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Metastasis is the primary cause for mortality in breast cancer. MicroRNAs, gene expression master regulators, constitute an attractive candidate to control metastasis. Here we show that breast cancer metastasis can be prevented by miR-96 or miR-182 treatment, and decipher the mechanism of action. We found that miR-96/miR-182 downregulate Palladin protein levels, thereby reducing breast cancer cell migration and invasion. A common SNP, rs1071738, at the miR-96/miR-182-binding site within the Palladin 3′-UTR abolishes miRNA:mRNA binding, thus diminishing Palladin regulation by these miRNAs. Regulation is successfully restored by applying complimentary miRNAs. A hydrogel-embedded, gold-nanoparticle-based delivery vehicle provides efficient local, selective, and sustained release of miR-96/miR-182, markedly suppressing metastasis in a breast cancer mouse model. Combined delivery of the miRNAs with a chemotherapy drug, cisplatin, enables significant primary tumour shrinkage and metastasis prevention. Our data corroborate the role of miRNAs in metastasis, and suggest miR-96/miR-182 delivery as a potential anti-metastatic drug. MicroRNAs represent potential therapeutic targets to control metastasis progression. Here the authors show that miR-96 and miR-182 regulate invasion via Palladin and demonstrate that local delivery of miR-96 and miR-182 may serve as a potential anti-metastatic drug in breast cancer.

In breast cancer patients, the lungs are among the first sites of cancer metastasis, and in nearly one quarter of metastatic patients, the exclusive first event. Two common mouse models mimic breast cancer lung colonization and distal metastasis: an orthotopic model and intravenous (IV) cell injections. Gene expression analysis of pulmonary lesions from these two methods demonstrated high inter-model resemblance. However, microRNA (miRNA) expression profiles were not compared. In this study, we compared the overall miRNA expression profiles (miRNome) of the orthotopic and IV breast cancer metastasis models and identified significant miRNome changes between the two models. Overexpression of the most significant candidate, miR-96 or downregulation of its validated gene-target, ABCE1 reduced cancer cells 2D/3D cell movement and proliferation in vitro, and abated tumor growth and metastasis formation in vivo. Human data analysis further strengthened miR-96/ABCE1 role in breast cancer tumor aggression. Taken together, our results indicate that IV- and orthotopic models differ by their miRNome. Specifically in our study, breast cancer aggressiveness was dictated by miR-96 regulating ABCE1. Overall, miRNome analysis of various metastatic cancer models may lead to the identification of candidate genes critical to metastasis development.

Although Familial Mediterranean fever (FMF) is categorized as autosomal recessive, frequent exceptions to this model exist and therefore we aimed to search epigenetic modifications in this disease. Ten M694V homozygous FMF patients (the most severe phenotype) were recruited for this study. Patients with inflammatory flare were excluded. Total RNA was extracted from peripheral blood, and microRNA expression profiled using NanoString nCounter technology. These patients were compared to 10 healthy age- and sex-matched controls. Seven hundred nighty-eight mature human miRNAs were probed, 103 of which had expression levels above the negative control probes. Seven miRNAs showed significant differences in expression in samples from FMF patients compared to healthy controls: four miRNAs were upregulated (miR-144-3p, miR-21-5p, miR-4454, and miR-451a), and three were downregulated (miR-107, let-7d-5p, and miR-148b-3p). In this pilot study, we identified epigenetic modifications in clinically quiescent FMF patients. More studies are required for exploration of their contribution to FMF pathogenesis and their potential role as clinical biomarkers.

Chikungunya virus (CHIKV), an alphavirus and member of the Togaviridae family, is capable of causing severe febrile disease in humans. In December of 2013 the Asian Lineage of CHIKV spread from the Old World to the Americas, spreading rapidly throughout the New World. Given this new emergence in naïve populations we studied the viral genetic diversity present in infected individuals to understand how CHIKV may have evolved during this continuing outbreak. We used deep-sequencing technologies coupled with well-established bioinformatics pipelines to characterize the minority variants and diversity present in CHIKV infected individuals from Guadeloupe and Martinique, two islands in the center of the epidemic. We observed changes in the consensus sequence as well as a diverse range of minority variants present at various levels in the population. Furthermore, we found that overall diversity was dramatically reduced after single passages in cell lines. Finally, we constructed an infectious clone from this outbreak and identified a novel 3' untranslated region (UTR) structure, not previously found in nature, that led to increased replication in insect cells. Here we preformed an intrahost quasispecies analysis of the new CHIKV outbreak in the Caribbean. We identified novel variants present in infected individuals, as well as a new 3'UTR structure, suggesting that CHIKV has rapidly evolved in a short period of time once it entered this naïve population. These studies highlight the need to continue viral diversity surveillance over time as this epidemic evolves in order to understand the evolutionary potential of CHIKV.

