http://pubget.com/search?q=latest%3A%22Translational+Research%22 Pubget is like Pubmed, except you get the PDFs right away Mon, 01 Apr 2013 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=23348026&q=latest%3A%22Translational+Research%22 Type 1 diabetes (T1D) is an autoimmune disease for which there is no cure. The pancreatic beta cells are the source of insulin that keeps blood glucose normal. When susceptible individuals develop T1D, their beta cells are destroyed by autoimmune T lymphocytes and no longer produce insulin. T1D patients therefore depend on daily insulin injections for survival. Gene therapy in T1D aims at the induction of new islets to replace those that have been destroyed by autoimmunity. A major goal of T1D research is to restore functional beta cell mass while eliminating diabetogenic T cells in the hope of achieving insulin independence. Multiple therapeutic strategies for the generation of new beta cells have been under intense investigations. However, newly formed beta cells would be immediately destroyed by diabetogenic T cells. Therefore, successful islet induction therapy must be supported by potent immunotherapy that will protect the newly formed beta cells. Herein, we will summarize the current information on immunotherapies that aim at modifying T cell response to beta cells. We will first outline the immune mechanisms that underlie T1D development and progression and review the scientific background and rationale for specific modes of immunotherapy. Numerous clinical trials using antigen-specific strategies and immune-modifying drugs have been published, though most have proved too toxic or have failed to provide long-term beta cell protection. To develop an effective immunotherapy, there must be a continued effort on defining the molecular basis that underlies T cell response to pancreatic islet antigens in T1D. Authors: ["Wenhao W Chen", "Aini A Xie", "Lawrence L Chan"] Mon, 01 Apr 2013 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=23348026&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=23360745&q=latest%3A%22Translational+Research%22 The use of lentiviral vectors (LV)s for in vivo gene therapy is an ideal platform for treating many types of disease. Since LVs can transduce a wide array of cells, support long-term gene expression, and be modified to enhance cell targeting, LVs are a powerful modality to deliver life-long therapeutic proteins. A major limitation facing the use of LVs for in vivo gene therapy is the induction of immune responses, which can reduce the transduction efficiency of LV, eliminate the transduced cells, and inhibit the effect of the therapeutic protein. LV strategies designed to restrict transgene expression to the liver to exploit its naturally tolerogenic properties have proven to significantly reduce the induction of pathogenic immune responses and increase therapeutic efficacy. In this review, we outline the immunological hurdles facing in vivo LV gene therapy and highlight the advantages and limitations of using liver-directed LV gene therapy. Authors: ["Andrea A Annoni", "Kevin K Goudy", "Maria Grazia MG Roncarolo", "5"] Mon, 01 Apr 2013 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=23360745&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=23146568&q=latest%3A%22Translational+Research%22 Fatty acids are carboxylic acids with aliphatic tails of different lengths, where short chain fatty acids (SCFAs) typically refer to carboxylic acids with aliphatic tails less than 6 carbons. In humans, SCFAs are derived in large part from fermentation of carbohydrates and proteins in the colon. By this process, the host is able to salvage energy from foods that cannot be processed normally in the upper parts of the gastrointestinal tract. In humans, SCFAs are a minor nutrient source, especially for people on Western diets. Intriguingly, recent studies, as highlighted here, have described multiple beneficial roles of SCFAs in the regulation of metabolism. Further interest in SCFAs has emerged due to the association of gut flora composition with obesity and other metabolic states. The recent identification of receptors specifically activated by SCFAs has further increased interest in this area. These receptors, free fatty acid receptor-2 and -3 (FFAR2 and FFAR3), are expressed not only in the gut epithelium where SCFAs are produced, but also at multiple other sites considered to be metabolically important, such as adipose tissue and pancreatic islets. Because of these relatively recent findings, studies examining the role of these receptors, FFAR2 and FFAR3, and their ligands, SCFAs, in metabolism are emerging. This review provides a critical analysis of SCFAs, their recently identified receptors, and their connection to metabolism. Authors: ["Brian T BT Layden", "Anthony R AR Angueira", "William L WL Lowe", "5"] Fri, 01 Mar 2013 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=23146568&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=23416084&q=latest%3A%22Translational+Research%22 Authors: ["Jakub J Tolar"] Mon, 01 Apr 2013 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=23416084&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=23369825&q=latest%3A%22Translational+Research%22 Arthritis is a disease of joints. The biology of joints makes them very difficult targets for drug delivery in a manner that is specific and selective. This is especially true for proteinaceous drugs ("biologics"). Gene transfer is the only technology that can solve the delivery problem in a clinically reasonable fashion. There is an abundance of preclinical data confirming that genes can be efficiently transferred to tissues within joints by intra-articular injection using a variety of different vectors in conjunction with ex vivo and in vivo strategies. Using the appropriate gene transfer technologies, long-term, intra-articular expression of anti-arthritic transgenes at therapeutic concentrations can be achieved. Numerous studies confirm that gene therapy is effective in treating experimental models of rheumatoid arthritis (RA) and osteoarthritis (OA) in the laboratory. A limited number of clinical trials have been completed, which confirm safety and feasibility but only 3 protocols have reached phase II; as yet, there is no unambiguous evidence of efficacy in human disease. Only 2 clinical trials are presently underway, both phase II studies using allogeneic chondrocytes expressing transforming growth factor-β1 for the treatment of OA. Phase I studies using adeno-associated virus to deliver interleukin-1Ra in OA and interferon-β in RA are going through the regulatory process. It is to be hoped that the recent successes in treating rare, Mendelian diseases by gene therapy will lead to accelerated development of genetic treatments for common, non-Mendelian diseases, such as arthritis. Authors: ["Christopher H CH Evans", "Steven C SC Ghivizzani", "Paul D PD Robbins"] Mon, 01 Apr 2013 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=23369825&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=23352600&q=latest%3A%22Translational+Research%22 Genetic correction of hemophilia A and B was long considered amenable to the available gene transfer technologies. This assumption has come to fruition with the recent results of a phase I/II trial for hemophilia B. Here we review the clinical application of gene therapy for the hemophilia's as a paradigm of the evolution of gene transfer science and technology. This review is not intended as comprehensive but rather to highlight current clinical developments of gene therapy for the hemophilias. Authors: ["Christopher E CE Walsh", "Katherine M KM Batt"] Mon, 01 Apr 2013 