyzed. Such downregulation of miR-15 and miR-16 in cancer-associated fibroblasts (CAFs) promoted tumor growth and progression through the reduced post-transcriptional repression of Fgf-2 and its receptor Fgfr1, which act on both stromal and tumor cells to enhance cancer cell survival, proliferation and migration. Moreover, reconstitution of miR-15 and miR-16 impaired considerably the tumor-supportive capability of stromal cells in vitro and in vivo. Our data suggest a molecular circuitry in which miR-15 and miR-16 and their correlated targets cooperate to promote tumor expansion and invasiveness through the concurrent activity on stromal and cancer cells, thus providing further support to the development of therapies aimed at reconstituting miR-15 and miR-16 in advanced prostate cancer.
Background: The benefit of neoadjuvant chemoradiotherapy in oesophageal cancer has been extensively studied but data on survival are still equivocal. Objective: To assess the effectiveness of ...chemoradiotherapy followed by surgery in the reduction of mortality in patients with resectable oesophageal cancer. Methods: Computerised bibliographic searches of MEDLINE and CANCERLIT (1970–2002) were supplemented with hand searches of reference lists. Study selection: Studies were included if they were randomised controlled trials (RCTs) comparing preoperative chemoradiotherapy plus surgery with surgery alone, and if they included patients with resectable histologically proven oesophageal cancer without metastatic disease. Six eligible RCTs were identified and included in the meta-analysis. Data extraction: Data on study populations, interventions, and outcomes were extracted from each RCT according to the intention to treat method by three independent observers and combined using the DerSimonian and Laird method. Results: Chemoradiotherapy plus surgery compared with surgery alone significantly reduced the three year mortality rate (odds ratio (OR) 0.53 (95% confidence interval (CI) 0.31–0.93); p = 0.03) (number needed to treat = 10). Pathological examination showed that preoperative chemoradiotherapy downstaged the tumour (that is, less advanced stage at pathological examination at the time of surgery) compared with surgery alone (OR 0.43 (95% CI 0.26–0.72); p = 0.001). The risk for postoperative mortality was higher in the chemoradiotherapy plus surgery group (OR 2.10 (95% CI 1.18–3.73); p = 0.01). Conclusions: In patients with resectable oesophageal cancer, chemoradiotherapy plus surgery significantly reduces three year mortality compared with surgery alone. However, postoperative mortality was significantly increased by neoadjuvant chemoradiotherapy. Further large scale multicentre RCTs may prove useful to substantiate the benefit on overall survival.
Summary Background Osteoporosis is diagnosed by the measurement of bone mineral density, which is a highly heritable and multifactorial trait. We aimed to identify genetic loci that are associated ...with bone mineral density. Methods In this genome-wide association study, we identified the most promising of 314 075 single nucleotide polymorphisms (SNPs) in 2094 women in a UK study. We then tested these SNPs for replication in 6463 people from three other cohorts in western Europe. We also investigated allelic expression in lymphoblast cell lines. We tested the association between the replicated SNPs and osteoporotic fractures with data from two studies. Findings We identified genome-wide evidence for an association between bone mineral density and two SNPs (p<5×10−8 ). The SNPs were rs4355801, on chromosome 8, near to the TNFRSF11B (osteoprotegerin) gene, and rs3736228, on chromosome 11 in the LRP5 (lipoprotein-receptor-related protein) gene. A non-synonymous SNP in the LRP5 gene was associated with decreased bone mineral density (rs3736228, p=6·3×10−12 for lumbar spine and p=1·9×10−4 for femoral neck) and an increased risk of both osteoporotic fractures (odds ratio OR 1·3, 95% CI 1·09–1·52, p=0·002) and osteoporosis (OR 1·3, 1·08–1·63, p=0·008). Three SNPs near the TNFRSF11B gene were associated with decreased bone mineral density (top SNP, rs4355801: p=7·6×10−10 for lumbar spine and p=3·3×10−8 for femoral neck) and increased risk of osteoporosis (OR 1·2, 95% CI 1·01–1·42, p=0·038). For carriers of the risk allele at rs4355801, expression of TNFRSF11B in lymphoblast cell lines was halved (p=3·0×10−6 ). 1883 (22%) of 8557 people were at least heterozygous for these risk alleles, and these alleles had a cumulative association with bone mineral density (trend p=2·3×10−17 ). The presence of both risk alleles increased the risk of osteoporotic fractures (OR 1·3, 1·08–1·63, p=0·006) and this effect was independent of bone mineral density. Interpretation Two gene variants of key biological proteins increase the risk of osteoporosis and osteoporotic fracture. The combined effect of these risk alleles on fractures is similar to that of most well-replicated environmental risk factors, and they are present in more than one in five white people, suggesting a potential role in screening. Funding Wellcome Trust, European Commission, NWO Investments, Arthritis Research Campaign, Chronic Disease Research Foundation, Canadian Institutes of Health Research, European Society for Clinical and Economic Aspects of Osteoporosis, Genome Canada, Genome Quebéc, Canada Research Chairs, National Health and Medical Research Council of Australia, and European Union.
