Telomerase and the control of telomere length are intimately linked to the process of tumourigenesis in humans. Here I review the evidence that variation at the 5p15.33 locus, which contains the TERT gene (encoding the catalytic subunit of telomerase), might play a role in the determination of cancer risk. Mutations in the coding regions of TERT can affect telomerase activity and telomere length, and create severe clinical phenotypes, including bone marrow failure syndromes and a substantive increase in cancer frequency. Variants within the TERT gene have been associated with increased risk of haematological malignancies, including myelodysplastic syndrome and acute myeloid leukaemia as well as chronic lymphocytic leukaemia. Furthermore, there is good evidence from a number of independent genome-wide association studies to implicate variants at the 5p15.33 locus in cancer risk at several different sites: lung cancer, basal cell carcinoma and pancreatic cancer show strong associations, while bladder, prostate and cervical cancer and glioma also show risk alleles in this region. Thus, multiple independent lines of evidence have implicated variation in the TERT gene as a risk factor for cancer. The mechanistic basis of these risk variants is yet to be established; however, the basic biology suggests that telomere length control is a tantalising candidate mechanism underlying cancer risk.

Many microbial pathogens subvert proteoglycans for their adhesion to host tissues, invasion of host cells, infection of neighbouring cells, dissemination into the systemic circulation, and evasion of host defence mechanisms. Where studied, specific virulence factors mediate these proteoglycan–pathogen interactions, which are thus thought to affect the onset, progression and outcome of infection. Proteoglycans are composites of glycosaminoglycan (GAG) chains attached covalently to specific core proteins. Proteoglycans are expressed ubiquitously on the cell surface, in intracellular compartments, and in the extracellular matrix. GAGs mediate the majority of ligand-binding activities of proteoglycans, and many microbial pathogens elaborate cell-surface and secreted factors that interact with GAGs. Some pathogens also modulate the expression and function of proteoglycans through known virulence factors. Several GAG-binding pathogens can no longer attach to and invade host cells whose GAG expression has been reduced by mutagenesis or enzymatic treatment. Furthermore, GAG antagonists have been shown to inhibit microbial attachment and host cell entry in vitro and reduce virulence in vivo. Together, these observations underscore the biological significance of proteoglycan–pathogen interactions in infectious diseases.

Tetraspanins, also called tetraspans or the transmembrane 4 superfamily (TM4SF), are cell-surface proteins that span the membrane four times and are found on many different cell types in many organisms. They display numerous properties that indicate their physiological importance in cell adhesion, motility, activation and proliferation, as well as their contribution to pathological conditions such as metastasis or viral infection. A major characteristic of tetraspanins is their ability to form cell-surface complexes with other molecules participating in cell adhesion, either to the extracellular matrix (ECM) or to other cells, and with molecules required for signalling. It is not yet known how the structure of the complexes might affect the functions of other molecules or what basic biochemical mechanisms allow their formation and regulation. Nevertheless, an intriguing association between tetraspanin expression and metastatic potential indicates that these molecules may provide novel insights into tumour progression.

Curcumin, the phytochemical agent in the spice turmeric, which gives Indian curry its yellow colour, is also a traditional Indian medicine. It has been used for millennia as a wound-healing agent and for treating a variety of ailments. The antioxidant, anti-inflammatory, antiproliferative and other properties of curcumin have only recently gained the attention of modern pharmacology. The mechanism of action of curcumin is complex and multifaceted. In part, curcumin acts by activating various cytoprotective proteins that are components of the phase II response. Over the past decade, research with curcumin has increased significantly. In vitro and in vivo studies have demonstrated that curcumin could target pathways involved in the pathophysiology of Alzheimer disease (AD), such as the β-amyloid cascade, tau phosphorylation, neuroinflammation or oxidative stress. These findings suggest that curcumin might be a promising compound for the development of AD therapy. However, its insolubility in water and poor bioavailability have limited clinical trials and its therapeutic applications. To be effective as a drug therapy, curcumin must be combined with other drugs, or new delivery strategies need to be developed.

Most proteins in the cell adopt a compact, globular fold that determines their stability and function. Partial protein unfolding under conditions of cellular stress results in the exposure of hydrophobic regions normally buried in the interior of the native structure. Interactions involving the exposed hydrophobic surfaces of misfolded protein conformers lead to the formation of toxic aggregates, including oligomers, protofibrils and amyloid fibrils. A significant number of human disorders (e.g. Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis and type II diabetes) are characterised by protein misfolding and aggregation. Over the past five years, outstanding progress has been made in the development of therapeutic strategies targeting these diseases. Three promising approaches include: (1) inhibiting protein aggregation with peptides or small molecules identified via structure-based drug design or high-throughput screening; (2) interfering with post-translational modifications that stimulate protein misfolding and aggregation; and (3) upregulating molecular chaperones or aggregate-clearance mechanisms. Ultimately, drug combinations that capitalise on more than one therapeutic strategy will constitute the most effective treatment for patients with these devastating illnesses.