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=23352600&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=23353080&q=latest%3A%22Translational+Research%22 Human pluripotent stem cells represent an accessible cell source for novel cell-based clinical research and therapies. With the realization of induced pluripotent stem cells (iPSCs), it is possible to produce almost any desired cell type from any patient's cells. Current developments in gene modification methods have opened the possibility for creating genetically corrected human iPSCs for certain genetic diseases that could be used later in autologous transplantation. Promising preclinical studies have demonstrated correction of disease-causing mutations in a number of hematological, neuronal, and muscular disorders. This review aims to summarize these recent advances with a focus on iPSC generation techniques, as well as gene modification methods. We will then further discuss some of the main obstacles remaining to be overcome before successful application of human pluripotent stem cell-based therapy arrives in the clinic and what the future of stem cell research may look like. Authors: ["Pavel P Simara", "Jason A JA Motl", "Dan S DS Kaufman"] Mon, 01 Apr 2013 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=23353080&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=23337292&q=latest%3A%22Translational+Research%22 Hemoglobinopathies are genetic inherited conditions that originate from the lack or malfunction of the hemoglobin (Hb) protein. Sickle cell disease (SCD) and thalassemia are the most common forms of these conditions. The severe anemia combined with complications that arise in the most affected patients raises the necessity for a cure to restore hemoglobin function. The current routine therapies for these conditions, namely transfusion and iron chelation, have significantly improved the quality of life in patients over the years, but still fail to address the underlying cause of the diseases. A curative option, allogeneic bone marrow transplantation is available, but limited by the availability of suitable donors and graft-vs-host disease. Gene therapy offers an alternative approach to cure patients with hemoglobinopathies and aims at the direct recovery of the hemoglobin function via globin gene transfer. In the last 2 decades, gene transfer tools based on lentiviral vector development have been significantly improved and proven curative in several animal models for SCD and thalassemia. As a result, clinical trials are in progress and 1 patient has been successfully treated with this approach. However, there are still frontiers to explore that might improve this approach: the stoichiometry between the transgenic hemoglobin and endogenous hemoglobin with respect to the different globin genetic mutations; donor cell sourcing, such as the use of induced pluripotent stem cells (iPSCs); and the use of safer gene insertion methods to prevent oncogenesis. With this review we will provide insights about (1) the different lentiviral gene therapy approaches in mouse models and human cells; (2) current and planned clinical trials; (3) hurdles to overcome for clinical trials, such as myeloablation toxicity, insertional oncogenesis, and high vector expression; and (4) future perspectives for gene therapy, including safe harbors and iPSCs technology. Authors: ["Alisa A Dong", "Stefano S Rivella", "Laura L Breda"] Mon, 01 Apr 2013 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=23337292&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=23313629&q=latest%3A%22Translational+Research%22 The field of oncolytic virus therapy, the use of live, replicating viruses for the treatment of cancer, has expanded rapidly over the past decade. Preclinical models have clearly demonstrated anticancer activity against a number of different cancer types. Several agents have entered clinical trials and promising results have led to late stage clinical development for some viruses. The early clinical trials have demonstrated that oncolytic viruses by themselves have potential to result in tumor regression. Engineering of viruses to express novel genes have also led to the use of these vectors as a novel form of gene therapy. As a result, interest in oncolytic virus therapy has gained traction. The following review will focus on the first wave of clinical translation of oncolytic virus therapy, what has been learned so far, and potential challenges ahead for advancing the field. Authors: ["Manish R MR Patel", "Robert A RA Kratzke"] Mon, 01 Apr 2013 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=23313629&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=23305707&q=latest%3A%22Translational+Research%22 Gene therapy strategies for the treatment of inherited retinal diseases have made major advances in recent years. This review focuses on adeno-associated viral (AAV) vector approaches to treat retinal degeneration and, thus, prevent or delay the onset of blindness. Data from human clinical trials of gene therapy for retinal disease show encouraging signs of safety and efficacy from AAV vectors. Recent progress in enhancing cell-specific targeting and transduction efficiency of the various retinal layers plus the use of AAV-delivered growth factors to augment the therapeutic effect and limit cell death suggest even greater success in future human trials is possible. Authors: ["Michelle E ME McClements", "Robert E RE Maclaren"] Mon, 01 Apr 2013 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=23305707&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=23313630&q=latest%3A%22Translational+Research%22 Investigational therapy can be successfully undertaken using viral- and nonviral-mediated ex vivo gene transfer. Indeed, recent clinical trials have established the potential for genetically modified T cells to improve and restore health. Recently, the Sleeping Beauty (SB) transposon/transposase system has been applied in clinical trials to stably insert a chimeric antigen receptor (CAR) to redirect T-cell specificity. We discuss the context in which the SB system can be harnessed for gene therapy and describe the human application of SB-modified CAR(+) T cells. We have focused on theoretical issues relating to insertional mutagenesis in the context of human genomes that are naturally subjected to remobilization of transposons and the experimental evidence over the last decade of employing SB transposons for defining genes that induce cancer. These findings are put into the context of the use of SB transposons in the treatment of human disease. Authors: ["Perry B PB Hackett", "David A DA Largaespada", "Laurence J N LJ Cooper", "4"] Mon, 01 Apr 2013 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=23313630&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=23036723&q=latest%3A%22Translational+Research%22 17α-hydroxylase/17,20-lyase deficiency (17OHD) is a rare autosomal recessive genetic disease that is characterized by low-renin hypertension, hypokalemia, and abnormal development of the genitalia. Mutations in the CYP17A1 gene account for this disease. We aim to investigate the CYP17A1 mutation and analyze its possible influence on phenotype in a Chinese patient with 17OHD. Steroid hormones were assayed. The 8 exons of the CYP17A1 gene were amplified and directly sequenced. Wild-type and mutant CYP17A1 cDNA were cloned into pcDNA3.1 expression vectors and transfected into 293T cells. Finally, 17-hydroxylase and 17,20-lyase activity were detected by using progesterone and 17-hydroxypregnenolone as the substrates. A novel missense mutation c.716 G>A located in exon 4 that changed the amino acid from arginine to glutamine (R239Q) was discovered in the patient. Steric model analysis of CYP17A1 