Hsa-miR-125a-3p and hsa-miR-125a-5p are downregulated in non-small cell lung cancer and have inverse effects on invasion and migration of lung cancer cells

<p>Abstract</p> <p>Background</p> <p>Two mature microRNAs (miRNAs), hsa-miR-125a-3p and hsa-miR-125a-5p (collectively referred to as hsa-miR-125a-3p/5p), are derived from 3' and 5' ends of pre-miR-125a, respectively. Although impaired regulation of hsa-miR-125a-5p has been observed in some tumors, the role of this miRNA in invasion and metastasis remains unclear, and few studies have examined the function of hsa-miR-125a-3p. In order to characterize the functions of hsa-miR-125a-3p/5p in invasion and metastasis of non-small cell lung cancer (NSCLC), we investigated the relationships between hsa-miR-125a-3p/5p expression and lymph node metastasis in NSCLC tissues. We also explored the impact of expression of these miRNAs on invasive and migratory capabilities of lung cancer cells.</p> <p>Methods</p> <p>Expression of hsa-miR-125a-3p/5p in NSCLC tissues was explored using real-time PCR. The relationships between hsa-miR-125a-3p/5p expression and pathological stage or lymph node metastasis were assessed using the Spearman correlation test. For in vitro studies, lung cancer cells were transfected with sense and antisense 2'-O-methyl oligonucleotides for gain-of-function and loss-of-function experiments. Transwell experiments were performed to evaluate cellular migration and invasion.</p> <p>Results</p> <p>Expression of hsa-miR-125a-3p/5p was lower in NSCLC tissues than in adjacent normal lung tissues (LAC). Furthermore, the results from the Spearman correlation test showed a negative relationship between hsa-miR-125a-3p expression and pathological stage or lymph node metastasis and an inverse relationship between hsa-miR-125a-5p expression and pathological stage or lymph node metastasis. In vitro gain-of-function experiments indicated that hsa-miR-125a-3p and hsa-miR-125a-5p function in an opposing manner, suppressing or enhancing cell migration and invasion in A549 and SPC-A-1 cell lines, respectively. These opposing functions were further validated by suppression of hsa-miR-125a-3p and hsa-miR-125a-5p expression in loss-of-function experiments.</p> <p>Conclusion</p> <p>Hsa-miR-125a-3p and hsa-miR-125a-5p play distinct roles in regulation of invasive and metastatic capabilities of lung cancer cells, consistent with the opposing correlations between the expression of these miRNAs and lymph node metastasis in NSCLC. These results provide new insights into the roles of miR-125a family members in the development of NSCLC.</p

Tumour dormancy in breast cancer: an update

Delayed recurrences, common in breast cancer, are well explained by the concept of tumour dormancy. Numerous publications describe clinical times to disease recurrence or death, using mathematical approaches to infer mechanisms responsible for delayed recurrences. However, most of the clinical literature discussing tumour dormancy uses data from over a half century ago and much has since changed. This review explores how current breast cancer treatment could change our understanding of the biology of breast cancer tumour dormancy, and summarizes relevant experimental models to date. Current knowledge gaps are highlighted and potential areas of future research are identified

Polymorphisms in the RNASE3 Gene Are Associated with Susceptibility to Cerebral Malaria in Ghanaian Children