Background The Mexican population and others with Amerindian heritage exhibit a substantial predisposition to dyslipidemias and coronary heart disease. Yet, these populations remain underinvestigated by genomic studies, and to date, no genome-wide association (GWA) studies have been reported for lipids in these rapidly expanding populations. Methods and findings We performed a two-stage GWA study for hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) in Mexicans (n=4361), and identified a novel Mexican-specific genome-wide significant locus for serum triglycerides (TGs) near the Niemann–Pick type C1 protein gene (p=2.43×10−08). Furthermore, three European loci for TGs (APOA5, GCKR and LPL), and four loci for HDL-C (ABCA1, CETP, LIPC and LOC55908) reached genome-wide significance in Mexicans. We used cross-ethnic mapping to narrow three European TG GWA loci, APOA5, MLXIPL, and CILP2 that were wide and contained multiple candidate variants in the European scan. At the APOA5 locus, this reduced the most likely susceptibility variants to one, rs964184. Importantly, our functional analysis demonstrated a direct link between rs964184 and postprandial serum apoAV protein levels, supporting rs964184 as the causative variant underlying the European and Mexican GWA signal. Overall, 52 of the 100 reported associations from European lipid GWA meta-analysis generalised to Mexicans. However, in 82 of the 100 European GWA loci, a different variant other than the European lead/best-proxy variant had the strongest regional evidence of association in Mexicans. Conclusions This first Mexican GWA study of lipids identified a novel GWA locus for high TG levels; used the interpopulation heterogeneity to significantly restrict three previously known European GWA signals, and surveyed whether the European lipid GWA SNPs extend to the Mexican population.

Despite recent advances in our understanding of the pathogenesis of ectodermal dysplasias (EDs), the molecular basis of many of these disorders remains unknown. In the present study, we aimed at elucidating the genetic basis of a new form of ED featuring facial dysmorphism, scalp hypotrichosis and hypodontia. Using whole exome sequencing, we identified 2 frameshift and 2 missense mutations in TSPEAR segregating with the disease phenotype in 3 families. TSPEAR encodes the thrombospondin-type laminin G domain and EAR repeats (TSPEAR) protein, whose function is poorly understood. TSPEAR knock-down resulted in altered expression of genes known to be regulated by NOTCH and to be involved in murine hair and tooth development. Pathway analysis confirmed that down-regulation of TSPEAR in keratinocytes is likely to affect Notch signaling. Accordingly, using a luciferase-based reporter assay, we showed that TSPEAR knock-down is associated with decreased Notch signaling. In addition, NOTCH1 protein expression was reduced in patient scalp skin. Moreover, TSPEAR silencing in mouse hair follicle organ cultures was found to induce apoptosis in follicular epithelial cells, resulting in decreased hair bulb diameter. Collectively, these observations indicate that TSPEAR plays a critical, previously unrecognized role in human tooth and hair follicle morphogenesis through regulation of the Notch signaling pathway.

Whole‐exome sequencing (WES) arises as a new approach in diagnosing individuals affected by multigenic and complex phenotypes. Herein, we aim to examine whether WES is useful in screening asymptomatic individuals for actionable interventions, which has not yet been established. Twenty‐five healthy adults underwent WES, bioinformatics, and manual curation of their exomes. Six participants (24%) harbored significant, management‐changing variants in cancer predisposition genes, American College of Medical Genetics, and genomics reportable cardiac diseases and pharmacogenomic biomarkers that have led to clinical recommendations and interventions. Furthermore, more than 80% of the participants (21) carried 1–3 genetic variants with an associated clinical guideline for an altered drug dosing or administration based on the FDA's table of pharmacogenomics. These results support WES potential not only to answer specific diagnostic questions presented by the relevant personal and/or family history but also to uncover clinically important genetic findings unrelated to the primary indication for sequencing. Significant, Clinically actionable variants can be detected in healthy individuals undergoing WES.

This is an issue edsumm for 24. Identification of the Palaeocene/Eocene thermal maximum in a marine sedimentary sequence shows that sea surface temperatures near the North Pole increased from roughly 18 degrees Celsius to over 23 degrees Celsius — such warm values imply the absence of ice and thus exclude the influence of ice-albedo feedbacks on this Arctic warming. Hypertriglyceridemia is a hallmark of many disorders, including metabolic syndrome, diabetes, atherosclerosis and obesity 1 , 2 , 3 . A well-known cause is the deficiency of lipoprotein lipase (LPL), a key enzyme in plasma triglyceride hydrolysis 4 , 5 , 6 . Mice carrying the combined lipase deficiency ( cld ) mutation show severe hypertriglyceridemia owing to a decrease in the activity of LPL and a related enzyme, hepatic lipase (HL) 7 , 8 , 9 , caused by impaired maturation of nascent LPL and hepatic lipase polypeptides in the endoplasmic reticulum (ER) 10 . Here we identify the gene containing the cld mutation as Tmem112 and rename it Lmf1 (Lipase maturation factor 1). Lmf1 encodes a transmembrane protein with an evolutionarily conserved domain of unknown function that localizes to the ER. A human subject homozygous for a deleterious mutation in LMF1 also shows combined lipase deficiency with concomitant hypertriglyceridemia and associated disorders. Thus, through its profound effect on lipase activity, LMF1 emerges as an important candidate gene in hypertriglyceridemia 4 , 11 , 12 .

