Chemokine receptor antagonists that held much promise for the treatment of autoimmune and inflammatory diseases have recently performed poorly in clinical trials, resulting in disappointment for both pharmaceutical companies and patients. This review focuses on the redundancy of the molecular target as one potential reason for the failure of some of these antagonists to fulfil their initial promise, and discusses the use of drugs that are capable of interacting with more than one drug target – so-called promiscuous drugs – as possible approaches to overcome this difficulty. Several clinically approved promiscuous drugs, such as aspirin and olanzapine, are already used successfully. This review discusses examples of promiscuous drugs for G-protein-coupled receptors, including progress in developing dual-specific chemokine receptor antagonists, and considers evidence for the possible therapeutic utility of such drugs.

Thrombosis is a common disorder with a relevant burden of morbidity and mortality worldwide, particularly among elderly patients. Growing evidence demonstrated a direct role of oxidative stress in thrombosis, with various cell types contributing to this process. Among them, erythrocytes produce high quantities of intracellular reactive oxygen species (ROS) by NADPH oxidase activation and haemoglobin autoxidation. Concomitantly, extracellular ROS released by other cells in the blood flow can be uptaken and accumulate within erythrocytes. This oxidative milieu can alter erythrocyte membrane structure, leading to an impaired erythrocyte function, and promoting erythrocytes lysis, binding to endothelial cells, activation of platelet and of coagulation factors, phosphatidylserine exposure and release of microvesicles. Moreover, these abnormal erythrocytes are able to adhere to the vessel wall, contributing to thrombin generation within the thrombus. This process results in accelerated haemolysis and in a hypercoagulable state, in which structurally impaired erythrocytes contribute to increase thrombus size, to reduce its permeability and susceptibility to lysis. However, the wide plethora of mechanisms by which oxidised erythrocytes contribute to thrombosis is not completely elucidated. This review discusses the main biochemical aspects linking erythrocytes, oxidative stress and thrombosis, addressing their potential implication for clinical and therapeutic management.

Haematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for many patients with malignant and non-malignant haematological diseases. The success of HSCT is greatly reduced by the development of complications, which include graft-versus-host disease (GVHD), relapse and infection. Human leukocyte antigen (HLA) matching of patients and donors is essential, but does not completely prevent these complications; non-HLA genes may also have an impact upon transplant outcome. Polymorphisms within genes that are associated with an individual's capability to mount an immune response to alloantigen and infectious pathogens and/or response to drugs (pharmacogenomics) are all currently being studied for their association with HSCT outcome. This review summarises the potential role of non-HLA polymorphisms in predicting HSCT outcome, from studies on retrospective transplant cohorts of HLA-identical siblings and matched unrelated donors. The clinical relevance and interpretation of non-HLA genetics, and how these could be used alongside clinical risk factors in HSCT, are also discussed.

The analysis of cell-free fetal nucleic acids in maternal blood for prenatal diagnosis has been transformed by several recent profound technology developments. The most noteworthy of these are ‘digital PCR’ and ‘next-generation sequencing’ (NGS), which might finally deliver the long-sought goal of noninvasive detection of fetal aneuploidy. Recent data, however, indicate that NGS might even be able to offer a much more detailed appraisal of the fetal genome, including paternal and maternal inheritance of point mutations for mendelian disorders such as β-thalassaemia. Although these developments are very exciting, in their current form they are still too complex and costly, and will need to be simplified considerably for their optimal translation to the clinic. In this regard, targeted NGS does appear to be a step in the right direction, although this should be seen in the context of ongoing progress with the isolation of fetal cells and with proteomic screening markers.

The pleiotropic nature of the clinical phenotypes of patients with ataxia-telangiectasia (A-T) – which encompass cerebellar degeneration (leading to ataxia), gonadal atrophy, and cancer predisposition – suggests multiple functions of the gene responsible for the disease. The ataxia-telangiectasia mutated gene product (ATM), whose loss of function is responsible for ataxia-telangiectasia, is a protein kinase that interacts with several substrates and is implicated in mitogenic signal transduction, chromosome condensation, meiotic recombination, cell-cycle control and telomere maintenance. This review focuses on the critical roles that ATM appears to play in cell-cycle checkpoints, DNA repair, telomere metabolism and oxidative stress, indicating how defects in these processes might lead to ataxia-telangiectasia.

