Adriano Henney

• PhD, Medicine
• CEO at Avicenna Alliance for Predictive Medicine

The term ‘in silico clinical trials indicates the use of individualised computer simulation in the development or regulatory evaluation of a medicinal product, medical device, or medical intervention. This review article summarises the research and technological roadmap developed by the Avicenna Support Action during an 18 month consensus process t...

The term ‘in silico clinical trials’ refers to: “The use of individualised computer simulation in the development or regulatory evaluation of a medicinal product, medical device, or medical intervention.” While computer simulation is widely used for the development and de-risking of a number of ‘mission-critical’ products such as civil aircraft, nu...

Biological responses are determined by information processing at multiple and highly interconnected scales. Within a tissue the individual cells respond to extracellular stimuli by regulating intracellular signaling pathways that in turn determine cell fate decisions and influence the behavior of neighboring cells. As a consequence the cellular res...

Adriano Henney speaks to Hannah Coaker, Commissioning Editor. After achieving a PhD in medicine and spending many years in academic research in the field of cardiovascular disease, Adriano Henney was recruited by Zeneca Pharmaceuticals from a British Heart Foundation Senior Fellowship, where he led the exploration of new therapeutic approaches in a...

The liver is the central detoxifying organ, continuously removing xenobiotics from the vascular system. Given its role in drug metabolism, a functional understanding of liver physiology is crucial to optimizing drug efficacy and patient safety. The Virtual Liver Network (VLN), a German national flagship research program, focuses on producing valida...

Despite wide-spread consensus on the need to transform toxicology and risk assessment in order to keep pace with technological and computational changes that have revolutionized the life sciences, there remains much work to be done to achieve the vision of toxicology based on a mechanistic foundation. A workshop was organized to explore one key asp...

Despite wide-spread consensus on the need to transform toxicology and risk assessment in order to keep pace with technological and computational changes that have revolutionized the life sciences, there remains much work to be done to achieve the vision of toxicology based on a mechanistic foundation. To this end, a workshop was organized to explor...

The concept of personalized medicine is not new. It is being discussed with increasing interest in the medical, scientific, and general media because of the availability of advanced scientific and computational technologies, and the promise of the potential to improve the targeting and delivery of novel medicines. It is also being seen as one appro...

The liver is the central metabolic organ in human physiology, with functions that are fundamentally important to the detoxification of xenobiotics (drugs), the maintenance of homeostasis of numerous blood metabolites, and the production of mediators of the acute phase response. Liver toxicity, whether actual or implied is the reason for the failure...

No abstract available.

In 2002, the Editorial that accompanied the launch of Nature Reviews Drug Discovery stated that “[d]espite all the excitement that accompanies each wave of technical innovation, from protein structure determination to proteomics, and from combinatorial chemistry to e‐clinical trials, the fundamental truth is that pharmaceutical companies are not pr...

The main conclusion is that systems biology approaches can indeed advance cancer research, having already proved successful in a very wide variety of cancer‐related areas, and are likely to prove superior to many current research strategies. Major points include: Systems biology and computational approaches can make important contributions to resea...

With the right plan, systems biology can empower drug discovery, say Adriano Henney and Giulio Superti-Furga. Field leaders have contributed and now the authors want to hear from you.

The rapid expansion of biomedical information following the mapping of the human genome has contributed to significant advances in acquiring a highly detailed picture of disease mechanisms at the molecular level. This revolution in biomedical science has also generated hope and expectation for the delivery of novel treatments for serious illnesses....

Atherosclerosis is an example of a complex trait, where the course of the disease is influenced by a combination of common variation in a constellation of genes and the effect of a wide range of environmental variables. Thus, the underlying disease mechanisms will be modulated by genetic diversity and the effect this diversity has on an individual'...

The remodelling of connective tissue matrices is fundamentally important for normal growth and development, as well as for the repair and maintenance of the functional integrity of tissues. These remodelling processes are tightly controlled to maintain a fine balance between the extracellular matrix-degrading enzymes and their inhibitors and thus r...

Matrix metalloproteinases (MMPs) and their inhibitors are important in connective tissue re-modelling in diseases of the cardiovascular system, such as atherosclerosis. Various members of the MMP family have been shown to be expressed in atherosclerotic lesions, but MMP9 is consistently seen in inflammatory atherosclerotic lesions. MMP9 over-expres...

