Systematic review and meta-analysis of the risk of severe and life-threatening thromboembolism in cancer patients receiving anti-EGFR monoclonal antibodies (cetuximab or panitumumab)

Cancer-associated thromboembolism is a substantial problem in clinical practice. An increase in the level of fibrinopeptide A (a substance associated with hypercoagulable states) has been observed in humans exposed to fluorouracil. Anti-EGFR monoclonal antibodies cetuximab and panitumumab, which are now widely used in patients with metastatic colorectal cancer, could prolong the uncovering of endothelial structures resulting from flouorouracil or other co-administered agents, thus favouring several factors leading to thromboembolism. We performed a systematic review and meta-analysis of randomised, controlled trials assessing whether cancer patients receiving anti-EGFR monoclonal antibodies cetuximab and panitumumab are at increased risk of thromboembolic events. We searched electronic databases (Medline, Embase, Web of Science, Central) and reference lists. Phase II/III randomised, controlled trials comparing standard anti-cancer regimens with or without anti-EGFR monoclonal antibodies and reporting serious venous thromboembolic events were included in the analysis. Seventeen studies (12,870 patients) were considered for quantitative analysis. The relative risk (RR) for venous thromboembolism (18 comparisons) was 1.46 (95% CI 1.26 to 1.69); the RR of pulmonary embolism, on the basis of eight studies providing nine comparisons, was 1.55 (1.20 to 2.00). Cancer patients receiving anti-EGFR monoclonal antibodies-containing regimens are approximately 1.5 times more likely to experience venous or pulmonary embolism, compared to those treated with the same regimens without anti-EGFR monoclonal antibodies. Clinicians should consider patient's baseline thromboembolic risk when selecting regimens that include cetuximab or panitumumab. Potential non-reporting of these important adverse events remains a concern. PROSPERO registration number is CRD42014009165

The Viscoelastic Properties of Passive Eye Muscle in Primates. II: Testing the Quasi-Linear Theory

We have extensively investigated the mechanical properties of passive eye muscles, in vivo, in anesthetized and paralyzed monkeys. The complexity inherent in rheological measurements makes it desirable to present the results in terms of a mathematical model. Because Fung's quasi-linear viscoelastic (QLV) model has been particularly successful in capturing the viscoelastic properties of passive biological tissues, here we analyze this dataset within the framework of Fung's theory

Subtype Specificity of Genetic Loci Associated With Stroke in 16 664 Cases and 32 792 Controls

Background: Genome-wide association studies have identified multiple loci associated with stroke. However, the specific stroke subtypes affected, and whether loci influence both ischemic and hemorrhagic stroke, remains unknown. For loci associated with stroke, we aimed to infer the combination of stroke subtypes likely to be affected, and in doing so assess the extent to which such loci have homogeneous effects across stroke subtypes. Methods: We performed Bayesian multinomial regression in 16 664 stroke cases and 32 792 controls of European ancestry to determine the most likely combination of stroke subtypes affected for loci with published genome-wide stroke associations, using model selection. Cases were subtyped under 2 commonly used stroke classification systems, TOAST (Trial of Org 10172 Acute Stroke Treatment) and causative classification of stroke. All individuals had genotypes imputed to the Haplotype Reference Consortium 1.1 Panel. Results: Sixteen loci were considered for analysis. Seven loci influenced both hemorrhagic and ischemic stroke, 3 of which influenced ischemic and hemorrhagic subtypes under both TOAST and causative classification of stroke. Under causative classification of stroke, 4 loci influenced both small vessel stroke and intracerebral hemorrhage. An EDNRA locus demonstrated opposing effects on ischemic and hemorrhagic stroke. No loci were predicted to influence all stroke subtypes in the same direction, and only one locus (12q24) was predicted to influence all ischemic stroke subtypes. Conclusions: Heterogeneity in the influence of stroke-associated loci on stroke subtypes is pervasive, reflecting differing causal pathways. However, overlap exists between hemorrhagic and ischemic stroke, which may reflect shared pathobiology predisposing to small vessel arteriopathy. Stroke is a complex, heterogeneous disorder requiring tailored analytic strategies to decipher genetic mechanisms

Subtype Specificity of Genetic Loci Associated With Stroke in 16 664 Cases and 32 792 Controls

Background: Genome-wide association studies have identified multiple loci associated with stroke. However, the specific stroke subtypes affected, and whether loci influence both ischemic and hemorrhagic stroke, remains unknown. For loci associated with stroke, we aimed to infer the combination of stroke subtypes likely to be affected, and in doing so assess the extent to which such loci have homogeneous effects across stroke subtypes. Methods: We performed Bayesian multinomial regression in 16 664 stroke cases and 32 792 controls of European ancestry to determine the most likely combination of stroke subtypes affected for loci with published genome-wide stroke associations, using model selection. Cases were subtyped under 2 commonly used stroke classification systems, TOAST (Trial of Org 10172 Acute Stroke Treatment) and causative classification of stroke. All individuals had genotypes imputed to the Haplotype Reference Consortium 1.1 Panel. Results: Sixteen loci were considered for analysis. Seven loci influenced both hemorrhagic and ischemic stroke, 3 of which influenced ischemic and hemorrhagic subtypes under both TOAST and causative classification of stroke. Under causative classification of stroke, 4 loci influenced both small vessel stroke and intracerebral hemorrhage. An EDNRA locus demonstrated opposing effects on ischemic and hemorrhagic stroke. No loci were predicted to influence all stroke subtypes in the same direction, and only one locus (12q24) was predicted to influence all ischemic stroke subtypes. Conclusions: Heterogeneity in the influence of stroke-associated loci on stroke subtypes is pervasive, reflecting differing causal pathways. However, overlap exists between hemorrhagic and ischemic stroke, which may reflect shared pathobiology predisposing to small vessel arteriopathy. Stroke is a complex, heterogeneous disorder requiring tailored analytic strategies to decipher genetic mechanisms