BACKGROUND: Cerebral malaria (CM) is the most severe outcome of Plasmodium falciparum infection and a major cause of death in children from 2 to 4 years of age. A hospital based study in Ghana showed that P. falciparum induces eosinophilia and found a significantly higher serum level of eosinophil cationic protein (ECP) in CM patients than in uncomplicated malaria (UM) and severe malaria anemia (SA) patients. Single nucleotide polymorphisms (SNPs) have been described in the ECP encoding-gene (RNASE3) of which the c.371G>C polymorphism (rs2073342) results in an arginine to threonine amino acid substitution p.R124T in the polypeptide and abolishes the cytotoxicity of ECP. The present study aimed to investigate the potential association between polymorphisms in RNASE3 and CM. METHODOLOGY/PRINCIPAL FINDINGS: The RNASE3 gene and flanking regions were sequenced in 206 Ghanaian children enrolled in a hospital based malaria study. An association study was carried out to assess the significance of five SNPs in CM (n=45) and SA (n=56) cases, respectively. The two severe case groups (CM and SA) were compared with the non-severe control group comprising children suffering from UM (n=105). The 371G allele was significantly associated with CM (p=0.00945, OR=2.29, 95% CI=1.22-4.32) but not with SA. Linkage disequilibrium analysis demonstrated significant linkage between three SNPs and the haplotype combination 371G/*16G/*94A was strongly associated with susceptibility to CM (p=0.000913, OR=4.14, 95% CI=1.79-9.56), thus, defining a risk haplotype. The RNASE3 371GG genotype was found to be under frequency-dependent selection. CONCLUSIONS/SIGNIFICANCE: The 371G allele of RNASE3 is associated with susceptibility to CM and forms part of a risk associated haplotype GGA defined by the markers: rs2073342 (G-allele), rs2233860 (G-allele) and rs8019343 (A-allele) respectively. Collectively, these results suggest a hitherto unrecognized role for eosinophils in CM pathogenesis

Co-Expression of α9β1 Integrin and VEGF-D Confers Lymphatic Metastatic Ability to a Human Breast Cancer Cell Line MDA-MB-468LN

INTRODUCTION AND OBJECTIVES: Lymphatic metastasis is a common occurrence in human breast cancer, mechanisms remaining poorly understood. MDA-MB-468LN (468LN), a variant of the MDA-MB-468GFP (468GFP) human breast cancer cell line, produces extensive lymphatic metastasis in nude mice. 468LN cells differentially express α9β1 integrin, a receptor for lymphangiogenic factors VEGF-C/-D. We explored whether (1) differential production of VEGF-C/-D by 468LN cells provides an autocrine stimulus for cellular motility by interacting with α9β1 and a paracrine stimulus for lymphangiogenesis in vitro as measured with capillary-like tube formation by human lymphatic endothelial cells (HMVEC-dLy); (2) differential expression of α9 also promotes cellular motility/invasiveness by interacting with macrophage derived factors; (3) stable knock-down of VEGF-D or α9 in 468LN cells abrogates lymphangiogenesis and lymphatic metastasis in vivo in nude mice. RESULTS: A comparison of expression of cyclo-oxygenase (COX)-2 (a VEGF-C/-D inducer), VEGF-C/-D and their receptors revealed little COX-2 expression by either cells. However, 468LN cells showed differential VEGF-D and α9β1 expression, VEGF-D secretion, proliferative, migratory/invasive capacities, latter functions being stimulated further with VEGF-D. The requirement of α9β1 for native and VEGF-D-stimulated proliferation, migration and Erk activation was demonstrated by treating with α9β1 blocking antibody or knock-down of α9. An autocrine role of VEGF-D in migration was shown by its impairment by silencing VEGF-D and restoration with VEGF-D. 468LN cells and their soluble products stimulated tube formation, migration/invasiveness of HMVEC-dLy cell in a VEGF-D dependent manner as indicated by the loss of stimulation by silencing VEGF-D in 468LN cells. Furthermore, 468LN cells showed α9-dependent stimulation of migration/invasiveness by macrophage products. Finally, capacity for intra-tumoral lymphangiogenesis and lymphatic metastasis in nude mice was completely abrogated by stable knock-down of either VEGF-D or α9 in 468LN cells. CONCLUSION: Differential capacity for VEGF-D production and α9β1 integrin expression by 468LN cells jointly contributed to their lymphatic metastatic phenotype

Association between neighborhood safety and overweight status among urban adolescents