showed that R239Q changed the local structure and the electrostatic potential. Functional study indicated that the R239Q mutant caused the complete loss of both 17α-hydroxylase and 17,20-lyase activities. Our study expanded the CYP17A1 mutation spectrum. With a functional study, we confirmed that the novel mutation caused the complete loss of both 17α-hydroxylase and 17,20-lyase activities. Authors: ["Li-Qiong LQ Xue", "Bing B Han", "Huai-Dong HD Song", "12"] Tue, 01 Jan 2013 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=23036723&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=23273902&q=latest%3A%22Translational+Research%22 Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene and is the most common life-shortening genetic defect in Caucasians. Life expectancy in CF has improved substantially over the last 75 years because of treatments aimed at end-organ complications. Since the CFTR gene was discovered in 1989 more than 1900 mutations have been reported to cause CF and significant effort has been put forth into gene therapy to find a mutation independent "cure" for CF. Gene-based approaches have not yet led to a viable therapy but have provided insights into hurdles that limit the efficacy of gene therapy. This review will address the nomenclature of CFTR mutations, attempts at viral and nonviral gene therapy, and recent advances in mutation-specific molecules. Authors: ["Michelle M Prickett", "Manu M Jain"] Mon, 01 Apr 2013 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=23273902&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=23274305&q=latest%3A%22Translational+Research%22 Ischemic cardiovascular disease remains the leading cause of death worldwide. Despite advances in the medical management of atherosclerosis over the past several decades, many patients require arterial revascularization to reduce mortality and alleviate ischemic symptoms. Technological advancements have led to dramatic increases in the use of percutaneous and endovascular approaches, yet surgical revascularization (bypass surgery) with autologous vein grafts remains a mainstay of therapy for both coronary and peripheral artery disease. Although bypass surgery is highly efficacious in the short term, long-term outcomes are limited by relatively high failure rates as a result of intimal hyperplasia, which is a common feature of vein graft disease. The supply of native veins is limited, and many individuals require multiple grafts and repeat procedures. The need to prevent vein graft failure has led to great interest in gene therapy approaches to this problem. Bypass grafting presents an ideal opportunity for gene therapy, as surgically harvested vein grafts can be treated with gene delivery vectors ex vivo, thereby maximizing gene delivery while minimizing the potential for systemic toxicity and targeting the pathogenesis of vein graft disease at its onset. Here we will review the pathogenesis of vein graft disease and discuss vector delivery strategies and potential molecular targets for its prevention. We will summarize the preclinical and clinical literature on gene therapy in vein grafting and discuss additional considerations for future therapies to prevent vein graft disease. Authors: ["Kevin W KW Southerland", "Sarah B SB Frazier", "Christopher D CD Kontos", "5"] Mon, 01 Apr 2013 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=23274305&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=23261978&q=latest%3A%22Translational+Research%22 Congestive heart failure is a major cause of morbidity and mortality with increasing social and economic costs. There have been no new high impact therapeutic agents for this devastating disease for more than a decade. However, many pivotal regulators of cardiac function have been identified using cardiac-directed transgene expression and gene deletion in preclinical studies. Some of these increase function of the failing heart. Altering the expression of these pivotal regulators using gene transfer is now either being tested in clinical gene transfer trials, or soon will be. In this review, we summarize recent progress in cardiac gene transfer for clinical congestive heart failure. Authors: ["Tong T Tang", "H Kirk HK Hammond"] Mon, 01 Apr 2013 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=23261978&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=23246627&q=latest%3A%22Translational+Research%22 Glioblastoma (GBM) is the most common and deadliest primary brain tumor in adults, with current treatments having limited impact on disease progression. Therefore the development of alternative treatment options is greatly needed. Gene therapy is a treatment strategy that relies on the delivery of genetic material, usually transgenes or viruses, into cells for therapeutic purposes, and has been applied to GBM with increasing promise. We have included selectively replication-competent oncolytic viruses within this strategy, although the virus acts directly as a complex biologic anti-tumor agent rather than as a classic gene delivery vehicle. GBM is a good candidate for gene therapy because tumors remain locally within the brain and only rarely metastasize to other tissues; the majority of cells in the brain are post-mitotic, which allows for specific targeting of dividing tumor cells; and tumors can often be accessed neurosurgically for administration of therapy. Delivery vehicles used for brain tumors include nonreplicating viral vectors, normal adult stem/progenitor cells, and oncolytic viruses. The therapeutic transgenes or viruses are typically cytotoxic or express prodrug activating suicide genes to kill glioma cells, immunostimulatory to induce or amplify anti-tumor immune responses, and/or modify the tumor microenvironment such as blocking angiogenesis. This review describes current preclinical and clinical gene therapy strategies for the treatment of glioma. Authors: ["Andrea M AM Murphy", "Samuel D SD Rabkin"] Mon, 01 Apr 2013 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=23246627&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=23246626&q=latest%3A%22Translational+Research%22 Adoptive immunotherapy using gene engineered T cells is a promising and rapidly evolving field, and the ability to engineer T cells to manifest desired phenotypes and functions has become a practical reality. In this review, we describe and summarize current thought about gene engineering of T cells. We focus on the identified requirements for the successful application of T cell based immunotherapy and discuss gene-therapy based strategies that address these requirements and have the potential to enhance the successful implementation of this promising approach to treat cancer. Authors: ["Saar S Gill", "Michael M Kalos"] Mon, 01 Apr 2013 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=23246626&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=23177795&q=latest%3A%22Translational+Research%22 Authors: ["Robert D RD Blank"] Fri, 01 Mar 2013 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=23177795&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=23177794&q=latest%3A%22Translational+Research%22 The existence of mild forms of celiac disease (CD) can make the histology-based diagnosis difficult to reach. Since anti-endomysium (EMA) and anti-tissue transglutaminase (anti-tTG) are detectable in culture supernatants of duodenal biopsies from CD patients, our aim was to assess if this system can support the histology in the diagnostic work-up. A total of 559 suspected CD patients underwent serum EMA/anti-tTG detection, upper endoscopy with duodenal biopsy sampling, histologic analysis, and organ culture to detect EMA/anti-tTG in supernatants. A subgroup of 30 patients with