Representation of target-bound drugs by computed conformers: implications for conformational libraries

BACKGROUND: The increasing number of known protein structures provides valuable information about pharmaceutical targets. Drug binding sites are identifiable and suitable lead compounds can be proposed. The flexibility of ligands is a critical point for the selection of potential drugs. Since computed 3D structures of millions of compounds are available, the knowledge of their binding conformations would be a great benefit for the development of efficient screening methods. RESULTS: Integration of two public databases allowed superposition of conformers for 193 approved drugs with 5507 crystallised target-bound counterparts. The generation of 9600 drug conformers using an atomic force field was carried out to obtain an optimal coverage of the conformational space. Bioactive conformations are best described by a conformational ensemble: half of all drugs exhibit multiple active states, distributed over the entire range of the reachable energy and conformational space. A number of up to 100 conformers per drug enabled us to reproduce the bound states within a similarity threshold of 1.0 Å in 70% of all cases. This fraction rises to about 90% for smaller or average sized drugs. CONCLUSION: Single drugs adopt multiple bioactive conformations if they interact with different target proteins. Due to the structural diversity of binding sites they adopt conformations that are distributed over a broad conformational space and wide energy range. Since the majority of drugs is well represented by a predefined low number of conformers (up to 100) this procedure is a valuable method to compare compounds by three-dimensional features or for fast similarity searches starting with pharmacophores. The underlying 9600 generated drug conformers are downloadable from the Super Drug Web site [1]. All superpositions are visualised at the same source. Additional conformers (110,000) of 2400 classified WHO-drugs are also available

Mechanisms and treatment of ischaemic stroke: insights from genetic associations

The precise pathophysiology of ischaemic stroke is unclear, and a greater understanding of the different mechanisms that underlie large-artery, cardioembolic and lacunar ischaemic stroke subtypes would enable the development of more-effective, subtype-specific therapies. Genome-wide association studies (GWASs) are identifying novel genetic variants that associate with the risk of stroke. These associations provide insight into the pathophysiological mechanisms, and present opportunities for novel therapeutic approaches. In this Review, we summarize the genetic variants that have been linked to ischaemic stroke in GWASs to date and discuss the implications of these associations for both our understanding and treatment of ischaemic stroke. The majority of genetic variants identified are associated with specific subtypes of ischaemic stroke, implying that these subtypes have distinct genetic architectures and pathophysiological mechanisms. The findings from the GWASs highlight the need to consider whether therapies should be subtype-specific. Further GWASs that include large cohorts are likely to provide further insights, and emerging technologies will complement and build on the GWAS findings

Thermodynamic Basis for the Emergence of Genomes during Prebiotic Evolution

The RNA world hypothesis views modern organisms as descendants of RNA molecules. The earliest RNA molecules must have been random sequences, from which the first genomes that coded for polymerase ribozymes emerged. The quasispecies theory by Eigen predicts the existence of an error threshold limiting genomic stability during such transitions, but does not address the spontaneity of changes. Following a recent theoretical approach, we applied the quasispecies theory combined with kinetic/thermodynamic descriptions of RNA replication to analyze the collective behavior of RNA replicators based on known experimental kinetics data. We find that, with increasing fidelity (relative rate of base-extension for Watson-Crick versus mismatched base pairs), replications without enzymes, with ribozymes, and with protein-based polymerases are above, near, and below a critical point, respectively. The prebiotic evolution therefore must have crossed this critical region. Over large regions of the phase diagram, fitness increases with increasing fidelity, biasing random drifts in sequence space toward ‘crystallization.’ This region encloses the experimental nonenzymatic fidelity value, favoring evolutions toward polymerase sequences with ever higher fidelity, despite error rates above the error catastrophe threshold. Our work shows that experimentally characterized kinetics and thermodynamics of RNA replication allow us to determine the physicochemical conditions required for the spontaneous crystallization of biological information. Our findings also suggest that among many potential oligomers capable of templated replication, RNAs may have evolved to form prebiotic genomes due to the value of their nonenzymatic fidelity

COL4A2 is associated with lacunar ischemic stroke and deep ICH: Meta-analyses among 21,500 cases and 40,600 controls

Objective: To determine whether common variants in familial cerebral small vessel disease (SVD) genes confer risk of sporadic cerebral SVD. Methods: We meta-analyzed genotype data from individuals of European ancestry to determine associations of common single nucleotide polymorphisms (SNPs) in 6 familial cerebral SVD genes (COL4A1, COL4A2, NOTCH3, HTRA1, TREX1, and CECR1) with intracerebral hemorrhage (ICH) (deep, lobar, all; 1,878 cases, 2,830 controls) and ischemic stroke (IS) (lacunar, cardioembolic, large vessel disease, all; 19,569 cases, 37,853 controls). We applied data quality filters and set statistical significance thresholds accounting for linkage disequilibrium and multiple testing. Results: A locus in COL4A2 was associated (significance threshold p , 3.5 3 1024) with both lacunar IS (lead SNP rs9515201: odds ratio [OR] 1.17, 95%confidence interval [CI] 1.11-1.24, p 56.62 31028) and deep ICH (lead SNP rs4771674: OR 1.28, 95%CI 1.13-1.44, p 55.76 3 1025). A SNP in HTRA1 was associated (significance threshold p , 5.5 3 1024) with lacunar IS (rs79043147: OR 1.23, 95%CI 1.10-1.37, p 5 1.90 3 1024) and less robustly with deep ICH. There was no clear evidence for association of common variants in either COL4A2 or HTRA1 with non-SVD strokes or in any of the other genes with any stroke phenotype