Sigfried and Janet Weis Center for Research

Danville, PA, United States

Sigfried and Janet Weis Center for Research

Danville, PA, United States
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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.

Sakalihasan N.,University of Liège | Defraigne J.-O.,University of Liège | Kerstenne M.-A.,University of Liège | Cheramy-Bien J.-P.,University of Liège | And 4 more authors.
Annals of Vascular Surgery | Year: 2014

Background: The objectives were to answer the following questions with the help of a well-characterized population in Liège, Belgium: 1) what percentage of patients with abdominal aortic aneurysm (AAA) have a positive family history for AAA? 2) what is the prevalence of AAAs among relatives of patients with AAA? and 3) do familial and sporadic AAA cases differ in clinical characteristics? Methods: Patients with unrelated AAA diagnosed at the Cardiovascular Surgery Department, University Hospital of Liège, Belgium, between 1999 and 2012 were invited to the study. A detailed family history was obtained in interviews and recorded using Progeny software. We divided the 618 patients into 2 study groups: group I, 296 patients with AAA (268; 91% men) were followed up with computerized tomography combined with positron emission tomography; and group II, 322 patients with AAA (295; 92% men) whose families were invited to ultrasonographic screening. Results: In the initial interview, 62 (10%) of the 618 patients with AAA reported a positive family history for AAA. Ultrasonographic screening identified 24 new AAAs among 186 relatives (≥50 years) of 144 families yielding a prevalence of 13%. The highest prevalence (25%) was found among brothers. By combining the number of AAAs found by ultrasonographic screening with those diagnosed previously the observed lifetime prevalence of AAA was estimated to be 32% in brothers. The familial AAA cases were more likely to have a ruptured AAA than the sporadic cases (8% vs. 2.4%; P < 0.0001). Conclusions: The findings confirm previously found high prevalence of AAA among brothers, support genetic contribution to AAA pathogenesis, and provide rationale for targeted screening of relatives of patients with AAA. © 2014 Elsevier Inc. All rights reserved.

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.

Hinterseher I.,Sigfried and Janet Weis Center for Research | Tromp G.,Sigfried and Janet Weis Center for Research | Kuivaniemi H.,Sigfried and Janet Weis Center for Research
Annals of Vascular Surgery | Year: 2011

Abdominal aortic aneurysm (AAA) is a multifactorial disease with a strong genetic component. Since the first candidate gene studies were published 20 years ago, approximately 100 genetic association studies using single nucleotide polymorphisms (SNPs) in biologically relevant genes have been reported on AAA. These studies investigated SNPs in genes of the extracellular matrix, the cardiovascular system, the immune system, and signaling pathways. Very few studies were large enough to draw firm conclusions and very few results could be replicated in another sample set. The more recent unbiased approaches are family-based DNA linkage studies and genome-wide genetic association studies, which have the potential of identifying the genetic basis for AAA, only when appropriately powered and well-characterized large AAA cohorts are used. SNPs associated with AAA have already been identified in these large multicenter studies. One significant association was of a variant in a gene called contactin-3, which is located on chromosome 3p12.3. However, two follow-up studies could not replicate this association. Two other SNPs, which are located on chromosome 9p21 and 9q33, were replicated in other samples. The two genes with the strongest supporting evidence of contribution to the genetic risk for AAA are the CDKN2BAS gene, also known as ANRIL, which encodes an antisense ribonucleic acid that regulates expression of the cyclin-dependent kinase inhibitors CDKN2A and CDKN2B, and DAB2IP, which encodes an inhibitor of cell growth and survival. Functional studies are now needed to establish the mechanisms by which these genes contribute toward AAA pathogenesis. © Annals of Vascular Surgery Inc.

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 | And 2 more authors.
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.

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.

Estrelinha M.,New University of Lisbon | Hinterseher I.,Charité - 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.

