VEGF levels in healthy volunteers and cancer patients.

<p>Controls; healthy volunteers; Non-RCC; non-renal carcinoma patients; RCC; renal cell carcinoma patients. VEGF levels in median [interquartile range].</p

TAFI deficiency does not improve outcome after experimental stroke in mice.

<p>Infarct size and functional outcome in <i>TAFI^-/-</i> mice and controls (WT, wild-type) 24h after 60 min transient middle cerebral artery occlusion (tMCAO). (A) (top) Representative 2,3,5-Triphenyltetrazoliumchloride (TTC)-stained coronal brain sections from the two animal groups. Ischemic infarctions appear white and regularly include the neocortex and basal ganglia as confirmed by hematoxylin and eosin (H&E) staining (bar represents 250 µm, dotted white line indicates the border between the cortex and the basal ganglia). (bottom) Infarct volumes on day 1 after tMCAO in <i>TAFI^-/-</i> mice and controls as determined by planimetry (n = 11–12/group). Non-parametric Mann Whitney test. (B) Neurological Bederson score and grip test score on day 1 after tMCAO in <i>TAFI^-/-</i> mice and controls. In line with the results on infarct volumes, no significant functional differences became apparent. Non-parametric Mann Whitney test (C) Accumulation of fibrin(ogen) in the infarcted (+) and contralateral (−) cortices of <i>TAFI^-/-</i> mice and controls. Fibrin(ogen) was analyzed by immunoblotting 24 h after ischemia. Two representative immunoblots of each group are shown.</p

Scatter plot presentation of the distribution of β-TG and PF4.

<p>A) β-TG and PF4 measured in PECT plasma of cancer patients compared to controls. B) β-TG and PF4 measured in platelets of cancer patients compared to controls. Bars represent the medians.</p

rCBF and the anatomy of the cerebral vasculature do not differ between <i>TAFI^-/-</i> mice and controls.

<p>(A) Determination of regional cerebral blood flow (rCBF) using Laser Doppler flowmetry before the occlusion of the middle cerebral artery (baseline), 10 min after the occlusion (ischemia) and again 10 min after the removal of the filament (reperfusion) in <i>TAFI^-/-</i> mice and wild-type controls (n = 4/group). No significant differences in rCBF were observed between the two groups. 1-way ANOVA, Bonferroni post hoc test. (B) Assessment of the cerebral vasculature in wild-type and <i>TAFI^-/-</i> mice. A complete Circle of Willis (white arrows) was identified in all animals studied and the distribution of the MCA trunk and branch appeared to be anatomically identical among the genotypes.</p

VEGF levels in cancer patients and controls.

<p>A) VEGF-levels measured in citrate plasma of cancer patients compared to healthy persons. B) VEGF-levels measured in PECT plasma of cancer patients compared to healthy persons. C) VEGF levels measured in platelets of cancer patients versus healthy persons. Bars represent the medians.</p

Correlation between VEGF and PF4 in citrate plasma in cancer patients and controls.

<p>VEGF and PF4 measured in citrate plasma correlated significantly (r = 0.457, p = 0.008).</p

Platelet and platelet activation parameters.

<p>Controls; healthy volunteers; Non-RCC; non-renal carcinoma patients. VEGF levels in median [interquartile range].</p

Whole exome sequencing in thrombophilic pedigrees to identify genetic risk factors for venous thromboembolism

<div><p>Background</p><p>Family studies have shown a strong heritability component for venous thromboembolism (VTE), but established genetic risk factors are present in only half of VTE patients.</p><p>Aim</p><p>To identify genetic risk factors in two large families with unexplained hereditary VTE.</p><p>Methods</p><p>We performed whole exome sequencing in 10 affected relatives of two unrelated families with an unexplained tendency for VTE. We prioritized variants shared by all affected relatives from both families, and evaluated these in the remaining affected and unaffected individuals. We prioritized variants based on 3 different filter strategies: variants within candidate genes, rare variants across the exome, and SNPs present in patients with familial VTE and with low frequency in the general population. We used whole exome sequencing data available from 96 unrelated VTE cases with a positive family history of VTE from an affected sib study (the GIFT study) to identify additional carriers and compared the risk-allele frequencies with the general population. Variants found in only one individual were also retained for further analysis. Finally, we assessed the association of these variants with VTE in a population-based case-control study (the MEGA study) with 4,291 cases and 4,866 controls.</p><p>Results</p><p>Six variants remained as putative disease-risk candidates. These variants are located in 6 genes spread among 3 different loci: 2p21 (<i>PLEKHH2</i> NM_172069:c.3105T>C, <i>LRPPRC</i> rs372371276, <i>SRBD1</i> rs34959371), 5q35.2 (<i>UNC5A</i> NM_133369.2:c.1869+23C>A), and 17q25.1 (<i>GPRC5C</i> rs142232982, <i>RAB37</i> rs556450784). In GIFT, additional carriers were identified only for the variants located in the 2p21 locus. In MEGA, additional carriers for several of these variants were identified in both cases and controls, without a difference in prevalence; no carrier of the <i>UNC5A</i> variant was present.</p><p>Conclusion</p><p>Despite sequencing of several individuals from two thrombophilic families resulting in 6 candidate variants, we were unable to confirm their relevance as novel thrombophilic defects.</p></div

Candidate variants genotyped in MEGA.

<p>Candidate variants genotyped in MEGA.</p

Number of variants located in autosomes retained after each filter step.

<p>Abbreviations: SNPs, single nucleotide variants/polymorphisms; INDELs, insertions and deletions; MAF, minor allele frequency; GoNL, Genome of the Netherlands project database, 498 unrelated Dutch individuals; EA, NHLBI Exome Sequencing Project database, 4,300 European-American unrelated individuals; 1000G, 1000 Genomes Project, 2,500 individuals from about 25 populations around the world; VTE, venous thromboembolism; GIFT, Genetics In Familial Thrombosis study, 96 unrelated VTE cases with positive family history of VTE.</p