The essential role of genes is in encoding structural proteins and enzymes which enable the cell or organism to maintain homeostasis in the face of the environmental challenges experienced (1). DNA containing such genetic information varies from one species to another. Even within a species, there are interindividual differences in DNA sequence, gi...

The matrix Gla protein (MGP) is an important inhibitor of vessel and cartilage calcification that is strongly expressed in human calcified, atherosclerotic plaques and could modulate plaque calcification and coronary heart disease risk. Using a genetic approach, we explored this possibility by identifying polymorphisms of the MGP gene and testing t...

Atherosclerosis is an example of a complex trait, where the course of the disease is influenced by a combination of common variation in a constellation of genes and the effect of a wide range of environmental variables. Thus, the underlying disease mechanisms will be modulated by genetic diversity and the effect this diversity has on an individual'...

Both the processes of atherosclerosis and plaque rupture are indicated to be influenced by matrix metalloproteinase (MMP) activity. We therefore searched for common functional variation in the matrix metalloelastase (MMP-12) gene locus that may be implicated in coronary artery disease. Single-strand conformation polymorphism analysis of DNA from he...

Allelic association methods are better suited than linkage analysis for mapping of susceptibility genes that confer modest increases in risk in complex diseases. In both family- and population-based association studies, it is very useful to have prior knowledge of all sequence variants and the degree of linkage disequilibrium in a candidate gene re...

Allelic association methods are better suited than linkage analysis for mapping of susceptibility genes that confer modest increases in risk in complex diseases. In both family- and population-based association studies, it is very useful to have prior knowledge of all sequence variants and the degree of linkage disequilibrium in a candidate gene re...

One of the earliest events in the formation of an atherosclerotic lesion is the adherence of circulating monocytes to the vascular endothelium, through which they then gain entry to the sub-intimal tissue. This early lesion subsequently evolves over a number of years to form an atherosclerotic plaque, through the migration and proliferation of cell...

Matrix metalloproteinase expression is under strict regulation in physiological conditions. Disruption of the regulatory mechanisms can lead to tissue destruction and is associated with tumour invasion and metastasis. Using the one-hybrid assay technique with a cis-element in the promoter region of the stromelysin (matrix metalloproteinase-3) gene,...

Gelatinase B, a matrix metalloproteinase that has proteolytic activity against connective tissue proteins, has been suggested to be important in the connective tissue remodeling processes associated with atherogenesis and plaque rupture. This study tested the hypothesis that sequence variation in the promoter region of the gelatinase B gene influen...

It has proved difficult to identify high-risk patients for atherosclerosis and to determine how they might respond to medication. Recently, a common promoter variant of the human stromelysin-1 gene has been reported, which has been shown to affect the transcription. We investigated whether this polymorphism had any impact on the risk of events, esp...

Over the last 15 years, there has been remarkably rapid progress in defining the molecular basis of inherited disorders. Many disease genes (the majority of which are genes responsible for monogenic Mendelian diseases) have now been identified, predominately through linkage analysis and positional cloning approaches. With the continuing expansion i...

1. The matrix metalloproteinases are a family of at least 16 zinc-dependent endopeptidases possessing catalytic activity against extracellular matrix components. Some members of this family have been implicated in vascular matrix remodelling in the pathogenesis of atherosclerosis. 2. A common, naturally occurring variant has been identified in the...

To investigate whether variation in the fibrillin-1 gene was associated with blood pressure in healthy middle aged men, as had been observed in patients with abdominal aortic aneurysm. Middle aged men (n = 245), aged 50 to 61 years, were recruited from one of the nine general practices participating in the second Northwick Park heart study. Blood s...

The temporal relationship of matrix metalloproteinases (MMPs) and a specific tissue inhibitor (TIMP-1) has been examined by reverse transcription-polymerase chain reaction and substrate zymography, after balloon catheter angioplasty of the rat carotid artery. The contralateral uninjured carotid artery was used as a comparative control. Of the MMPs...

Background: Recently, an association was reported between the progression of atherosclerosis and a common promoter variant, which has been shown to affect the transcription of the human stromelysin-1 gene, an enzyme involved in connective tissue turnover. Aim: To assess whether this genetic variant confers any measurable risk of the progression of...