Cardiovascular disease remains the leading cause of death worldwide. Acute ischaemic injury and chronic cardiomyopathies lead to permanent loss of cardiac tissue and ultimately heart failure. Current therapies aim largely to attenuate the pathological remodelling that occurs after injury and to reduce risk factors for cardiovascular disease. Studies in animal models indicate that transplantation of mesenchymal stem cells, bone-marrow-derived haematopoietic stem cells, skeletal myoblasts, or embryonic stem cells has the potential to improve the function of ventricular muscle after ischaemic injury. Clinical trials using primarily bone-marrow-derived cells and skeletal myoblasts have also produced some encouraging results. However, the current experimental evidence suggests that the benefits of cell therapy are modest, the generation of new cardiac tissue is low, and the predominant mechanisms of action of transplanted stem cells involve favourable paracrine effects on injured myocardium. Recent studies show that the adult heart possesses various pools of putative resident stem cells, raising the hope that these cells can be isolated for therapy or manipulated in vivo to improve the healing of cardiac muscle after injury. This article reviews the properties and potential of the various stem cell populations for cardiac repair and regeneration as well as the barriers that might lie ahead.

Gap junctions allow the exchange of ions and small molecules between adjacent cells through intercellular channels formed by connexin proteins, which can also form functional hemichannels in nonjunctional membranes. Mutations in connexin genes cause a variety of human diseases. For example, mutations in GJB2, the gene encoding connexin-26 (Cx26), are not only a major cause of nonsyndromic deafness, but also cause syndromic deafness associated with skin disorders such as palmoplantar keratoderma, keratitis–ichthyosis deafness syndrome, Vohwinkel syndrome, hystrix–ichthyosis deafness syndrome and Bart–Pumphrey syndrome. The most common mutation in the Cx26 gene linked to nonsyndromic deafness is 35ΔG, a frameshift mutation leading to an early stop codon. The large number of deaf individuals homozygous for 35ΔG do not develop skin disease. Similarly, there is abundant experimental evidence to suggest that other Cx26 loss-of-function mutations cause deafness, but not skin disease. By contrast, Cx26 mutations that cause both skin diseases and deafness are all single amino acid changes. Since nonsyndromic deafness is predominantly a loss-of-function disorder, it follows that the syndromic mutants must show an alteration, or gain, of function to cause skin disease. Here, we summarise the functional consequences and clinical phenotypes resulting from Cx26 mutations that cause deafness and skin disease.

Sarcoglycanopathies are a group of autosomal recessive muscle-wasting disorders caused by genetic defects in one of four cell membrane glycoproteins, α-, β-, γ- or δ-sarcoglycan. These four sarcoglycans form a subcomplex that is closely linked to the major dystrophin-associated protein complex, which is essential for membrane integrity during muscle contraction and provides a scaffold for important signalling molecules. Proper assembly, trafficking and targeting of the sarcoglycan complex is of vital importance, and mutations that severely perturb tetramer formation and localisation result in sarcoglycanopathy. Gene defects in one sarcoglycan cause the absence or reduced concentration of the other subunits. Most genetic defects generate mutated proteins that are degraded through the cell's quality control system; however, in many cases, conformational modifications do not affect the function of the protein, yet it is recognised as misfolded and prematurely degraded. Recent evidence shows that misfolded sarcoglycans could be rescued to the cell membrane by assisting their maturation along the ER secretory pathway. This review summarises the etiopathogenesis of sarcoglycanopathies and highlights the quality control machinery as a potential pharmacological target for therapy of these genetic disorders.