Cancer risks and tumor types in male BRCA1 and BRCA2 mutation carriers are still unsettled. Cancer risks in men who were found to harbor a BRCA1 ( n  = 150) or a BRCA2 ( n  = 88) mutation or both ( n  = 2) were assessed by cross referencing with data on cancer occurrence in the Israeli National Cancer Registry. Incidence rates in mutation carriers were compared with men who were counseled, genotyped, and found not to harbor the familial mutation (true negative n  = 122), and with standardized incidence rates (SIRs). Of 210 cancer-free individuals at initial counseling, 11 cancers were diagnosed after a mean follow-up of 5.06 ± 4.1 years (1064 person/years) compared with 1/122 in a BRCA true-negative man. The SIR for all BRCA1/2 mutation carriers compared with the rates in the general population were elevated for pancreatic cancer [2.97 (95 % CI 1.83–4.29)] and breast cancer [16.44 (95 % CI 9.65–26.24)]. For prostate cancer these rates were 0.59 (95 % CI 0.4–0.84). Jewish BRCA1/2 mutation carriers are at an increased risk for breast and pancreatic, but not prostate cancer. These cancer risks and the consequent recommendations, if validated, should be transmitted to carriers at test result disclosure.

Common Hepatic Nuclear Factor-4α Variants Are Associated With High Serum Lipid Levels and the Metabolic Syndrome Daphna Weissglas-Volkov 1 , Adriana Huertas-Vazquez 1 , Elina Suviolahti 1 , Jenny Lee 1 , Christopher Plaisier 1 , Samuel Canizales-Quinteros 2 , Teresa Tusie-Luna 2 , Carlos Aguilar-Salinas 3 , Marja-Riitta Taskinen 4 and Päivi Pajukanta 1 1 Department of Human Genetics, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, California 2 Department of Molecular Biology and Genomic Medicine, Instituto de Investigaciones Biomédicas de la Universidad National Autónoma de Mexico, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Mexico City, Mexico 3 Department of Endocrinology and Metabolism, INCMNSZ, Mexico City, Mexico 4 Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland Address correspondence and reprint requests to Päivi Pajukanta, MD, PhD, Assistant Professor, UCLA, Department of Human Genetics, Gonda Neuroscience and Genetics Research Center, 695 Charles E. Young Dr. South, Los Angeles, CA 90095-7088. E-mail: ppajukanta{at}mednet.ucla.edu Abstract Hepatic nuclear factor-4α (HNF-4α), a transcription factor involved in the regulation of serum lipid and glucose levels, has recently been associated with type 2 diabetes. The HNF-4α gene (HNF4A) resides on chromosome 20q12-q13.1, which, in addition to type 2 diabetes, has also previously been linked to high triglycerides in Finnish familial combined hyperlipidemia (FCHL) families. FCHL, characterized by elevated levels of serum total cholesterol, triglycerides, or both, is a common dyslipidemia observed in up to 20% of patients with premature coronary heart disease. Considering the clear phenotypic overlap between type 2 diabetes and FCHL, both predisposing to high serum triglycerides and glucose intolerance, we tested this gene for association in dyslipidemic families originating from two distinct populations, Finnish and Mexican, and comprising 1,447 subjects. Our data show that common HNF4A variants and haplotypes are associated with elevated serum lipid levels and the metabolic syndrome ( P = 0.008–0.04), as well as with elevated glucose parameters ( P = 0.008–0.03), using family-based association analysis. Importantly, both Finnish and Mexican families shared two common lipid-associated HNF4A haplotypes ( P = 0.005 for total cholesterol and 0.006 for triglycerides). In conclusion, we show for the first time that common HNF4A variants are associated with high serum lipid levels and the metabolic syndrome. apo, apolipoprotein AUC, area under the curve CHD, coronary heart disease FBAT, family-based association test HBAT, haplotype-based association test FCHL, familial combined hyperlipidemia HNF-4α, hepatic nuclear factor-4α IGT, impaired glucose tolerance OGTT, oral glucose tolerance test SNP, single nucleotide polymorphism USF1, upstream transcription factor 1 Footnotes D.W.-V. and A.H.-V. contributed equally to this work. M.-R.T. has received honoraria and consulting fees from Merck Sharp and Dome, Pfizer, Laboratoires Fournier, GlaxoSmithKline, Bristol-Myers Squibb, Takeda, and Sanofi Aventis and research support from Laboratoires Fournier, Elli Lilly, and Novartis. Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact Accepted March 24, 2006. Received January 6, 2006. DIABETES