Extracellular matrix breakdown is likely to be essential for the migration and proliferation of vascular smooth muscle cells (VSMC) in angioplasty restenosis. Tissue inhibitor of metalloproteinases- 1 (TIMP-1) potently inhibits the matrix metalloproteinase enzymes. A recombinant replication deficient adenoviral vector Av1.TIMP-1 containing the cDNA...

Debate as to whether abdominal aortic aneurysms (AAA) are caused by atherosclerosis or whether they have a strong genetic etiology continues. We have investigated the hypothesis that risk factors are likely to be strongest in patients with generalized aneurysmal disease. We screened 232 consecutive AAA patients for popliteal aneurysm and investigat...

To screen patients with abdominal aortic aneurysm for popliteal aneurysm and investigate cardiovascular and genetic risk factors associated with aneurysmal disease at more than one site (generalised aneurysmal disease). SUBJECTS, DESIGN AND SETTING: All patients referred to the Regional Vascular Surgical Service at Charing Cross Hospital with unrup...

There is a common polymorphism in the promoter sequence of the human stromelysin-1 gene, with one allele having a run of six adenosines (6A) and the other five adenosines (5A). We have previously reported, in a 3-year follow-up study of patients with coronary atherosclerosis, that those patients who are homozygous for the 6A allele show a more rapi...

There is a common polymorphism in the promoter sequence of the human stromelysin-1 gene, with one allele having a run of six adenosines (6A) and the other five adenosines (5A), We have previously reported, in a 3-year follow-up study of patients with coronary atherosclerosis, that those patients who are homozygous for the 6A allele show a more rapi...

The vessel wall is an integrated functional component of the circulatory system that is continually remodeling in response to hemodynamic conditions and disease states. The endothelium releases locally active mediators, such as nitric oxide and endothelin, which have immediate vasoactive properties and longer-term trophic effects on the medial SMCs...

Stromelysin is a member of the family of metalloproteinases that degrade extracellular matrix. In situ hybridisation and histopathological studies suggest that stromelysin activity may be important in the connective tissue remodelling processes associated with atherogenesis and plaque rupture. Single strand conformation polymorphism analysis identi...

Proteolytic imbalance may play a role in the pathogenesis of abdominal aortic aneurysms (AAA). CLG4B, which encodes the 92-kDa form of type IV collagenase, is a candidate gene for AAA. We genotyped a polymorphic dinucleotide repeat in the 5' flanking region of CLG4B in 94 unrelated Caucasian controls and in 127 unrelated Caucasian AAA cases. Eight...

Type III collagen contributes to the tensile strength of the aortic wall, and mutations in the type III collagen gene have been suggested as the basis for the familial tendency to abdominal aortic aneurysm (AAA). Variation in this gene was investigated in 153 patients with AAA, 87 with aortoiliac stenosis and 98 age-matched controls. The rare mutat...

Informative polymorphisms have been very difficult to detect in the elastin gene, and this has hampered the analysis of heritable connective tissue disorders, notably the Marfan syndrome. We have recently detected a dinucleotide repeat polymorphism in intron 17 of the human elastin gene consisting of 8 alleles with sizes between 161 and 175 bp. Ana...

We have detected a common (allele frequency 0.53/0.47) single base pair insertion/deletion polymorphism 675 base pairs upstream from the start of transcription of the plasminogen activator inhibitor-1 (PAI-1) gene, using the chemical cleavage mismatch analysis. "Band shift assays" suggest that the allele with the single base pair insertion contains...

Abdominal aortic aneurysm (AAA) is a disorder that mainly affects the elderly. The prevalence of aneurysmal disease has rapidly increased in individuals aged over 55. Rupture is a common cause of sudden death, and emergency repair has a high risk (40-50%) of perioperative mortality. By contrast, the risk associated with elective resection is substa...

Plasminogen activator inhibitor-1 (PAI-1) is a rapid inhibitor of tissue plasminogen (tPA) in vivo. Evidence suggests that the level of plasma PAI-1 activity is responsible for the regulation of the whole fibrinolytic process through this tPA/PAI-1 interaction. Levels of PAI-1 have therefore emerged as a candidate for a thrombotic risk factor. Rece...