von Hippel–Lindau (VHL) disease is a dominantly inherited cancer syndrome characterised by predisposition to multiple tumours of the eyes and central nervous system (haemangioblastomas), kidneys (renal cell carcinoma; RCC), adrenal chromaffin cells (phaeochromocytoma), and other organs. The VHL gene was isolated in 1993 and mutations or deletions in the VHL gene have been identified in the germline of nearly all tested individuals with VHL disease. Genotype–phenotype correlations have been observed: individuals with missense mutations are more likely to develop phaeochromocytoma than those with deletions or protein-truncating mutations are, and specific missense mutations at certain codons might not predispose to RCC. In accordance with its role as a tumour suppressor gene, the normal allele of the VHL gene is deleted, mutated or silenced by promoter methylation in the tumours from VHL patients, and in a large proportion of sporadic tumours of the same histological types as observed in VHL disease. Thus, the VHL gene is of major importance in the development of RCC in the general population. Recent advances in understanding the structure and function of the VHL protein (pVHL) have revealed insights into the different phenotypes, with indications that some retention of function might be required for predisposition to phaeochromocytoma. pVHL interacts with many cellular proteins, mainly via one of two protein-binding domains (α and β). The best-characterised interaction is that of pVHL with elongin C, which forms a complex with elongin B and Cullin 2 proteins. This complex has E3 ubiquitin ligase activity and promotes ubiquitin-mediated proteasomal degradation of the hypoxia-inducible factor 1α (HIF-1α) transcription factor under normal oxygen (normoxic) conditions. Loss of pVHL function leads to stabilisation of HIF-1 and expression under normoxic conditions of hypoxia-inducible genes including vascular endothelial growth factor (VEGF), which might explain the hypervascular phenotype of VHL tumours. Several other genes implicated in intra- and intercellular signalling and control of tumour growth are overexpressed in the absence of pVHL, but it is not yet clear which features of pVHL function are most significant for tumour suppression in different tissues. Further advances in understanding pVHL function might eventually enable development of specific therapies for prevention or treatment of VHL tumours and RCC.

Sorsby's fundus dystrophy (SFD) is a rare autosomal dominant disorder that results in degeneration of the macular region of the retina, with onset usually in the fourth to fifth decade of life. It leads to the rapid loss of central vision, often followed by further loss of peripheral vision. SFD shares several pathological features commonly found in the ‘wet’ or exudative form of age-related macular degeneration (AMD), the most common cause of blindness in the elderly in developed countries. These phenotypic similarities have led to SFD being proposed as an acceptable genetic model for AMD. Whereas AMD appears to have a complex aetiology, with both genetic and environmental factors playing a role, SFD has been shown to be a single-gene disorder, linked to mutations in exon 5 of the tissue inhibitor of metalloproteinases 3 (TIMP3) gene on chromosome 22q12-q13. This review confines itself to a discussion of the known biochemical properties of the wild-type and SFD TIMP3 proteins and attempts to relate these to the pathology encountered in SFD patients. We also discuss briefly how, despite the lack of inherited mutations in the structural gene, the TIMP3 protein might play a role in the onset and progression of AMD.

Autism, at its most extreme, is a severe neurodevelopmental disorder, and recent studies have indicated that autism spectrum disorders are considerably more common than previously supposed. However, although one of the most heritable neuropsychiatric syndromes, autism has so far eluded attempts to discover its genetic origins in the majority of cases. Several whole-genome scans for autism-susceptibility loci have identified specific chromosomal regions, but the results have been inconclusive and fine mapping and association studies have failed to identify the underlying genes. Recent advances in knowledge from the Human Genome and HapMap Projects, and progress in technology and bioinformatic resources, have aided study design and made data generation more efficient and cost-effective. Broadening horizons about the landscape of structural genetic variation and the field of epigenetics are indicating new possible mechanisms underlying autism aetiology, while endophenotypes are being used in an attempt to break down the complexity of the syndrome and refine genetic data. Although the genetic variants underlying idiopathic autism have proven elusive so far, the future for this field looks promising.

There has been an alarming increase in the incidence of autoimmune and allergic diseases in Western countries in the past few decades. However, in countries endemic for parasitic helminth infections, such diseases remain relatively rare. Hence, it has been hypothesised that helminths may protect against the development of autoimmunity and allergy. This article reviews the evidence supporting this idea with respect to helminths of the phylum Nematoda (nematodes), considering data from human studies and animal models of inflammatory disease. The nature and mode of action of nematode-derived molecules with immunomodulatory properties are considered, and their therapeutic efficacy in models of autoimmunity and allergy described. The recent and future use of nematodes and their products in treating human disease are also discussed.