organ culture positive results were put on a gluten-free diet (GFD). Their gluten-dependency was evaluated by the psychological general well-being and beck depression inventory indexes. Statistical analysis was performed by Cohen k inter-test, Friedman test, and Dunn multiple comparison. Two hundred forty-one out of 559 (43.1%) patients showed intestinal villous atrophy, whereas serum and organ culture EMA/anti-tTG were positive in 293/559 (52.4%) and 334/559 (59.7%) patients, respectively. The strength of agreement resulted good for serology vs histology (k = 0.730), good for organ culture vs histology (k = 0.662), and very good for serology vs organ culture (k = 0.852). After 12 months of GFD, psychological general well-being index significantly increased, and beck depression inventory index significantly decreased (P Authors: ["Antonio A Picarelli", "Marco M Di Tola", "Enrico E Corazziari", "12"] Fri, 01 Mar 2013 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=23177794&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=23177796&q=latest%3A%22Translational+Research%22 A plethora of somatic mutations and germline variations in mitochondrial DNA (mtDNA) have been increasingly reported in numerous cancer entities including osteosarcoma. However, it remains largely unclear whether mtDNA copy number changes occur during the multistep process of osteosarcoma carcinogenesis. For this purpose, we determined quantitative mtDNA levels in 31 primary osteosarcoma specimens and 5 normal bone tissue samples using a real-time polymerase chain reaction assay. Our data showed that the average mtDNA amount was significantly reduced in osteosarcoma tissues compared with normal bone controls. The copy number of mtDNA was statistically associated with tumor metastasis. There was an approximately 2-fold decrease of mtDNA quantity in tumors with metastasis than that in low-grade tumors without metastasis. Furthermore, change in mtDNA content was linked with somatic mutations in the D-loop regulatory region. Tumors carrying somatic D-loop mutations, at the polycytidine stretch between nucleotide positions 303 and 309 or close to the replication origin sites of the heavy strand, had significantly lowered mtDNA levels in comparison with those without mutations. Taken together, these results provide evidence for the first time that reduced mtDNA content may be critically implicated in the development and/or progression of osteosarcoma. Somatic D-loop mutation is likely one key factor among others leading to altered mtDNA amount in osteosarcoma. Authors: ["Man M Yu", "Yanfang Y Wan", "Qinghua Q Zou"] Fri, 01 Mar 2013 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=23177796&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=23138105&q=latest%3A%22Translational+Research%22 Peripheral whole blood is relatively easily obtained for monitoring gene expression for biomarker discovery using transcriptomic platforms such as genome-wide microarrays. However, whole blood provides challenges caused by sensitivity for ex vivo incubation and overrepresentation of globin mRNAs. We compared the performance of 2 commercial whole blood preservation methods, TEMPUS (Applied Biosystems, Foster City, CA) and PAXgene (PreAnalytiX, Qiagen BD, Valencia, CA), using 2 RNA amplification protocols and high-density microarrays. Performance of commercial globin mRNA reduction protocol also was studied. Human peripheral blood samples collected with TEMPUS and PAXgene Blood RNA tubes were amplified with the RiboAmp OA 1 Round RNA Amplification Kit (Arcturus; Applied Biosystems) and the Affymetrix (Santa Clara, CA) small sample protocol. Affymetrix globin reduction protocol was applied for total RNA samples. Samples amplified with RiboAmp were hybridized on Illumina Sentrix HumanRef-8 Expression BeadChips (Illumina Inc, San Diego, CA) and subjected to statistical analyses. RiboAmp mRNA amplification did not notably amplify globin mRNA that is overrepresented in RNA isolated by both TEMPUS and PAXgene preservation. Enzymatic depletion of globin transcript reduced the quality of total RNA and is thus not recommendable. Microarray analysis showed acceptable correlation within and between the RNA preservation methods, but altogether 443 transcripts were differentially expressed between RNA samples preserved in TEMPUS and PAXgene tubes. We demonstrated that the 2 tested blood RNA-preservation methods combined with RiboAmp mRNA amplification may be used for microarray experiments without the need for a prior globin RNA reduction. However, because genes involved in immune cell functions and gene regulatory pathways were differentially expressed as a result of the technical bias between the preservation methods, they should not be used in the same analytic setting. Authors: ["Tuomas T Nikula", "Juha J Mykkänen", "Riitta R Lahesmaa", "4"] Fri, 01 Mar 2013 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=23138105&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=22709740&q=latest%3A%22Translational+Research%22 Anomalies in gonadal development in a mouse knockout model of Cited2 have been recently described. In Cited2(-/-) female gonads, an ectopic cell migration was observed and the female program of sex determination was transiently delayed. We hypothesize that, in humans, this temporary inhibition of genes should be sufficient to provoke a developmental impairment of the female gonads, conducive to premature ovarian failure (POF). To establish whether CITED2 mutations are a common cause of the disease, we performed a mutational analysis of this gene in a panel of patients with POF and in a group of control women with normal fertility. We amplified and directly sequenced the complete open reading frame of CITED2 in 139 patients with POF and 290 controls. This study revealed 5 synonymous and 3 nonsynonymous variants. Among these, 7 are novel. The nonsynonymous variant c.604C>A (p.Pro202Thr) was found uniquely in 1 woman from the POF group. In silico analysis of this mutation indicated a potential deleterious effect. We conclude that mutations in CITED2 may be involved in POF pathogenesis. Authors: ["Dora Janeth DJ Fonseca", "Diego D Ojeda", "Paul P Laissue", "19"] Thu, 01 Nov 2012 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=22709740&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=pgtmp_ebb78e916a4813dd1f0a93bd08243dfb&q=latest%3A%22Translational+Research%22 Anomalies in gonadal development in a mouse knockout model of Cited2 have been recently described. In Cited2(-/-) female gonads, an ectopic cell migration was observed and the female program of sex determination was transiently delayed. We hypothesize that, in humans, this temporary inhibition of genes should be sufficient to provoke a developmental impairment of the female gonads, conducive to premature ovarian failure (POF). To establish whether CITED2 mutations are a common cause of the disease, we performed a mutational analysis of this gene in a panel of patients with POF and in a group of control women with normal fertility. We amplified and directly sequenced the complete open reading frame of CITED2 in 139 patients with POF and 290 controls. This study revealed 5 synonymous and 3 nonsynonymous variants. Among these, 7 are novel. The nonsynonymous variant c.604C>A (p.Pro202Thr) was found uniquely in 1 woman from the POF group. In silico analysis of this mutation indicated a potential deleterious effect. We conclude that mutations in CITED2 may be involved in POF pathogenesis. Authors: ["Dora Janeth DJ Fonseca", "Diego D Ojeda", "Paul P Laissue", "19"] Thu, 01 Nov 2012 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=pgtmp_ebb78e916a4813dd1f0a93bd08243dfb&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=23072926&q=latest%3A%22Translational+Research%22 