We aimed to identify patients' clinical characteristics associated with respiratory viruses identified among patients presenting with influenza-like illness (ILI).
A sample of patients of all ages ...presenting with ILI was included by physicians of the French Sentinelles network during two seasons (2015/16 and 2016/17). Nasopharyngeal samples were tested for the presence of influenza virus (IV), respiratory syncytial virus (RSV), human rhinovirus (HRV) and human metapneumovirus (HMPV). Patients' characteristics associated with each of the four virus classes were studied using multivariate logistic regressions.
A total of 5859 individuals were included in the study: 48.0% tested positive for IV, 7.9% for HRV, 7.5% for RSV and 4.1% for HMPV. Cough was associated with IV (OR 2.14, 95% CI 1.81–2.52) RSV (OR 2.52, 95% CI 1.75–3.74) and HMPV detection (OR 2.15, 95% CI 1.40–3.45). Rhinorrhoea was associated mainly with HRV detection (OR 1.75, 95% CI 1.34–2.32). Headache was associated with IV detection (OR 1.75, 95% CI 1.34–2.32), whereas absence of headache was associated with RSV and HMPV detection. Dyspnoea was associated with RSV detection (OR 2.33, 95% CI 1.73–3.12) and absence of dyspnoea with IV detection. Conjunctivitis was associated with IV detection (OR 1.27, 95% CI 1.08–1.50). Some associations were observed only in children: dyspnoea and cough with RSV detection (age <5 years), conjunctivitis with IV detection (age <15 years). Period of onset of symptoms differed among aetiological diagnoses. Seasonal influenza vaccination decreased the risk of IV detection (OR, 0.67, 95% CI 0.51–0.86).
This study allowed the identification of symptoms associated with several viral aetiologies in patients with ILI. A proper knowledge and understanding of these clinical signs may improve the medical management of patients.
The dietary sesquiterpene dienone zerumbone (ZER) selectively targets cancer cells, inducing mitochondrial dysfunction and apoptosis, and protects non-cancerous cells towards oxidative stress and ...insult. This study examines the in vitro effects of ZER on lipid peroxidation in biological systems (cholesterol and phospholipid membrane oxidation) and explores its antitumor action in terms of its ability to modulate cancer cell lipid profile. Evaluation of the antioxidant activity of ZER showed that this compound is unable to trap lipoperoxyl radicals per se. ZER significantly modulated the total lipid and fatty acid profiles in cancer cells, inducing marked changes in the phospholipid/cholesterol ratio, with significant decreases in the levels of oleic and palmitic acids and a marked increase of stearic acid. Cell-based fluorescent measurements of intracellular membranes and lipid droplets using the Nile Red staining technique showed that in cancer cells, ZER induced significant accumulation of cytosolic lipid droplets and altered cell membrane organization/protein dynamics, depolarizing the mitochondrial membranes and inducing apoptosis and alteration of nuclear morphology. The modulatory activity of ZER on the total lipid and fatty acid profiles and lipid droplets may therefore represent another possible mechanism of its anticancer properties.
Background Immunoglobulin (Ig) glycosylation modulates the immune response and plays a critical role in ageing and diseases. Studies have mainly focused on IgG glycosylation, and little is known ...about the genetics and epidemiology of IgA glycosylation. Methods We generated, using a novel liquid chromatography-mass spectrometry method, the first large-scale IgA glycomics dataset in serum from 2423 twins, encompassing 71 N- and O-glycan species. Results We showed that, despite the lack of a direct genetic template, glycosylation is highly heritable, and that glycopeptide structures are sex-specific, and undergo substantial changes with ageing. We observe extensive correlations between the IgA and IgG glycomes, and, exploiting the twin design, show that they are predominantly influenced by shared genetic factors. A genome-wide association study identified eight loci associated with both the IgA and IgG glycomes (ST6GAL1, ELL2, B4GALT1, ABCF2, TMEM121, SLC38A10, SMARCB1, and MGAT3) and two novel loci specifically modulating IgA O-glycosylation (C1GALT1 and ST3GAL1). Validation of our findings in an independent cohort of 320 individuals from Qatar showed that the underlying genetic architecture is conserved across ancestries. Conclusions Our study delineates the genetic landscape of IgA glycosylation and provides novel potential functional links with the aetiology of complex immune diseases, including genetic factors involved in IgA nephropathy risk. Keywords: Immunoglobulin A, Glycosylation, IgA/IgG shared genetics
We discussed which method between the test-negative design (TND) and the screening method (SM) could provide more robust real-time and end-of-season vaccine effectiveness (VE) estimates using data ...collected from routine influenza surveillance in primary care.