Recent progress in understanding the molecular mechanisms of the initiation and progression of melanoma has created new opportunities for developing novel therapeutic modalities to manage this potentially lethal disease. Although at first glance, melanoma carcinogenesis appears to be a chaotic system, it is indeed, arguably, a deterministic multistep process involving sequential alterations of proto-oncogenes, tumour suppressors and miRNA genes. The scope of this article is to discuss the most recent and significant advances in melanoma molecular therapeutics. It is apparent that using single agents targeting solely individual melanoma pathways might be insufficient for long-term survival. However, the outstanding results on melanoma survival observed with novel selective inhibitors of B-RAF, such as PLX4032 give hope that melanoma can be cured. The fact that melanoma develops acquired resistance to PLX4032 emphasises the importance of simultaneously targeting several pathways. Because the most striking feature of melanoma is its unsurpassed ability to metastasise, it is important to implement newer systems for drug delivery adapted from research on stem cells and nanotechnology.

Transmissible spongiform encephalopathies (TSEs), or prion diseases, are fatal neurodegenerative disorders characterised by long incubation period, short clinical duration, and transmissibility to susceptible species. Neuronal loss, spongiform changes, gliosis and the accumulation in the brain of the misfolded version of a membrane-bound cellular prion protein (PrPC), termed PrPTSE, are diagnostic markers of these diseases. Compelling evidence links protein misfolding and its accumulation with neurodegenerative changes. Accordingly, several mechanisms of prion-mediated neurotoxicity have been proposed. In this paper, we provide an overview of the recent knowledge on the mechanisms of neuropathogenesis, the neurotoxic PrP species and the possible therapeutic approaches to treat these devastating disorders.

Asthma is a chronic inflammatory disease of the airways, involving recurrent episodes of airway obstruction and wheezing. A common pathological feature in asthma is the presence of a characteristic allergic airway inflammatory response involving extensive leukocyte infiltration, mucus overproduction and airway hyper-reactivity. The pathogenesis of allergic airway inflammation is complex, involving multiple cell types such as T helper 2 cells, regulatory T cells, eosinophils, dendritic cells, mast cells, and parenchymal cells of the lung. The cellular response in allergic airway inflammation is controlled by a broad range of bioactive mediators, including IgE, cytokines and chemokines. The asthmatic allergic inflammatory response has been a particular focus of efforts to develop novel therapeutic agents. Animal models are widely used to investigate inflammatory mechanisms. Although these models are not perfect replicas of clinical asthma, such studies have led to the development of numerous novel therapeutic agents, of which some have already been successful in clinical trials.

Familial Alzheimer's disease (FAD) accounts for 5–10% of deaths from Alzheimer's disease (AD), and approximately 50% of these cases have been definitely linked to missense mutations in three genes, encoding the amyloid precursor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2). Of these, the vast majority of FAD-linked mutations are within PS1. There has been an extensive effort to identify proteins that functionally interact with PS1 and PS2 because of their clear roles in FAD. The goal of this review is to describe these proteins and to discuss in more detail the probable biological functions of a subset of the better-studied interacting proteins. In particular, the review examines APP, Notch, nicastrin, modifier of cellular adhesion (MOCA), β-catenin, and the group of proteins involved in cell death, calcium metabolism and cell adhesion. We argue that, although a few of the interacting proteins are unambiguously involved in well-studied cellular pathways, their exact roles within these pathways have not been clearly defined, and indeed might vary between cell types. We also question the physiological relevance of some of the work linking PS to cell death pathways. Finally, we point out the value of using flies and worms to sort out the often contradictory work in the PS field, and we mention how knowledge of PS-interacting pathways will contribute to the development of new therapeutic strategies in AD.

Coinfection with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) is associated with increased HCV replication and a more rapid progression to severe liver disease, including the development of cirrhosis and hepatocellular carcinoma. In this review, we discuss the current understanding of the pathogenesis of HCV/HIV coinfection and the cellular and molecular mechanisms associated with the accelerated course of liver disease. The strength and breadth of HCV-specific T-cell responses are reduced in HCV/HIV-coinfected patients compared with those infected with HCV alone, suggesting that the immunosuppression induced by HIV compromises immune responses to HCV. HCV is not directly cytopathic, but many of the pathological changes observed in the liver of infected patients are a direct result of the intrahepatic antiviral immune responses. Apoptosis also has a role in HCV-mediated liver damage through the induction of apoptotic pathways involving the host immune response and HCV viral proteins. This review summarises the evidence correlating the role of cell-mediated immune responses and apoptosis with liver disease progression in HCV/HIV-coinfected patients.

Traditional anti-cancer drugs preferentially kill rapidly growing tumour cells rather than normal cells. However, most of these drugs have no preferential selection towards cancer cells and are taken up by the whole body, resulting in significant adverse side effects. Therapeutic molecules that could specifically inhibit undesirable phenotypes are an attractive way of eliminating cancer cells. There is a widespread effort to develop inhibitors against signal transduction molecules that play a key role in the proliferative, migratory and invasive properties of a cancer cell. Grb7 is an adaptor-type signalling protein that is recruited via its Src-homology 2 (SH2) domain to a variety of tyrosine kinases. Grb7 is overexpressed in breast, oesophageal and gastric cancers, and may contribute to the invasive potential of cancer cells. Molecular interactions involving Grb7 therefore provide attractive targets for therapeutic intervention.