Oxidative stress (OS) has been observed in conditions affecting the cardiovascular system. Familial hypercholesterolemia (FH) is associated with an increased risk of premature coronary heart disease. In the postprandial state, circulating lipids and lipoproteins can modulate OS status. Our aim was to study the response of lymphomonocyte OS status and reactive oxygen species by-products after an oral unsaturated fat load test (OFLT) in those with FH and to compare this response with that obtained in normolipidemic, normoglycemic subjects. We studied 12 patients with FH and 20 healthy controls. In both groups, lymphomonocyte, oxidized/reduced glutathione ratio, and malondialdehyde were determined at baseline and at 2, 4, 6, and 8 hours after an OFLT. Fasting urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine and isoprostane were measured using standard procedures. In both groups, oxidized/reduced glutathione ratio and malondialdehyde significantly decreased in the postprandial state after the OFLT. Both parameters were significantly higher in the FH group at baseline and during all the postprandial points, but the reduction from the baseline levels was significantly higher in the FH group than in the control group. Urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine was significantly increased in the FH group compared with the healthy control group, indicating a higher fasting OS status. We conclude that subjects with FH exhibited OS levels that were higher than in controls before and after an OFLT, but the improvement in the OS status after the unsaturated fat load was significantly higher in subjects with FH. Authors: ["Teresa T Pedro", "Sergio S Martinez-Hervas", "Jose T JT Real", "9"] Tue, 01 Jan 2013 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=23072926&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=23084780&q=latest%3A%22Translational+Research%22 The study objective was to investigate the role of hypoxia-inducible factor 1 (HIF-1) in the transcriptional activation of MUC5AC in human bronchial epithelial (HBE) 16 cells under hypoxia conditions and the effect of hypoxia on expression and secretion of MUC5AC. Cells were incubated in hypoxia medium. Serial deletions or mutations of the MUC5AC promoter were cloned in the reporter pGL3-basic plasmid (Promega Biotech Co, Ltd, Beijing, China). These reporter plasmids were cotransfected with HIF-1α small interfering RNA. Hypoxia markedly increased the level of MUC5AC secretion and the transcriptional activity of MUC5AC promoters. Western blot analysis showed that HIF-1α and MUC5AC proteins were strongly increased after HBE16 cells were exposed to hypoxic conditions. Treatment of HBE16 cells with HIF-1α inhibitor (YC-1) or HIF-1α small interfering RNA significantly inhibited the expression of HIF-1α and MUC5AC, and the secretion of MUC5AC. Depletion of the promoter sequence did not reduce the MUC5AC promoter activity to hypoxia. Luciferase assay indicated that HRE in the MUC5AC promoter was in the region from -120 to +54. Promoter sequence analysis showed that 1 HRE site at -65 plays an important role in hypoxia activation of the MUC5AC. The inactivation of the HRE site using site-directed mutagenesis led to the complete loss of induction by hypoxia, which further confirmed the key role of the HRE site. MUC5AC expression and secretion are upregulated in response to hypoxia. The HRE site at -65 in the MUC5AC promoter and the HIF-1α are the major regulators for the cellular response against hypoxia in human bronchial epithelial cells. Authors: ["Xiangdong X Zhou", "Jing J Tu", "Juliy M JM Perelman", "5"] Sat, 01 Dec 2012 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=23084780&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=23063585&q=latest%3A%22Translational+Research%22 A major mechanism of DNA repair related to homologous recombination is the Fanconi anemia (FA) pathway. FA genes collaborate with BRCA genes to form foci of DNA repair on chromatin after DNA damage or during the S phase of the cell cycle. Our goal was to develop a method capable of evaluating the functional status of the pathway in patients' tumor tissue, which could also be practically incorporated into large-scale screening. To develop this method, we first used Western immunoblot to detect FANCD2 protein monoubiquitination in fresh tumor specimens of patients with ovarian cancer undergoing surgery and stained formalin-fixed paraffin-embedded tumor tissue simultaneously with 4',6-diamidino-2-phenylindole, FANCD2, and Ki67 antibodies, eventually extending this method to other solid tumors. This triple stain permitted evaluation of the presence, or lack thereof, of FANCD2 subnuclear repair foci in proliferating cells by immunofluorescence microscopy. Overall, we evaluated 156 formalin-fixed paraffin-embedded tumor samples using the FA triple-staining immunofluorescence method. The ratios of FANCD2 foci-negative tumors in ovarian, lung, and breast tumor samples were 21%, 20%, and 29.4%, respectively. Our studies have led to the development of a suitable method for screening, capable of identifying tumors with somatic functional defects in the FA pathway. The use of paraffin-embedded tissues renders the reported method suitable for large-scale screening to select patients for treatment with DNA interstrand crosslinking agents, poly ADP-ribose polymerase inhibitors, or their combination. Authors: ["Wenrui W Duan", "Li L Gao", "Miguel A MA Villalona-Calero", "14"] Fri, 01 Mar 2013 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=23063585&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=23041443&q=latest%3A%22Translational+Research%22 Approximately 40% of patients with Henoch-Schonlein purpura (HSP) develop Henoch-Schonlein purpura nephritis (HSPN) after 4 to 6 weeks of subcutaneous hemorrhaging. Immunoglobulin-A nephropathy (IgAN) and HSPN have numerous similarities, which can cause difficulty in correctly diagnosing the disorder during a differential diagnosis. The pathogenesis of the 2 diseases is not clear. We enrolled 137 patients with HSPN, 107 patients with IgAN, and 28 healthy (control) patients in our study. The levels of alpha-smooth muscle actin (α-SMA), c-Met, and Gal-deficient IgA1 (Gd-IgA1) in the 3 patient groups were determined and compared. The α-SMA, c-Met, and Gd-IgA1 levels and the clinical data from the patients with HSPN were analyzed for any correlations. The α-SMA and c-Met levels of the HSPN group were significantly higher than those of the IgAN and healthy control groups (P Authors: ["Lei L Zhang", "Changsong C Han", "Xiaoming X Jin", "9"] Tue, 01 Jan 2013 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=23041443&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=22995932&q=latest%3A%22Translational+Research%22 Mutations in genes encoding ion channel pore-forming α-subunits and accessory β-subunits as well as intracellular calcium-handling proteins that collectively maintain the electromechanical function of the human heart serve as the underlying pathogenic substrate for a spectrum of sudden cardiac death (SCD)-predisposing heritable cardiac arrhythmia syndromes, including long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome (BrS), and catecholaminergic polymorphic ventricular tachycardia (CPVT). Similar to many Mendelian disorders, the cardiac "channelopathies" exhibit incomplete penetrance, variable expressivity, and phenotypic overlap, whereby genotype-positive individuals within the same genetic lineage assume vastly different clinical courses as objectively assessed by phenotypic features such electrocardiographic abnormalities and number/type of