Characterization of TEM1/endosialin in human and murine brain tumors

<p>Abstract</p> <p>Background</p> <p><it>TEM1/endosialin </it>is an emerging microvascular marker of tumor angiogenesis. We characterized the expression pattern of <it>TEM1/endosialin </it>in astrocytic and metastatic brain tumors and investigated its role as a therapeutic target in human endothelial cells and mouse xenograft models.</p> <p>Methods</p> <p><it>In situ </it>hybridization (ISH), immunohistochemistry (IH) and immunofluorescence (IF) were used to localize <it>TEM1/endosialin </it>expression in grade II-IV astrocytomas and metastatic brain tumors on tissue microarrays. Changes in <it>TEM1/endosialin </it>expression in response to pro-angiogenic conditions were assessed in human endothelial cells grown <it>in vitro</it>. Intracranial U87MG glioblastoma (GBM) xenografts were analyzed in nude <it>TEM1/endosialin </it>knockout (KO) and wildtype (WT) mice.</p> <p>Results</p> <p><it>TEM1/endosialin </it>was upregulated in primary and metastatic human brain tumors, where it localized primarily to the tumor vasculature and a subset of tumor stromal cells. Analysis of 275 arrayed grade II-IV astrocytomas demonstrated <it>TEM1/endosialin </it>expression in 79% of tumors. Robust <it>TEM1/endosialin </it>expression occurred in 31% of glioblastomas (grade IV astroctyomas). <it>TEM1/endosialin </it>expression was inversely correlated with patient age. TEM1/endosialin showed limited co-localization with CD31, αSMA and fibronectin in clinical specimens. <it>In vitro</it>, <it>TEM1/endosialin </it>was upregulated in human endothelial cells cultured in matrigel. Vascular <it>Tem1/endosialin </it>was induced in intracranial U87MG GBM xenografts grown in mice. <it>Tem1/endosialin </it>KO vs WT mice demonstrated equivalent survival and tumor growth when implanted with intracranial GBM xenografts, although <it>Tem1/endosialin </it>KO tumors were significantly more vascular than the WT counterparts.</p> <p>Conclusion</p> <p><it>TEM1/endosialin </it>was induced in the vasculature of high-grade brain tumors where its expression was inversely correlated with patient age. Although lack of <it>TEM1/endosialin </it>did not suppress growth of intracranial GBM xenografts, it did increase tumor vascularity. The cellular localization of <it>TEM1/endosialin </it>and its expression profile in primary and metastatic brain tumors support efforts to therapeutically target this protein, potentially via antibody mediated drug delivery strategies.</p

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP

Genetic loci influencing kidney function and chronic kidney disease

Using genome-wide association, we identify common variants at 2p12-p13, 6q26, 17q23 and 19q13 associated with serum creatinine, a marker of kidney function (P = 10 10 to 10 15). Of these, rs10206899 (near NAT8, 2p12-p13) and rs4805834 (near SLC7A9, 19q13) were also associated with chronic kidney disease (P = 5.0 × 10 5 and P = 3.6 × 10 4, respectively). Our findings provide insight into metabolic, solute and drug-transport pathways underlying susceptibility to chronic kidney disease

Place of genotyping and phenotyping in understanding and potentially modifying outcomes in peritoneal dialysis patients

With the landmark publication of the human genome sequence and its subsequent division into haplotype blocks, the characterization of genetic variations is becoming a feasible approach to study both the pathophysiology and risk factors of complex traits. A number of strategies are available today for identifying candidate genes or polymorphisms associated with pertinent phenotypes. For Mendelian diseases with high penetrance owing to mutations in a single gene, such as polycystic kidney disease, linkage studies have been very successful in mapping the disease loci owing to the availability of families with multiple affected members. In contrast to monogenic conditions, complex diseases such as end-stage renal disease (ESRD) and complex traits such as individual variations in membrane transport and complications during the course of peritoneal dialysis (PD) therapy have a number of competing determinants and inhibitors, both genetic and environmental. Current results reflect this complexity, with few studies showing a large effect of any single risk factor on survival or outcome on PD. However, these studies have so far been small (less than 500 patients) and have not utilized bioinformatics or novel technologies (e.g., multiplex genotyping equipment). In the following review, we outline current approaches for using genetic data in clinical studies as well as highlight some of the most promising results in ESRD patients, particularly those on PD

Genetics/Genomics in Chronic Kidney Disease-Towards Personalized Medicine?

The progression rate of chronic kidney disease (CKD) to its terminal stage, end-stage renal disease (ESRD), and the development and severity of various complications, are at least indirectly influenced by genetic-and epigenetic-factors. For years, scientists have held out hope that the rapidly evolving field of genetics could transform medical diagnosis and treatment, moving beyond a trial-and-error approach towards "personalized medicine." Indeed, there are now signs that the role of genetics and the pursuit of "personalized medicine" in medical care will be a priority for governments during years to come. But the vision of individualized treatment based on a patient's genetic makeup and other biological markers has yet to materialize in the field of CKD and ESRD. As the toxic uremic environment may render CKD patients more sensitive to the effects of genetic variants, it is likely that genetic factors could be of special importance in this high-risk population. Therefore, outcome in the CKD population may be improved by establishing individual genetic/epigenetic profiles, thus enabling physicians to design an individualized therapeutic strategy. Personalized medicine based on a more individualized therapy could be applied in, for example, pharmacotherapy (CYP genes), dialysis therapy, and nutritional and lifestyle modifications

Telomere attrition is associated with inflammation, low fetuin-A levels and high mortality in prevalent haemodialysis patients

&lt;p&gt;Introduction.  Chronic kidney disease (CKD) predisposes to a 10- to 20-fold increased cardiovascular risk. Patients undergo accelerated atherogenesis and vascular ageing. We investigated whether telomere attrition, a marker of cell senescence, contributes to this increased mortality risk.&lt;/p&gt; &lt;p&gt;Methods.  This is a cross-sectional study in prevalent haemodialysis patients [n = 175; 98 Males; median (range) age: 66 (23–86) years]. Biochemical markers of oxidative stress and inflammatory status were measured in relation to the patient’s leucocyte telomere length. Overall mortality was assessed after a median of 31 (range 2–42) months.&lt;/p&gt; &lt;p&gt;Results.  Telomere length was shorter in CKD men, despite women being older (average ± SD 6.41 ± 1.23 vs. 6.96 ± 1.48 kb, P = 0.002). Telomere length was associated with age (rho = −0.18, P = 0.01), fetuin-A (rho = 0.26, P = 0.0004), high-sensitivity C-reactive protein (rho = −0.21, P = 0.005) and IL-6 (rho = −0.17, P = 0.02). In a multivariate logistic regression (pseudo r2 = 0.14), telomere length was associated with age &#x3E; 65 years (odds ratio: 2.11; 95% CI: 1.10, 4.06), sex (2.01; 1.05, 3.86), fetuin-A (1.85; 0.97, 3.50) and white blood cell count (2.04; 1.02, 4.09). Receiver operating characteristic curves identified a telomere length &#x3C; 6.28 kb as a fair predictor of mortality. Finally, reduced telomere length was associated with increased mortality, independently of age, gender and inflammation (likelihood ratio 41.6, P &#x3C; 0.0001), but dependently on fetuin-A levels.&lt;/p&gt; &lt;p&gt;Conclusion.  Age and male gender seem to be important contributors to reduced telomere length in CKD patients, possibly via persistent inflammation. Reduced telomere length also contributes to the mortality risk of these patients through pathways that could involve circulating levels of fetuin-A.&lt;/p&gt