A class of developmental disorders caused by dysregulation of the Ras-induced mitogen-activated protein kinase (MAPK) cascade (the Ras–MAPK pathway) has emerged. Three of these disorders – Noonan, Costello and cardio–facio–cutaneous syndromes – have overlapping phenotypic features characterised by distinctive facial dysmorphia, cardiac defects, musculoskeletal and cutaneous abnormalities, and neurocognitive delay. The germline mutations associated with these disorders are in genes that encode proteins of the Ras–MAPK pathway. In vitro studies have determined that the overwhelming majority of these mutations result in increased signal transduction down the pathway, but usually to a lesser degree than somatic mutations in the same genes that are associated with cancer. The Ras–MAPK pathway is essential in the regulation of the cell cycle, differentiation, growth and senescence, so it is not surprising that germline mutations that affect its function have profound effects on development. Here we review the clinical consequences of the known molecular lesions associated with Noonan syndrome, Costello syndrome and cardio–facio–cutaneous syndrome, and explore possible therapeutic modalities for treatment.

Innate immune receptors play a key role in the early recognition of invading bacterial pathogens and initiate the crucial innate immune response. The diverse macrophage receptors recognise Gram-positive and Gram-negative bacteria via conserved structures on the bacterial surface and facilitate phagocytosis and/or signalling, providing the trigger for the adaptive immune response. These receptors include scavenger receptors, C-type lectins, integrins, Toll-like receptors and siglecs. The bacterial ligands generally recognised by these receptors range from lipopolysaccharides on Gram-negative bacteria to peptidoglycan and lipoteichoic acid on Gram-positive bacteria. However, emerging evidence indicates that bacterial proteins are also important ligands; for example, surface proteins from Neisseria meningitidis have been shown to be ligands for class A scavenger receptors. In addition, a group of cytosolic receptors, the NBS-LRR proteins, have been implicated in recognition of bacterial breakdown products. It is becoming increasingly apparent that macrophage receptors can act in conjunction with one another to deliver an appropriate response.

Noroviruses (NVs) are a major cause of acute gastroenteritis epidemics in both developing and developed countries and affect people of all ages. Three main human histo-blood group antigens (HBGAs) – the ABO, Lewis and secretor families – are involved in NV recognition and eight strain-specific receptor-binding patterns in two major binding groups have been described. The receptor-binding interface is located at the outermost surface of the P domain of the viral capsid. Each interface contains two major binding sites and each site interacts with a carbohydrate side-chain of the HBGAs via multiple hydrogen bonds. Soluble HBGAs in human milk are able to block binding of NV to HBGA receptors, suggesting a potential decoy receptor for the protection of infants from NV infection. Phylogenetic analysis has revealed limited genetic relatedness among NVs with similar receptor-binding patterns. This review summarises and discusses recent advances and highlights implications for future studies in the control and prevention of NV gastroenteritis.

Rheumatoid arthritis (RA) associates with increased cardiovascular mortality. This appears to be predominantly due to ischaemic causes, such as myocardial infarction and congestive heart failure. The higher prevalence of cardiac ischaemia in RA is thought to be due to the accelerated development of atherosclerosis. There are two main reasons for this, which might be inter-related: the systemic inflammatory load, characteristic of RA; and the accumulation in RA of classical risk factors for coronary heart disease, which is reminiscent of the metabolic syndrome. We describe and discuss in the context of RA the involvement of local and systemic inflammatory processes in the development and rupture of atherosclerotic plaques, as well as the role of individual risk factors for coronary heart disease. We also present the challenges facing the clinical and scientific communities addressing this problem, which is receiving increasing attention.

The claudin (CLDN) family of transmembrane proteins plays a critical role in the maintenance of epithelial and endothelial tight junctions. In addition to their function in preserving the structure of tight junctions, CLDNs might also play a role in the maintenance of the cytoskeleton and in cell signalling. Interestingly, several studies have recently reported specific CLDN family members to be overexpressed in a wide variety of cancer types. Although their functional role in cancer progression remains unclear, the differential expression of these proteins between tumour and normal cells, in addition to their membrane localisation, makes them prime candidates for cancer therapy. Preclinical studies have shown that tumour cells overexpressing CLDNs can be successfully targeted via several approaches, including the use of anti-CLDN antibodies as well as the cytolytic enterotoxin from Clostridium perfringens. Further studies are needed to determine the potential systemic toxicity of this approach considering the ubiquitous expression of CLDNs in the body, but CLDN-targeted therapeutics appear to have promise in the treatment of cancer.