Paget disease of bone (PDB) is a condition characterised by increased bone remodelling at discrete lesions throughout the skeleton. The primary cellular abnormality in PDB involves a net increase in the activity of bone-resorbing osteoclasts, with a secondary increase in bone-forming osteoblast activity. Genetic factors are known to play an important role, with mutations affecting different components of the RANK–NF-κB signalling pathway having been identified in patients with PDB and related disorders. Whilst the disease mechanism in these cases is likely to involve aberrant RANK-mediated osteoclast NF-κB signalling, the precise relationship between other potential contributors, such as viruses and environmental factors, and the molecular pathogenesis of PDB is less clear. This review considers the roles of these different factors in PDB, and concludes that a fuller understanding of their contributions to disease aetiology is likely to be central to future advances in the clinical management of this debilitating skeletal disorder.

Regenerative medicine using patient's own stem cells (SCs) to repair dysfunctional tissues is an attractive approach to complement surgical and pharmacological treatments for aging and degenerative disorders. Recently, dental SCs have drawn much attention owing to their accessibility, plasticity and applicability for regenerative use not only for dental, but also other body tissues. In ophthalmology, there has been increasing interest to differentiate dental pulp SC and periodontal ligament SC (PDLSC) towards ocular lineage. Both can commit to retinal fate expressing eye field transcription factors and generate rhodopsin-positive photoreceptor-like cells. This proposes a novel therapeutic alternative for retinal degeneration diseases. Moreover, as PDLSC shares similar cranial neural crest origin and proteoglycan secretion with corneal stromal keratoctyes and corneal endothelial cells, this offers the possibility of differentiating PDLSC to these corneal cell types. The advance could lead to a shift in the medical management of corneal opacities and endothelial disorders from highly invasive corneal transplantation using limited donor tissue to cell therapy utilizing autologous cells. This article provides an overview of dental SC research and the perspective of utilizing dental SCs for ocular regenerative medicine.

DNA damage and repair studies are at the core of the radiation biology field and represent also the fundamental principles informing radiation therapy (RT). DNA damage levels are a function of radiation dose, whereas the type of damage and biological effects such as DNA damage complexity, depend on radiation quality that is linear energy transfer (LET). Both levels and types of DNA damage determine cell fate, which can include necrosis, apoptosis, senescence or autophagy. Herein, we present an overview of current RT modalities in the light of DNA damage and repair with emphasis on medium to high-LET radiation. Proton radiation is discussed along with its new adaptation of FLASH RT. RT based on α-particles includes brachytherapy and nuclear-RT, that is proton-boron capture therapy (PBCT) and boron-neutron capture therapy (BNCT). We also discuss carbon ion therapy along with combinatorial immune-based therapies and high-LET RT. For each RT modality, we summarise relevant DNA damage studies. Finally, we provide an update of the role of DNA repair in high-LET RT and we explore the biological responses triggered by differential LET and dose.

Human tumours emerge as the result of multiple genetic and epigenetic aberrations that allow the proto-cancer cell to escape normal social control. Many signal transduction pathways become constitutively active during this process, and one whose importance is increasingly being appreciated involves phosphoinositide 3-kinase (PI3-kinase). This pathway normally regulates important cell decisions such as growth, division, survival and migration, and when deregulated it can confer malignant potential to the ensuing tumour. However, constitutive activation of the PI3-kinase pathway might provide attractive therapeutic targets for the design of small-molecule inhibitors. This review discusses events upstream and downstream of PI3-kinase activity in the PI3-kinase signalling pathway, how PI3-kinase is deregulated in human tumourigenesis, and how this is being targeted clinically.

Since the discovery of noncoding small RNAs such as microRNAs (miRNAs), and their roles as potential tumour suppressors or oncogenes, post-transcriptional and translational control of gene expression have become increasingly important in cancer research. Given that over a third of coding genes, as estimated by computational prediction, are regulated by miRNAs, various types of cancer will show direct association with changes in miRNA expression. The link of certain miRNAs with specific developmental stages, tissues and cancer contributes to their strong potential as biomarkers and novel therapeutic targets. In this review, we cover recent advances in miRNA research in human gastrointestinal cancer (colorectal, gastric, pancreatic and liver) and the potential of miRNAs as diagnostic and prognostic biomarkers.