Raised plasma levels of fibrinogen, factor VIIc, and plasminogen activator inhibitor-1 (PAI-1) are associated with an increased risk of ischemic heart disease. Levels of these proteins are determined in part by environmental influences such as smoking and dietary fat intake. However, genetic variation explains much of the interindividual variation...

We carried out a segregation analysis comparing the inheritance of collagen gene markers and joint hypermobility syndrome in two extended families. Our results exclude the genes encoding type III (COL3A1), type V alpha 2 chain (COL5A2) and type VI alpha 3 chain (COL6A3) unambiguously in both families. The simultaneous exclusion of both the type 1 a...

The stromelysins are members of a family of extracellular matrix metalloproteinases. These enzymes may erode the connective tissue in atherosclerotic plaques, leading to fissuring and acute thrombotic events. Cell-specific stromelysin expression in human atherosclerotic plaques was studied by in situ hybridization and immunocytochemistry. Sections...

Collagens provide the tensile strength of the aortic wall. Variations in collagen structure are recognised in Ehlers Danlos syndrome type IV and could also be associated with a predisposition to aortic aneurysm. The frequency of some minor genetic variants of type III collagen, present in the normal population, can be detected by restriction enzyme...

Plasminogen activator inhibitor-1 (PAI-1), a rapid inhibitor of tissue-type plasminogen activator, has been shown to be an independent risk factor for recurrent myocardial infarction (MI) at a young age. To investigate whether genetic variation in the PAI-1 gene is affecting plasma PAI-1 levels, a sample of 145 patients with an MI before the age of...

A marker for genetic variation at the PAI-1 locus was used to assess the contribution of genetic variation to between individual variances in plasma PAI-1 activity. This was done for two samples, a group of 107 young myocardial infarction patients and a group of 95 controls.

We have isolated and characterized portions of the alpha 1 (IX) collagen gene from mouse and human DNA. Nucleotide sequence analysis and comparison with the chicken gene suggest that the mammalian genes contain an alternative exon that is located within the intron between exons 6 and 7. Using oligonucleotide primers specific for exons 4, 8, and the...

1. There is a familial tendency to abdominal aortic aneurysms. We have followed up a previous report of a weak association between the haptoglobin 2-1 phenotype and aortic aneurysm and investigated polymorphisms of the haptoglobin gene and neighbouring cholesterol ester transfer protein gene on the long arm of chromosome 16 in patients with atheros...

DNA markers were used to assess the segregation of genes encoding the collagen types that predominate in the mitral valve (types I, III, and V) in two family pedigrees that are phenotypically different but showed dominantly inherited mitral valve prolapse. The inheritance of these markers was compared with the segregation of the phenotype for mitra...

Analysis of the conditioned medium from cultured human heart valves showed that these tissues secrete a biologically active factor that induces chondrocytes in cultured cartilage to degrade extracellular matrix proteoglycan. This activity was similar to that described for porcine interleukin-1 (catabolin) and a cytokine secreted by cultured porcine...

Cultured porcine heart valves secrete a factor that induces cells to degrade their extracellular matrix. This activity was routinely monitored by measuring the release of glycosaminoglycans from proteoglycan in cultured bovine nasal cartilage. It was observed that factor-mediated matrix degradation was dose dependent and required live target cells,...

A cardiac catabolic factor (CCF) has been partially purified from serum-free medium conditioned by minced porcine heart valves. CCF was prepared by a series of chromatographic techniques and compared directly with porcine synovial catabolin purified by the same protocol. CCF displayed a somewhat higher molecular weight (Mr 21,000) and isoelectric p...

Absolute rates of collagen and non-collagen protein synthesis were measured in organ cultures of normal, rheumatic and floppy heart valves. The incorporation of 14C-proline into the cultures was measured and standardised according to the specific activity of the isotope in the tissue and the amount of DNA present. It was observed that the mean rate...

Viability of human heart valves obtained routinely at necropsy was compared with that of antibiotic sterilised bank allografts and pathological valves, obtained at surgery, by assessing DNA and protein synthesis and tissue culture. None of the post-mortem samples nor any of the bank allografts showed viability comparable with that of surgical mater...

The main conclusion is that systems biology approaches can indeed advance cancer research, having already proved successful in a very wide variety of cancer-related areas, and are likely to prove superior to many current research strategies. Major points include: • Systems biology and computational approaches can make important contributions to res...