cardiac events. In this Review, we summarize the current understanding of the global architecture of complex electrocardiographic traits such as the QT interval, focusing on the role of common genetic variants in the modulation of ECG parameters in health and the environmental and genetic determinants of incomplete penetrance and variable expressivity in the heritable cardiac arrhythmia syndromes most likely to be encountered in clinical practice. Authors: ["John R JR Giudicessi", "Michael J MJ Ackerman"] Tue, 01 Jan 2013 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=22995932&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=22989614&q=latest%3A%22Translational+Research%22 Monocyte chemotactic protein-1 (MCP-1), also known as "chemokine ligand 2" (CCL2), is a monocyte-attracting chemokine produced in lung epithelial cells. We previously reported an association of increased levels of plasma MCP-1 with primary graft dysfunction (PGD) after lung transplantation in a nested case-control study of extreme phenotypes using a multiplex platform. In this study, we sought to evaluate the role of plasma MCP-1 level as a biomarker across the full spectrum of PGD. We performed a prospective cohort study of 108 lung transplant recipients within the Lung Transplant Outcomes Group cohort. Plasma MCP-1 levels were measured pretransplantation and 6 and 24 hours after transplantation. The primary outcome was development of grade 3 PGD within 72 hours of transplant, with secondary analyses at the 72-hour time point. Multivariable logistic regression was used to evaluate confounding. Thirty subjects (28%) developed PGD. Median MCP-1 measured at 24 hours post-transplant was elevated in subjects with PGD (167.95 vs 103.5 pg/mL, P = .04). MCP-1 levels at 24 hours were associated with increased odds of grade 3 PGD after lung transplantation (odds ratio for each 100 pg/mL, 1.24; 95% confidence interval, 1.00-1.53) and with grade 3 PGD present at the 72-hour time point (odds ratio for each 100 pg/mL, 1.57; 95% confidence interval, 1.18-2.08), independent of confounding variables in multivariable analyses. MCP-1 levels measured preoperatively and 6 hours after transplant were not significantly associated with PGD. Persistent elevations in MCP-1 levels at 24 hours are a biomarker of grade 3 PGD post-transplantation. Monocyte chemotaxis may play a role in the pathogenesis of PGD. Authors: ["Rupal J RJ Shah", "Joshua M JM Diamond", "Lorraine B LB Ware", "12"] Sat, 01 Dec 2012 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=22989614&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=22939913&q=latest%3A%22Translational+Research%22 Behçet's disease (BD) is a multi-systemic vasculitis. The aim of this study was to investigate the association between Rho-kinase (ROCK2) gene polymorphisms and patients with BD in a Turkish population. A total of 194 BD patients and 276 healthy controls with similar age and sex were included to this study. Polymorphisms were analyzed in genomic DNA using a BioMark 96.96 dynamic array system. mRNA from blood samples was extracted, and real-time polymerase chain reaction was performed for ROCK2 gene expression. There were marked changes in both genotype (TT, 41.8%; TA, 30.3%) and allele (T, 57%; A, 43%) frequencies for the rs35768389 (Asp601Val) polymorphism in patients compared with controls (TT, 64.6%; TA, 9.4%, P Authors: ["Elif E Oguz", "Belgin B Alasehirli", "Abdullah T AT Demiryürek", "9"] Sat, 01 Dec 2012 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=22939913&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=22901678&q=latest%3A%22Translational+Research%22 Authors: ["Jiping J Shan", "Shuchao S Pang", "Bo B Yan", "9"] Sat, 01 Sep 2012 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=22901678&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=22921838&q=latest%3A%22Translational+Research%22 C-reactive protein (CRP) levels and the erythrocyte sedimentation rate (ESR) are widely used tests of inflammation that sometimes show opposite results. We performed a retrospective cohort study to clarify the frequency and causes of CRP/ESR discordance in adults. Between January and December of 2011, the laboratories of Texas Health Presbyterian Hospital performed 2150 paired CRP/ESR measurements in 1753 patients, 1731 of whom were nonpregnant adults aged ≥ 18 years. Initial CRP and ESR results for each patient were divided into quartiles. CRP/ESR discordance, predefined as results differing by 2 or 3 quartiles, occurred in 212 patients (12%), 105 of whom had high CRP/low ESR discordance (6%) and 107 of whom had high ESR/low CRP discordance (6%). The 212 patients in the CRP/ESR-discordant group (128 women and 84 men) were subdivided into 1 of 6 diagnostic categories, and the causes of discordances were compared. The high CRP/low ESR-discordant group had more patients with infections than the high ESR/low CRP-discordant group (P = 0.001), particularly infections in the urinary tract (P = 0.03), gastrointestinal tract (P = 0.001), lungs (P = 0.005), and bloodstream (P = 0.03). However, they had fewer bone and joint infections than the high ESR/low CRP-discordant group (P = 0.001). Connective tissue diseases, such as systemic lupus erythematosus, were less common in the high CRP/low ESR-discordant group than in the high ESR/low CRP-discordant group (P = 0.001). Ischemic strokes or transient ischemic attacks almost invariably occurred in the high ESR/low CRP-discordant group (P = 0.001), whereas myocardial infarction or venous thromboembolism was limited to the high CRP/low ESR-discordant group (P = 0.001). Our findings provide information to physicians who order these 2 tests together and receive discordant results, which occurs in approximately 1 in 8 patients. Authors: ["Mark M Feldman", "Bilal B Aziz", "Connie C Sellers", "6"] Tue, 01 Jan 2013 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=22921838&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=22884677&q=latest%3A%22Translational+Research%22 Multiple clinical trials have been conducted to determine the outcome of stem cell transplantation on cardiac function. However, marked variability in design across these trials has generated ambiguity in interpretation of their results. This review systematically evaluates the currently available protocols to illustrate the need for a standardized protocol for future trials. Authors: ["Jason M JM Duran", "Sharven S Taghavi", "Jon C JC George"] Sat, 01 Dec 2012 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=22884677&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=22885175&q=latest%3A%22Translational+Research%22 The study was designed to evaluate the markers of oxidative damage and to establish their diagnostic utility in breast carcinoma patients. Levels of 8-hydroxy-2-deoxyguanosine (8-OH-dG), protein carbonyl (PC), and malondialdehyde (MDA) along with total antioxidant status (TAS) were measured in breast carcinoma patients and controls. Receiver operating characteristic (ROC) analysis was done to study the diagnostic potential of the oxidative damage markers. Significant increases in oxidative damage markers were observed in breast carcinoma patients compared with the normal controls, which were accompanied by significant decrease in TAS. The logistic regression analysis revealed higher levels of oxidative stress marker and reduced level of TAS were significantly associated with breast cancer. ROC curves analysis demonstrates that 8-OHdG and PC are better indicators for distinguishing cancer patients from controls, followed by MDA and TAS. Our results indicate increased oxidative damage is associated with malignancy in breast cancer patients. High accuracy of oxidative stress