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Long non-coding RNAs (lncRNAs) are a growing focus of cancer genomics studies, creating the need for a resource of lncRNAs with validated cancer roles. Furthermore, it remains debated whether mutated lncRNAs can drive tumorigenesis, and whether such functions could be conserved during evolution. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we introduce the Cancer LncRNA Census (CLC), a compilation of 122 GENCODE lncRNAs with causal roles in cancer phenotypes. In contrast to existing databases, CLC requires strong functional or genetic evidence. CLC genes are enriched amongst driver genes predicted from somatic mutations, and display characteristic genomic features. Strikingly, CLC genes are enriched for driver mutations from unbiased, genome-wide transposon-mutagenesis screens in mice. We identified 10 tumour-causing mutations in orthologues of 8 lncRNAs, including LINC-PINT and NEAT1, but not MALAT1. Thus CLC represents a dataset of high-confidence cancer lncRNAs. Mutagenesis maps are a novel means for identifying deeply-conserved roles of lncRNAs in tumorigenesis. Communications Biology, 3 (1) ISSN:2399-3642

Alcohol consumption increases the risk of breast cancer among women in the general population, but its effect on women who carry a BRCA gene mutation is unclear. We conducted a case-control study of 1925 matched pairs of predominantly premenopausal women who carry a BRCA1 or a BRCA2 mutation. Information on current alcohol consumption was obtained from a questionnaire administered during the course of genetic counselling or at the time of enrollment. A modest inverse association between breast cancer and reported current alcohol consumption was observed among women with a BRCA1 mutation (OR = 0.82, 95% CI 0.70-0.96), but not among women with a BRCA2 mutation (OR = 1.00; 95% CI 0.71-1.41). Compared to non-drinkers, exclusive consumption of wine was associated with a significant reduction in the risk of breast cancer among BRCA1 carriers (p-trend = 0.01). Alcohol consumption does not appear to increase breast cancer risk in women carrying a BRCA gene mutation.

Defects of motile cilia cause primary ciliary dyskinesia (PCD), characterized by recurrent respiratory infections and male infertility. Using whole-exome resequencing and high-throughput mutation analysis, we identified recessive biallelic mutations in ZMYND10 in 14 families and mutations in the recently identified LRRC6 in 13 families. We show that ZMYND10 and LRRC6 interact and that certain ZMYND10 and LRRC6 mutations abrogate the interaction between the LRRC6 CS domain and the ZMYND10 C-terminal domain. Additionally, ZMYND10 and LRRC6 colocalize with the centriole markers SAS6 and PCM1. Mutations in ZMYND10 result in the absence of the axonemal protein components DNAH5 and DNALI1 from respiratory cilia. Animal models support the association between ZMYND10 and human PCD, given that zmynd10 knockdown in zebrafish caused ciliary paralysis leading to cystic kidneys and otolith defects and that knockdown in Xenopus interfered with ciliogenesis. Our findings suggest that a cytoplasmic protein complex containing ZMYND10 and LRRC6 is necessary for motile ciliary function. © 2013 The American Society of Human Genetics.

Chronic limb ischemia, a complication commonly observed in conjunction with cardiovascular disease, is characterized by insufficient neovascularization despite the up-regulation of pro-angiogenic mediators. One hypothesis is that ischemia induces inhibitory signals that circumvent the normal capillary growth response. FoxO transcription factors exert anti-proliferative and pro-apoptotic effects on many cell types. We studied the regulation of FoxO1 protein in ischemic rat skeletal muscle following iliac artery ligation and in cultured endothelial cells. We found that FoxO1 expression was increased in capillaries within ischemic muscles compared with those from rats that underwent a sham operation. This finding correlated with increased expression of p27(Kip1) and reduced expression of Cyclin D1. Phosphorylated Akt was reduced concurrently with the increase in FoxO1 protein. In skeletal muscle endothelial cells, nutrient stress as well as lack of shear stress stabilized FoxO1 protein, whereas shear stress induced FoxO1 degradation. Endogenous FoxO1 co-precipitated with the E3 ubiquitin ligase murine double minute-2 (Mdm2) in endothelial cells, and this interaction varied in direct relation to the extent of Akt and Mdm2 phosphorylation. Moreover, ischemic muscles had a decreased level of Mdm2 phosphorylation and a reduced interaction between Mdm2 and FoxO1. Our results provide novel evidence that the Akt-Mdm2 pathway acts to regulate endothelial cell FoxO1 expression and illustrate a potential mechanism underlying the pathophysiological up-regulation of FoxO1 under ischemic conditions.

Interferometric detectors will very soon give us an unprecedented view of the gravitational-wave sky, and in particular of the explosive and transient Universe. Now is the time to challenge our theoretical understanding of short-duration gravitational-wave signatures from cataclysmic events, their connection to more traditional electromagnetic and particle astrophysics, and the data analysis techniques that will make the observations a reality. This paper summarizes the state of the art, future science opportunities, and current challenges in understanding gravitational-wave transients. 33 pages, 2 figures

Autophagy, a self-defense mechanism, has been found to be associated with drug resistance in hepatocellular carcinoma (HCC). Our study was designed to investigate the role and related mechanisms of autophagy in matrine-induced apoptosis in hepatoma cells of HepG2 and Bel7402. Cell apoptosis was detected by flow cytometry analysis (Annexin V–FITC/PI double-staining assay), the activity and activating cleavages of caspase-3, -8, and -9. MTT assay and colony forming assay were used to assess the effect of matrine on growth and proliferation of HCC cells. Autophagic flux in HCC cells was analyzed using the expression of LC3BI/II and p62/SQSTM1, GFP-LC3 transfection, and transmission electron microscopy. Moreover, regarding to the associated mechanisms, the effects of matrine on the phosphoinositide 3-kinase/AKT/mTOR pathway and beclin-1 were studied. Our results showed that: (1) both autophagy and apoptosis could be induced by treatment with matrine; (2) using the autophagic inhibitor chloroquine and beclin-1 small-interfering RNA, cell apoptosis induced by matrine could be enhanced in a caspase-dependent manner; and (3) autophagy was induced via inhibition of PI3K/AKT/mTOR pathway and up-regulation of beclin-1. In conclusion, inhibition of autophagy could enhance matrine-induced apoptosis in human hepatoma cells.

Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a metaanalysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P= 2.1 x 10(-12) and LGR6, P = 1.4 x 10(-8)), 2p24.1 (P = 4.6 x 10(-8)) and 16q12.2 (FTO, P = 4.0 x 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P> 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.

We present a theory of graphene quantum rings designed to produce degenerate shells of single particle states close to the Fermi level. We show that populating these shells with carriers using a gate leads to correlated ground states with finite total electronic spin. Using a combination of tight-binding and configuration interaction methods we predict ground state and total spin of the system as a function of the filling of the shell. We show that for smaller quantum rings, the spin polarization of the ground state at half filling depends strongly on the size of the system, but reaches a maximum value after reaching a critical size. Comment: 7 pages, 8 figures

GA2LEN EAACI This methods report describes the process of guideline development in detail. It is the result of a systematic literature review using the 'Grading of Recommendations Assessment, Development and Evaluation' (GRADE) methodology and a structured consensus conference held on 28 and 29 November 2012, in Berlin. It is a joint initiative of the Dermatology Section of the European Academy of Allergy and Clinical Immunology (EAACI), the EU-funded network of excellence, the Global Allergy and Asthma European Network (GA(2)LEN), the European Dermatology Forum (EDF), and the World Allergy Organization (WAO) with the participation of delegates of 21 national and international societies. This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors and pathomechanisms. in addition, it outlines evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS) and is published in Allergy 2014; 69:868-887. Charite, Allergy Ctr Charite, Dept Dermatol & Allergy, Berlin, Germany Med Univ Graz, Dept Dermatol, Graz, Austria Clin San Carlo, Allergy Clin, Paderno Dugnano, Italy Odense Univ Hosp, Dept Dermatol, DK-5000 Odense, Denmark Odense Univ Hosp, Allergy Ctr, DK-5000 Odense, Denmark Univ Southern Denmark, Odense, Denmark Med Univ Silesia, Allergol & Clin Immunol Katowice, Dept Internal Dis, Katowice, Poland Univ Genoa, IRCCS AOU SanMartino, Genoa, Italy Universidade Federal de São Paulo, São Paulo, Brazil Univ Autonoma Barcelona, Hosp Mar Parc Salut Mar, E-08193 Barcelona, Spain Dr DY Patil Med Coll & Hosp, Dept Dermatol, Navi Mumbai, India Fac Med, Dermatol Clin, Coimbra, Portugal Univ Hosp, Coimbra, Portugal Guys & St Thomas Hosp NHS Fdn Trust, St Johns Inst Dermatol, London, England Ctr Appl Res Allergy Quebec, Quebec City, PQ, Canada Hiroshima Univ, Dept Dermatol, Inst Biomed & Hlth Sci, Hiroshima, Japan Med Univ S Carolina, Dept Med, Div Pulm & Crit Care Med, Charleston, SC 29425 USA Hannover Med Sch, Dept Dermatol & Allergy, Hannover, Germany Pantai Hosp Kuala Lumpur, Dept Paediat, Bangsar, Malaysia Univ Hosp Tenon, Dept Dermatol & Allergy, Paris, France Johns Hopkins Asthma & Allergy Ctr, Baltimore, MD USA Ctr Medicodocente Trinidad, Allergy & Clin Immunol Dept, Caracas, Venezuela Univ Hosp, Dept Dermatol, Allergy Unit, Zurich, Switzerland Univ Manitoba, Dept Pediat & Child Hlth, Winnipeg, MB R3T 2N2, Canada Univ Manitoba, Dept Immunol, Winnipeg, MB, Canada Univ Med Ctr Mainz, Dept Dermatol, Mainz, Germany Univ Toronto, Div Allergy & Clin Immunol, Toronto, ON, Canada Technion, Bnai Zion Med Ctr, Fac Med, Haifa, Israel Univ Bari, Dept Biomed Sci & Human Oncol, Unit Dermatol & Venereol, Bari, Italy Universidade Federal de São Paulo, EPM, São Paulo, Brazil Web of Science