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Golledge J.,James Cook University | Kuivaniemi H.,Sigfried and Janet Weis Center for Research
Current Opinion in Cardiology | Year: 2013

PURPOSE OF REVIEW: Family history is a risk factor for abdominal aortic aneurysm (AAA), suggesting that genetic factors play an important role in AAA development, growth and rupture. Identification of these factors could improve understanding of the AAA pathogenesis and be useful to identify at risk individuals. RECENT FINDINGS: Many approaches are used to examine genetic determinants of AAA, including genome-wide association studies (GWAS) and DNA linkage studies. Two recent GWAS have identified genetic markers associated with an increased risk of AAA located within the genes for DAB2 interacting protein (DAB2IP) and low density lipoprotein receptor-related protein 1 (LRP1). In addition, a marker on 9p21 associated with other vascular diseases is also strongly associated with AAA. The exact means by which these genes currently control AAA risk is not clear; however, in support of these findings, mice with vascular smooth muscle cell deficiency of Lrp1 are prone to aneurysm development. Further current work is concentrated on other molecular mechanisms relevant in AAA pathogenesis, including noncoding RNAs such as microRNAs. SUMMARY: Current studies assessing genetic mechanisms for AAA have significant potential to identify novel mechanisms involved in AAA pathogenesis of high relevance to better clinical management of the disease. © 2013 Wolters Kluwer Health | Lippincott Williams &Wilkins. Source

Gallego-Perez D.,Ohio State University | Higuita-Castro N.,Ohio State University | Denning L.,Ohio State University | Dejesus J.,Ohio State University | And 3 more authors.
Lab on a Chip - Miniaturisation for Chemistry and Biology | Year: 2012

Guided cell migration plays a crucial role in tumor metastasis, which is considered to be the major cause of death in cancer patients. Such behavior is regulated in part by micro/nanoscale topographical cues present in the parenchyma or stroma in the form of fiber-like and/or conduit-like structures (e.g., white matter tracts, blood/lymphatic vessels, subpial and subperitoneal spaces). In this paper we used soft lithography micromolding to develop a tissue culture polystyrene platform with a microscale surface pattern that was able to induce guided cell motility along/through fiber-/conduit-like structures. The migratory behaviors of primary (glioma) and metastatic (lung and colon) tumors excised from the brain were monitored via time-lapse microscopy at the single cell level. All the tumor cells exhibited axially persistent cell migration, with percentages of unidirectionally motile cells of 84.0 ± 3.5%, 58.3 ± 6.8% and 69.4 ± 5.4% for the glioma, lung, and colon tumor cells, respectively. Lung tumor cells showed the highest migratory velocities (41.8 ± 4.6 μm h-1) compared to glioma (24.0 ± 1.8 μm h-1) and colon (26.7 ± 2.8 μm h-1) tumor cells. This platform could potentially be used in conjunction with other biological assays to probe the mechanisms underlying the metastatic phenotype under guided cell migration conditions, and possibly by itself as an indicator of the effectiveness of treatments that target specific tumor cell motility behaviors. © 2012 The Royal Society of Chemistry. Source

Estrelinha M.,New University of Lisbon | Hinterseher I.,Charite - Medical University of Berlin | Kuivaniemi H.,Sigfried and Janet Weis Center for Research | Kuivaniemi H.,Temple University
Reviews in Vascular Medicine | Year: 2014

Abdominal aortic aneurysm (AAA), defined as a dilatation of the aorta (>3 cm) below the renal arteries, has a complex etiology and it is associated with a risk of rupture. Surgical repair, open or endovascular, is the only available treatment option. Genome-wide studies using microarrays with the purpose of identifying mRNAs and microRNAs involved in the pathogenesis of AAA have been published recently. They provided strong evidence that genes involved in immune and inflammatory pathways and a wide range of other biological functions, such as calcium signaling, cell adhesion or regulation of apoptosis differ in expression when comparing aortic tissue taken from AAA and non-aneurysmal controls. MicroRNAs that control gene expression were also found to be up or down regulated providing a potential mechanism for differences in mRNA levels in the AAA tissue. Future studies to confirm these findings and to elucidate the molecular mechanisms of pathophysiology are needed to develop better diagnostic tests, using biomarkers, and to identify new therapeutic targets for AAA. © 2014 Elsevier GmbH. Source

Morris D.R.,James Cook University | Biros E.,James Cook University | Cronin O.,James Cook University | Kuivaniemi H.,Sigfried and Janet Weis Center for Research | Golledge J.,James Cook University
Heart | Year: 2014

Context Aberrant matrix turnover is believed to play a key role in the pathogenesis of abdominal aortic aneurysm (AAA). Matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitor of metalloproteinases; TIMPs) are important enzymes in the control of extracellular matrix remodelling. Objective The aim of this study was to investigate if single nucleotide polymorphisms (SNPs) within MMP and TIMP gene families are associated with the presence of AAA. Data sources We performed a search of MEDLINE and EMBASE databases on the 21st November 2012. Study selection Case-control studies assessing the association of at least one SNP in a MMP or TIMP gene with AAA were included. Data extraction Data were independently extracted by two reviewers. A random effects model was used to calculate combined odds ratios for commonly investigated SNPs according to dominant, recessive and additive inheritance. Results Thirteen studies examining 58 SNPs within 10 different MMP and TIMP genes were identified. Eight SNPs were assessed in at least 3 studies (combined sample size ranging from 141- 2191 AAA cases and 340-2013 controls) and included in a meta-analysis. Results on 1258 cases and 1406 controls for MMP3 rs3025058 showed an association with AAA presence; best described by a dominant pattern of inheritance (OR=1.48 95%CI 1.23 - 1.78, p=3.95×10-5). No associations with AAA were identified for other SNPs assessed in this study including rs1799750 (MMP1), rs3918242 (MMP9), rs486055 (MMP10), rs2276109 (MMP12), rs2252070 (MMP13), rs4898 (TIMP1) or rs9619311 (TIMP3). Conclusion A common SNP within the MMP3 promoter region, previously suggested to increase MMP3 expression, appears to be a moderate risk factor for AAA. Source

Kuivaniemi H.,Sigfried and Janet Weis Center for Research | Elmore J.R.,Sigfried and Janet Weis Center for Research
Annals of Vascular Surgery | Year: 2012

Aortic aneurysms are a complex genetic disorder with known environmental risk factors such as smoking. Along the length of the aorta, significant heterogeneity occurs in the distribution of aneurysmal disease. The prevalence of aneurysm in the abdominal aorta is at least nine times higher than that in the thoracic section of the aorta. A number of studies have shown that aortic aneurysms are frequently familial, even when they are not associated with rare heritable disorders such as Marfan syndrome or Ehlers-Danlos syndrome type IV. The pathobiology of aortic aneurysms is complex and largely unsolved. Unbiased whole-genome approaches are now being used to elucidate the genetic basis of aortic aneurysms to uncover the germline genetic variants that influence the disease risk. The findings will provide critical information about underlying biology of the disease and will help identify potential targets for pharmacological therapies. These studies may lead to therapies that may increase survival rates for individuals with aortic aneurysms and reduce the need for surgical interventions. Abdominal aortic aneurysms were the topic of an international conference "Abdominal Aortic Aneurysm: Epidemiology, Genetics, and Pathophysiology" held recently at the Geisinger Clinic, Danville, Pennsylvania. © 2012 Annals of Vascular Surgery Inc. Source

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