markers in indicating cancer presence can be used as discriminatory makers for efficient diagnosis. Authors: ["Deepti D Pande", "Reena R Negi", "H D HD Khanna", "6"] Sat, 01 Dec 2012 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=22885175&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=22885174&q=latest%3A%22Translational+Research%22 Authors: ["Silvia S Pulignani", "Monica M Cresci", "Maria Grazia MG Andreassi"] Tue, 01 Jan 2013 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=22885174&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=22857867&q=latest%3A%22Translational+Research%22 Authors: ["Akira A Haketa", "Masayoshi M Soma", "Shigeaki S Hinohara", "10"] Tue, 01 Jan 2013 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=22857867&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=22858685&q=latest%3A%22Translational+Research%22 Authors: ["Aparna A AA Bhanushali", "Aashish A Contractor", "Bibhu R BR Das"] Sat, 01 Dec 2012 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=22858685&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=22814359&q=latest%3A%22Translational+Research%22 The molecular basis of the reduced half-life of chronic kidney disease (CKD) erythrocytes is unclear. The erythrocyte membrane plays a key role in the erythrocyte mechanical properties and survival. The aim of the present work is to uncover erythrocyte membrane proteins whose expression could be altered in CKD. The erythrocyte membrane subproteome was analyzed by a non-biased approach where the whole set of proteins was simultaneously investigated by 2D fluorescence difference gel electrophoresis without preselection of potential targets. Proteins significantly altered in CKD were identified by mass spectrometry (MS) and results validation was performed by Western blot and confocal microscopy. Nine differentially expressed spots among healthy individuals, non-dialyzed CKD and erythropoietin/dialysis-treated CKD patients were identified by MS/MS corresponding to 5 proteins (beta-adducin, HSP71/72, tropomodulin-1, ezrin, and radixin). Ezrin and radixin were higher in dialyzed CKD patients than in the other 2 groups. Beta-adducin was increased in CKD patients (dialyzed or not). Three spots were normalized in patients on the dialysis/erythropoietin combination compared with non-dialyzed CKD. Among these, a spot corresponding to tropomodulin 1, was found to be of higher abundance in non-dialyzed CKD patients compared with controls or dialyzed CKD. In conclusion, this study identifies changes in erythrocyte membrane proteins in CKD, which may be relevant for the pathogenesis of red cell abnormalities in uremia. Authors: ["Gloria G Alvarez-Llamas", "Irene I Zubiri", "Fernando F Vivanco", "11"] Thu, 01 Nov 2012 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=22814359&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=22782072&q=latest%3A%22Translational+Research%22 Authors: ["Dana L Felice", "Terry G Unterman"] Sun, 01 Jul 2012 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=22782072&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=22749670&q=latest%3A%22Translational+Research%22 Authors: [] Wed, 01 Aug 2012 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=22749670&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=22735028&q=latest%3A%22Translational+Research%22 Illicit drug use has been associated with chronic kidney disease (CKD) in select populations, but it is unknown whether the same association exists in the general population. By using data from the National Health and Nutrition Examination Survey 2005-2008, we conducted a cross-sectional analysis of 5861 adults who were questioned about illicit drug use, including cocaine, methamphetamines, and heroin, during their lifetime. The primary outcome was CKD as defined by an estimated glomerular filtration rate ≤60 mL/min/1.73 m(2) using the Chronic Kidney Disease Epidemiology Collaboration equation or by microalbuminuria. We also examined the association between illicit drug use and blood pressure (BP) ≥120/80, ≥130/85, and ≥140/90 mm Hg. Logistic regression was used to examine the association between illicit drug use and CKD and BP. Mean estimated glomerular filtration rate was similar between illicit drug users and nonusers (100.7 vs 101.4 mL/min/1.73 m(2), P = 0.4), as was albuminuria (5.7 vs 6.0 mg/g creatinine, P = 0.5). Accordingly, illicit drug use was not significantly associated with CKD in logistic regression models (odds ratio [OR], 0.98; confidence interval [CI], 0.75-1.27) after adjusting for other important factors. However, illicit drug users had higher systolic (120 vs 118 mm Hg, P = 0.04) and diastolic BP (73 vs 71 mm Hg, P = 0.0003) compared with nonusers. Cocaine use was independently associated with BP ≥130/85 mm Hg (OR, 1.24; CI, 1.00-1.54), especially when used more during a lifetime (6-49 times; OR, 1.42; CI, 1.06-1.91). In a representative sample of the US population, illicit drug use was not associated with CKD, but cocaine users were more likely to have elevated BP. Authors: ["Sanjeev K SK Akkina", "Ana C AC Ricardo", "James P JP Lash", "8"] Sat, 01 Dec 2012 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=22735028&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=22750084&q=latest%3A%22Translational+Research%22 Authors: ["David D Della-Morte", "Chuanhui C Dong", "Tatjana T Rundek", "7"] Thu, 01 Nov 2012 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=22750084&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=22732305&q=latest%3A%22Translational+Research%22 Authors: ["Edward N EN Janoff", "Claire C Gustafson", "Daniel N DN Frank"] Mon, 01 Oct 2012 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=22732305&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=22687960&q=latest%3A%22Translational+Research%22 Inflammatory bowel disease (IBD) encompasses several chronic inflammatory disorders leading to the damage of the gastrointestinal tract. The 2 principal forms of these disorders are ulcerative colitis (UC) and Crohn's disease (CD). Bacteria are involved in the etiology of IBD. Many microorganisms have been put forward as causative factors in IBD, but the primary etiologic agents are still not known. The underlying genetic, environmental, and lifestyle issues can affect the individual's predisposition to these diseases. Immune factors identified in IBD are: dysregulation of the innate and adaptive immune system directed against luminal bacteria or their products found in the intestinal lumen and inappropriate immune responses to organisms in the intestine that normally do not elicit a response, possibly because of intrinsic alterations in mucosal barrier function. However, recent advances in basic science research revealed new insights into the role of specific immune cells and their mediators in intestinal inflammation. The inflammatory mediators known as "inflammasome" are a consequence of the metabolic products (metabolom) of cells and commensal or pathogenic bacteria. Elucidation of inflammasome and metabolom has led to the development of biomarkers specific for each disease that are involved into management strategies targeted at altering specific pathogenic mechanisms that have the potential to modify or change the natural course of these disease entities. The review discusses the potential role of biomarkers in monitoring the inflammasome and therefore the severity of intestinal damage. The microbial ecosystem in the human gut in different microhabitats and metabolic niches contribute to the bowel metabolome.In addition, this review will focus on our expanding understanding of microbial factors associated with both the initiation and maintenance of IBD. New insights acquired from murine