We used data collected during two influenza seasons, 2014–15 and 2015–16. Using the SM, we estimated end-of-season VE in preventing medically attended influenza-like illness and laboratory-confirmed influenza among the population at risk. Using the TND, we estimated end-of-season VE in preventing influenza among both the general and the at-risk population. We estimated real-time VE using both methods.
For the SM, the overall adjusted end-of-season VE was 24% (95% confidence interval (CI), 16 to 32) and 12% (95% CI, −16 to 33) during season 2014–15, and 53% (95% CI, 44 to 60) and 47% (95% CI, 23 to 64) during season 2015–16, in preventing influenza-like illness and laboratory-confirmed influenza, respectively. For the TND, the overall adjusted end-of-season VE was −17% (95% CI, −79 to 24) and −38% (95% CI, −199 to 13) in 2014–15, and 10% (95% CI, −31 to 39) and 18% (95% CI, −33 to 50) in 2015–16, among the general and at-risk population, respectively. Real-time VE estimates obtained through the TND showed more variability across each season and lower precision than those estimated with the SM.
Although the worldwide use of the TND allows for comparison of overall VE estimates among countries, the SM performs better in providing robust real-time VE estimates among the population at risk.
We explored the changes in viability and lipid profile occurring in cancer cells, murine melanoma cells (B16F10 cells) and human cervical carcinoma cells (HeLa cells), when exposed to 24 h-treatments ...with an n-3 PUFA-rich oil obtained by supercritical extraction with CO
2
from
Mugil cephalus
processed roe (bottarga). The composition of the major lipid classes of bottarga oil was determined by the
13
C NMR technique. Reversed-phase HPLC with DAD/ELSD detection was performed to analyze cells' total fatty acid profile and the levels of phospholipids, total/free cholesterol, triacylglycerols, and cholesteryl esters. Cell-based fluorescent measurements of intracellular membranes and lipid droplets were performed on bottarga oil-treated cells using the Nile red staining technique. The treatments of cancer cells with bottarga oil reduced the viability and affected the fatty acid profile, with a significant n-3 PUFA increase in treated cells. Mullet roe oil uptake modulated the cancer cell lipid composition, inducing a remarkable incorporation of health beneficial n-3 PUFA in the polar and neutral lipid fractions. Bottarga oil treatment influenced the synthesis of intracellular membranes and accumulation of cytoplasmic lipid droplets in cancer cells.
We explored the changes in viability and lipid profile occurring in cancer cells, melanoma cells (B16F10 cells) and cervical carcinoma cells (HeLa cells), when exposed to an n-3 PUFA-rich oil obtained by SFE-CO
2
extraction from
Mugil cephalus
processed roe (bottarga).
Telomeres play a central role in cellular senescence and cancer pathobiology and are associated with age-related diseases such as atherosclerosis and dementia. Telomere length varies between ...individuals of the same age, is influenced by DNA-damaging factors such as oxidative stress, and is heritable. We performed a quantitative-trait linkage analysis using an ∼10-cM genomewide map for mean leukocyte terminal-restriction fragment (TRF) lengths measured by Southern blotting, in 2,050 unselected women aged 18–80 years, comprising 1,025 complete dizygotic twin pairs. Heritability of mean batch-adjusted TRF was 36% (95% confidence interval CI 18%–48%), with a large common environmental effect of 49% (95% CI 40%–58%). Significant linkage was observed on chromosome 14 (LOD 3.9) at 14q23.2, and suggestive linkage at 10q26.13 (LOD 2.4) and 3p26.1 (LOD 2.7). This is the first report of loci, mapped in a sample of healthy individuals, that influence mean telomere variation in humans.
In the present study the wake flow past an isolated propeller operating in oblique flow conditions is investigated experimentally. In particular, the investigation concerns a systematic topological ...comparison of the wake behaviour in axisymmetric and in oblique inflow conditions, for three inclination angles, and is focused on an analysis of the underlying mechanisms of wake evolution and instability. To this end, the experiment has been designed to investigate the dynamics of propeller vortical structures over a wide spatial extent covering the wake region from the propeller disk up to 4.5 diameters in the streamwise direction. Detailed flow measurements have been undertaken by particle image velocimetry (PIV), using a multicamera configuration with three cameras arranged side by side. This allowed simultaneous acquisition of a large flow extent at a spatial resolution adequate to resolve the smallest vortical structures involved in the process of propeller wake instability. The analysis has been based on both phase-locked averaged and instantaneous flow fields. The study extends the knowledge on the subject of propeller wake dynamics, highlighting the major hydrodynamic effects that non-axisymmetric propeller operating conditions exert on the mechanisms of wake evolution, instability and breakdown, such as asymmetric destabilization of the tip vortices on the leeward and windward sides of the wake, and the interference between the tip and the junction vortices, as well as the cause–effect relation between the breakdown of the blade trailing wake and the instability of the tip and hub vortices.
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