<p>Abstract</p> <p>Background</p> <p>Neighborhood safety may be an important social environmental determinant of overweight. We examined the relationship between perceived neighborhood safety and overweight status, and assessed the validity of reported neighborhood safety among a representative community sample of urban adolescents (who were racially and ethnically diverse).</p> <p>Methods</p> <p>Data come from the 2006 Boston Youth Survey, a cross-sectional study in which public high school students in Boston, MA completed a pencil-and-paper survey. The study used a two-stage, stratified sampling design whereby schools and then 9^th–12^thgrade classrooms within schools were selected (the analytic sample included 1,140 students). Students reported their perceptions of neighborhood safety and several associated dimensions. With self-reported height and weight data, we computed body mass index (BMI, kg/m²) for the adolescents based on CDC growth charts. Chi-square statistics and corresponding <it>p</it>-values were computed to compare perceived neighborhood safety by the several associated dimensions. Prevalence ratios (PRs) and 95% confidence intervals (CI) were calculated to examine the association between perceived neighborhood safety and the prevalence of overweight status controlling for relevant covariates and school site.</p> <p>Results</p> <p>More than one-third (35.6%) of students said they always felt safe in their neighborhood, 43.9% said they sometimes felt safe, 11.6% rarely felt safe, and 8.9% never felt safe. Those students who reported that they rarely or never feel safe in their neighborhoods were more likely than those who said they always or sometimes feel safe to believe that gang violence was a serious problem in their neighborhood or school (68.0% vs. 44.1%, <it>p </it>< 0.001), and to have seen someone in their neighborhood assaulted with a weapon (other than a firearm) in the past 12 months (17.8% vs. 11.3%, <it>p </it>= 0.025). In the fully adjusted model (including grade and school) stratified by race/ethnicity, we found a statistically significant association between feeling unsafe in one's own neighborhood and overweight status among those in the Other race/ethnicity group [(PR = 1.56, (95% CI: 1.02, 2.40)].</p> <p>Conclusion</p> <p>Data suggest that perception of neighborhood safety may be associated with overweight status among urban adolescents in certain racial/ethnic groups. Policies and programs to address neighborhood safety may also be preventive for adolescent overweight.</p

Plant–Rhizobium symbiosis, seed nutraceuticals, and waste quality for energy production of Vicia faba L. as affected by crop management

Background: Broad bean fits sustainable agriculture model due to symbiosis with Rhizobium, the seeds being a good source of energy, proteins, polyphenols, and fiber. The large amount of broad bean biomass residues can be employed for biofuel production, thus valorizing the overall production process. This research was aimed to investigate on the effects of farming management, such as greenhouse cultivation and appropriate planting time on the qualities of broad bean seeds and residual biomass for conversion into biofuel. The related balances of energy gain associated to both ethanol yield and nitrogen fertilizer saving due to Rhizobium nitrogen fixation were assessed. Methods: Research was carried out on broad bean in Portici, province of Naples, southern Italy, based on the factorial combination of two farming systems (open field, greenhouse) and five planting times: 27 September and 11 October, to obtain early production; 25 October, which fell in the usual period for broad bean planting in the province area; and 8 November and 22 November, for late production. For each of these cultivation conditions, the quality of seeds, in terms of protein, fiber and antioxidant concentrations, and of crop residual biomass were determined. In addition, the energy yield as ethanol production from residual biomass and nitrogen fertilizer saving due to Rhizobium atmospheric fixation were assessed. Results and discussion: The highest plant nitrogen uptake was recorded under the fourth planting time in open field and the third in greenhouse, the average accumulation attaining 87% in residual biomass, 7.4% in pods, and 5.6% in seeds. Seed protein content was 12.6% higher in greenhouse than in open field and 16.2% higher under the latest planting time compared to the earliest one. Seed polyphenol concentration was higher in open field than in greenhouse and with the two earliest planting times. Greenhouse grown biomass showed higher values of lignin, hemicellulose and pectin, compared to open field, whereas the opposite trend was for cellulose. Lignin showed a decrease from the first to the last crop cycle, opposite to cellulose, and glucose was the most represented monosaccharide. Both the highest theoretical ethanol and overall energy production were highest with the fourth planting time. Conclusions: Greenhouse management enabled broad bean plants to accumulate higher proteins in seeds, but open field conditions resulted in better residual biomass quality for ethanol and Rhizobium-depending energy production

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe