INTRODUCTORY PARAGRAPHTo identify genetic variants associated with birth weight, we meta-analyzed six genome-wide association (GWA) studies (N=10,623 Europeans from pregnancy/birth cohorts) and followed up two lead signals in thirteen replication studies (N=27,591). Rs900400 near LEKR1 and CCNL1 (P=2×10−35), and rs9883204 in ADCY5 (P=7×10−15) were robustly associated with birth weight. Correlated SNPs in ADCY5 were recently implicated in regulation of glucose levels and type 2 diabetes susceptibility,1 providing evidence that the well described association between lower birth weight and subsequent type 2 diabetes2,3 has a genetic component, distinct from the proposed role of programming by maternal nutrition. Using data from both SNPs, the 9% of Europeans with 4 birth weight-lowering alleles were, on average, 113g (95%CI 89-137g) lighter at birth than the 24% with 0 or 1 allele (Ptrend=7×10−30). The impact on birth weight is similar to that of a mother smoking 4-5 cigarettes per day in the third trimester of pregnancy.4

Critical reviews over the past 10 yrs have found increased respiratory and allergic health outcomes for children living in damp and mouldy environments. However, recent studies have suggested that early childhood exposure to specific mould components may actually protect children from developing allergy.We conducted a systematic review of observational studies published in English from January 1980 to July 2010. This review was conducted according to systematic guidelines for Metaanalyses of Observational Studies in Epidemiology (MOOSE). The literature was searched using a computerised bibliographic database, PubMed. In order to increase the quality of the reviewed studies, meta-analyses of the effects of visible mould exposure on allergic health outcomes were performed and we evaluated the findings according to the Bradford Hill criteria for evidence of causation.The literature search identified 1,398 peer-reviewed scientific publications, and 61 studies that fulfilled the inclusion criteria were included in this review. We observed increased risks of allergic respiratory health outcomes in children exposed to visible mould and mould spores. These findings were confirmed by the results of the meta-analysis and in line with the evaluation criteria according to Bradford Hill. Visible mould was positively associated with asthma (OR 1.49 (95% CI 1.28-1.72)), wheeze (OR 1.68 (95% CI 1.48-1.90)) and allergic rhinitis (OR 1.39 (95% CI 1.28-1.51)). However, there was a tendency of lower risk for allergic health outcomes in children exposed to mouldderived components such as (1,3)-b-D-glucan and extracellular polysaccharides.These findings suggest that home environments with visible mould and mould spore exposure increase the risk of allergic respiratory health outcomes in children. However, further investigations are needed to examine the effects of exposure to mould-derived components as the current literature is inconclusive. In order to disentangle the different effects of overall microbial exposure on children's health, research should focus on specific microbial markers in the home, in combination with new assessment techniques including molecular methods.

EGFR overexpression and chromosome 3p deletion are two frequent events in head and neck cancers. We previously mapped the smallest region of recurrent copy-number loss at 3p12.2-p14.1. LRIG1, a negative regulator of EGFR, was found at 3p14, and its copy-number loss correlated with poor clinical outcome. Inducible expression of LRIG1 in head and neck cancer TW01 cells, a line with low LRIG1 levels, suppressed cell proliferation in vitro and tumor growth in vivo. Gene expression profiling, quantitative RT-PCR, chromatin immunoprecipitation, and western blot analysis demonstrated that LRIG1 modulated extracellular matrix (ECM) remodeling and EGFR-MAPK-SPHK1 transduction pathway by suppressing expression of EGFR ligands/activators, MMPs and SPHK1. In addition, LRIG1 induction triggered cell morphology changes and integrin inactivation, which coupled with reduced SNAI2 expression. By contrast, knockdown of endogenous LRIG1 in TW06 cells, a line with normal LRIG1 levels, significantly enhanced cell proliferation, migration and invasiveness. Such tumor-promoting effects could be abolished by specific MAPK or SPHK1 inhibitors. Our data suggest LRIG1 as a tumor suppressor for head and neck cancers; LRIG1 downregulation in cancer cells enhances EGFR-MAPK-SPHK1 signaling and ECM remodeling activity, leading to malignant phenotypes of head and neck cancers.

Matrix metalloproteinase (MMP)-2 plays critical roles in tumor development and in the metastasis of multiple cancers, including human oral cavity squamous cell carcinoma (OCSCC). One of the upstream regulators of MMP-2 is FOXM1, which is overexpressed in a microarray dataset of OCSCC. It is interesting that FLJ10540 exhibits similar gene expression profiles with MMP-2 and FOXM1, raising the possibility that these molecules might participate in MMP-2-elicited cancer progression and metastasis of OCSCC. To examine this connection, we first showed that FLJ10540 was significantly overexpressed in OCSCC. A strong FLJ10540 expression was significantly correlated with an advanced tumor node metastasis stage and the cumulative 5-year survival rate. Thus, an elevated FLJ10540 expression is an indicator of poor survival. Functionally, FLJ10540 had the abilities to stimulate cell migration and invasion in oral cancer cells through increased FOXM1 and MMP-2 expressions. Conversely, the depletion of the FLJ10540 expression by small interefering RNAs suppressed the FOXM1 and MMP-2 protein expressions. The suppression of either FLJ10540 or FOXM1 could cause significant inhibition on cell migratory and invasive ability in oral cancer cells. Finally, the immunohistochemical and western blotting analyses of human aggressive OCSCC specimens showed a significant positive correlation among FLJ10540, FOXM1 and MMP-2 expressions. These findings suggest that FLJ10540 is not only an important prognostic factor but also a new therapeutic target in the FLJ10540/FOXM1/MMP-2 pathway for OCSCC treatment.