genetic models of inflammatory bowel disease will also be discussed. Authors: ["Radu M RM Nanau", "Manuela G MG Neuman"] Sun, 01 Jul 2012 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=22687960&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=22687963&q=latest%3A%22Translational+Research%22 Several studies have reported on the association between inflammatory bowel disease (IBD) and adverse pregnancy outcomes, such as preterm birth. The exact mechanisms of action are unclear; however, several pathways and processes are involved in both IBD and pregnancy that may help explain this. In this review, we discuss the immune system's T helper cells and human leukocyte antigens, inflammation, its function, and the role of Toll-like receptors (TLRs), NOD-like receptors (NLRs), and prostaglandins in the inflammatory response. For each of these topics, we consider their involvement in IBD and pregnancy, and we speculate as to how they can lead to preterm birth. Finally, we review briefly corticosteroids, biologic therapies, and immunosuppressants for the treatment of IBD, as well as their safety in use during pregnancy, with special focus on preterm birth. Authors: ["Noha Ahmed NA Nasef", "Lynnette R LR Ferguson"] Sun, 01 Jul 2012 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=22687963&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=22687964&q=latest%3A%22Translational+Research%22 Many aspects of tissue damage after acute or chronic inflammatory reactions can be attributed directly to the concomitant biosynthesis and release of inducible early proinflammatory cytokine tumor necrosis factor alpha (TNFα). Conversely, systemic inflammation is impacted by the consequences of tissue damage. Dysregulated TNFα contributes to numerous pathophysiologic conditions including inflammatory bowel disease (IBD) and arthritis. Inflammatory stimuli trigger proteolytic cleavage and shedding of extracellular domains of TNFα receptors giving rise to 2 soluble fragments (p55 soluble tumor necrosis factor receptor 1 (sTNFR1) and p75 sTNFR2) that block the additional binding, activity, and synthesis of TNFα. We hypothesized that absence of sTNFR inhibitory feedback control would result in accumulated high levels of TNFα and other inflammatory factors promoting the cardinal signs of chronic inflammation and pain. The current study reports a translational murine model of chronic arthritis precipitated by 2 consecutive inflammatory insults. The "double hit" procedures provoke a chronic inflammatory response and pain-related behaviors in mice that are dually deficient in p55 (TNFR1) and p75 (TNFR2). The inflammation- and pain-related behaviors are transient in similarly treated wild-type (WT) mice. The complete Freund's adjuvant (CFA) method was used initially to induce knee joint inflammation, tactile mechanical and heat hypersensitivity, and gait disturbance. After these transient effects of the insult were resolved, a recrudescence persisting at least through 23 weeks was promoted by gastrointestinal (GI) insult with dilute intracolonic mustard oil (MO) only in the mutant mice and was reversed by a P2X7 antagonist. A serum proteome profiling analysis revealed high levels of serum inflammatory factors TNFα, regulated upon activation normally T-cell expressed and secreted (RANTES), chemokine (C-X-C motif) ligand 9 [CXCL9 (MIG)], chemokine (C-X-C motif) ligand 10 [CXCL10 (IP-10)], and chemokine (C-C motif) ligand 2 [CCL2 (MCP-1)]. These data suggest that impaired signaling of TNFα as a result of the deficit of the 2 protective soluble p55 and p75 sTNFR inhibitory factors plays a pivotal role in the reactivation of the immune response to GI insult that can produce recrudescence of inflammatory injury and a chronic pain state through promotion of high levels of serum inflammatory factors. Authors: ["Karin N KN Westlund", "Liping L Zhang", "Helieh S HS Oz", "4"] Sun, 01 Jul 2012 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=22687964&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=22691914&q=latest%3A%22Translational+Research%22 Polymorphisms in the endothelial nitric oxide synthase (eNOS) gene reduce shear stress-induced nitric oxide production. Thus, we investigated the individual and combined impact of 3 variants in the eNOS gene (-786T>C, intron 4b4a, and 894G>T) on vascular reactivity before and after exercise. Sedentary, healthy subjects were studied (105 women/26 men, age 32 ± 1 years [mean ± standard error of the mean]). Genotypes were determined by polymerase chain reaction restriction fragment length polymorphism, and haplotypes were determined by a Bayesian-based algorithm. Vascular reactivity was evaluated by the percentage of change in forearm vascular conductance provoked by 5 minutes of circulatory occlusion before (baseline) and 10, 60, and 120 minutes after a maximal cardiopulmonary exercise test. Vascular reactivity increased 10 minutes after exercise in the entire sample (baseline: 218 ± 11% vs 10 minutes: 284 ± 15%, P T polymorphism had lower vascular reactivity than wild counterparts (group effect, P = 0.05). Furthermore, subjects with haplotype 2 (H2), containing the -786T>C and 894G>T polymorphisms, had lower vascular reactivity than wild counterparts (haplotype 1 [H1]) (group effect, P = 0.05), whereas subjects with haplotype 4 (H4), containing only the 894G>T polymorphism, had vascular reactivity similar to that of wild counterparts (H1) (group effect, P = 0.35). Altogether, these results indicate that the 894G>T polymorphism reduced exercise-mediated increase in vascular reactivity, particularly when it occurred concomitantly with the -786T>C polymorphism. Authors: ["Bruno M BM Silva", "Fabricia J FJ Neves", "Antonio Claudio Lucas da AC Nóbrega", "9"] Tue, 01 Jan 2013 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=22691914&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=22687961&q=latest%3A%22Translational+Research%22 Inflammatory bowel disease (IBD) encompassed several chronic inflammatory disorders leading to damage of the gastrointestinal tract (GI). The 2 principal forms of these disorders are ulcerative colitis (UC) and Crohn disease (CD). Bacteria are involved in the etiology of IBD, and the genetic susceptibility, environmental factors, and lifestyle factors can affect the individual's predisposition to IBD. The review discusses the potential role of environmental factors such as diet and microbiota as well as genetics in the etiology of IBD. It is suggested that microbial ecosystem in the human bowel colonizing the gut in many different microhabitats can be influence by diet, leading to formation of metabolic processes that are essential form the bowel metabolism. Authors: ["Manuela G MG Neuman", "Radu M RM Nanau"] Sun, 01 Jul 2012 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=22687961&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=22687962&q=latest%3A%22Translational+Research%22 Strong evidence indicates that inflammatory bowel disease, including Crohn disease and ulcerative colitis, is a result of an inappropriate inflammatory response in which genetic and environmental factors play important roles. This review discusses several single-nucleotide polymorphisms with either susceptibility or protective effects on inflammatory bowel disease. Authors: ["Manuela G MG Neuman", "Radu M RM Nanau"] Sun, 01 Jul 2012 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=22687962&q=latest%3A%22Translational+Research%22 http://pubget.com/search?escape=false&highlight=22633093&q=latest%3A%22Translational+Research%22 Authors: ["Carrie L CL Phillips"] Fri, 01 Jun 2012 00:00:00 +0000 http://pubget.com/search?escape=false&highlight=22633093&q=latest%3A%22Translational+Research%22