Makrygiannis G.,University of Liège | Courtois A.,University of Liège | Drion P.,University of Liège | Defraigne J.-O.,University of Liège | And 3 more authors.
Annals of Vascular Surgery | Year: 2014

Abdominal aortic aneurysm (AAA) is a complex multifactorial disease with genetic and environmental components. AAA is more common in men, whereas women have a greater risk of rupture and more frequently have concomitant thoracic aortic aneurysms. Moreover, women are diagnosed with AAA about 10 years later and seem to be protected by female sex hormones. In this MEDLINE-based review of literature, we examined human and animal in vivo and in vitro studies to further deepen our understanding of the sexual dimorphism of AAA. We focus on the role of sex hormones during the formation and growth of AAA. Endogenous estrogens and exogenous 17β-estradiol were found to exert favorable actions protecting from AAA in animal models, whereas exogenous hormone replacement therapy in humans had inconclusive results. Androgens, known to have detrimental effects in the vasculature, in sufficient levels maintain the integrity of the aortic wall through their anabolic actions and act differentially in men and women, whereas lower levels of testosterone have been associated with AAA in humans. In conclusion, sex differences remain an important area of AAA research, but further studies especially in humans are needed. Furthermore, differential molecular mechanisms of sex hormones constitute a potential therapeutic target for AAA. © 2014 Elsevier Inc. All rights reserved.

Stepanchick A.,Sigfried and Janet Weis Center for Research | Zhi H.,Sigfried and Janet Weis Center for Research | Cavanaugh A.H.,Sigfried and Janet Weis Center for Research | Rothblum K.,University of Oklahoma | And 2 more authors.
Journal of Biological Chemistry | Year: 2013

The human homologue of yeast Rrn3 is an RNA polymerase I-associated transcription factor that is essential for ribosomal DNA (rDNA) transcription. The generally accepted model is that Rrn3 functions as a bridge between RNA polymerase I and the transcription factors bound to the committed template. In this model Rrn3 would mediate an interaction between the mammalian Rrn3-polymerase I complex and SL1, the rDNA transcription factor that binds to the core promoter element of the rDNA. In the course of studying the role of Rrn3 in recruitment, we found that Rrn3 was in fact a DNA-binding protein. Analysis of the sequence of Rrn3 identified a domain with sequence similarity to the DNA binding domain of heat shock transcription factor 2. Randomization, or deletion, of the amino acids in this region in Rrn3, amino acids 382-400, abrogated its ability to bind DNA, indicating that this domain was an important contributor to DNA binding by Rrn3. Control experiments demonstrated that these mutant Rrn3 constructs were capable of interacting with both rpa43 and SL1, two other activities demonstrated to be essential for Rrn3 function. However, neither of these Rrn3 mutants was capable of functioning in transcription in vitro. Moreover, although wild-type human Rrn3 complemented a yeast rrn3-ts mutant, the DNA-binding site mutant did not. These results demonstrate that DNA binding by Rrn3 is essential for transcription by RNA polymerase I. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

PubMed | University of Otago, Sigfried and Janet Weis Center for Research, University of Rostock, Stony Brook University Medical Center and 5 more.
Type: Journal Article | Journal: Aorta (Stamford, Conn.) | Year: 2016

The current state of research and treatment on aortic diseases was discussed in the 3rd International Meeting on Aortic Diseases (IMAD3) held on October 4-6, 2012, in Lige, Belgium. The 3-day meeting covered a wide range of topics related to thoracic aortic aneurysms and dissections, abdominal aortic aneurysms, and valvular diseases. It brought together clinicians and basic scientists and provided an excellent opportunity to discuss future collaborative research projects for genetic, genomics, and biomarker studies, as well as clinical trials. Although great progress has been made in the past few years, there are still a large number of unsolved questions about aortic diseases. Obtaining answers to the key questions will require innovative, interdisciplinary approaches that integrate information from epidemiological, genetic, molecular biology, and bioengineering studies on humans and animal models. It is more evident than ever that multicenter collaborations are needed to accomplish these goals.

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