In addition to its loss playing a pivotal role in the development of a childhood kidney malignancy, the Wilms tumour 1 gene (WT1) has emerged as an important factor in normal and malignant haematopoiesis. Preferentially expressed in CD34+ haematopoietic progenitors and down-regulated in more-differentiated cells, the WT1 transcription factor has been implicated in regulation of apoptosis, proliferation and differentiation. Putative target genes, such as BCL2, MYC, A1 and cyclin E, may cooperate with WT1 to modulate cell growth. However, the effects of WT1 on target gene expression appear to be isoform-specific. Certain WT1 isoforms are over-represented in leukaemia, but the exact mechanisms underlying the role of WT1 in transformation remain unclear. The ubiquity of WT1 in haematological malignancies has led to efforts to exploit it as a marker for minimal residual disease and as a prognostic factor, with conflicting results. In vitro killing of tumour cells by WT1-specific CD8+ cytotoxic T lymphocytes facilitated design of Phase I vaccine trials that showed clinical regression of WT1-positive tumours. Alternative methods employing WT1-specific immunotherapy are being investigated and might ultimately be used to optimise multimodal therapy of haematological malignancies.

Methylation at DNA, RNA and protein levels plays critical roles in many cellular processes and is associated with diverse differentiation events, physiological activities and human diseases. To aid in the diagnostic and therapeutic design for cancer treatment utilising methylation, this review provides a boutique yet comprehensive overview on methylation at different levels including the mechanisms, cross-talking and clinical implications with a particular focus on cancers. We conclude that DNA methylation is the sole type of methylation that has been largely translated into clinics and used for, mostly, early diagnosis. Translating the onco-therapeutic and prognostic values of RNA and protein methylations into clinical use deserves intensive efforts. Simultaneous examination of methylations at multiple levels or together with other forms of molecular markers represents an interesting research direction with profound clinical translational potential.

Tendons are frequently affected by chronic pain or rupture. Many causative factors have been implicated in the pathology, which until relatively recently was under-researched and poorly understood. There is now a greater knowledge of the molecular basis of tendon disease. Most tendon pathology (tendinopathy) is associated with degeneration, which is thought to be an active, cell-mediated process involving increased turnover and remodelling of the tendon extracellular matrix. Degradation of the tendon matrix is mediated by a variety of metalloproteinase enzymes, including matrix metalloproteinases and ‘aggrecanases’. Neuropeptides and other factors released by stimulated cells or nerve endings in or around the tendon might influence matrix turnover, and could provide novel targets for therapeutic intervention.

Since the isolation and purification of erythropoietin (EPO) in 1977, the essential role of EPO for mature red blood cell production has been well established. The cloning of the EPO gene and production of recombinant human EPO led to the widespread use of EPO in treating patients with anaemia. However, the biological activity of EPO is not restricted to regulation of erythropoiesis. EPO receptor (EPOR) expression is also found in endothelial, brain, cardiovascular and other tissues, although at levels considerably lower than that of erythroid progenitor cells. This review discusses the survival and proliferative activity of EPO that extends beyond erythroid progenitor cells. Loss of EpoR expression in mouse models provides evidence for the role of endogenous EPO signalling in nonhaematopoietic tissue during development or for tissue maintenance and/or repair. Determining the extent and distribution of receptor expression provides insights into the potential protective activity of EPO in brain, heart and other nonhaematopoietic tissues.

Pseudomonas aeruginosa is the best described bacterium with regards to quorum sensing (QS), in vitro biofilm formation and the development of antibiotic tolerance. Biofilms composed of P. aeruginosa are thought to be the underlying cause of many chronic infections, including those in wounds and in the lungs of patients with cystic fibrosis. In this review, we provide an overview of the molecular mechanisms involved in QS, QS-enabled virulence, biofilm formation and biofilm-enabled antibiotic tolerance. We now have substantial knowledge of the multicellular behaviour of P. aeruginosa in vitro. A major task for the future is to investigate how such in vitro data correlate with the in vivo behaviour of P. aeruginosa, and how to treat chronic infections of this bacterium in patients.

Small-molecule inhibition of the direct protein–protein interactions that mediate many important biological processes is an emerging and challenging area in drug design. Conventional drug design has mainly focused on the inhibition of a single protein, usually an enzyme or receptor, since these proteins often contain a clearly defined ligand-binding site with which a small-molecule drug can be designed to interact. Designing a small molecule to bind to a protein–protein interface and subsequently inhibit the interaction poses several challenges, including the initial identification of suitable protein–protein interactions, the surface area of the interface (it is often large), and the location of ‘hot spots’ (small regions suitable for drug binding). This article reviews the general approach to designing inhibitors of protein–protein interactions, and then focuses on recent advances in the use of small molecules targeted against a variety of protein–protein interactions that have therapeutic potential for cancer.

Retinoids (derivatives of vitamin A) are signalling molecules that play important roles in cell growth, differentiation and death. Retinoids act through two types of receptors – retinoic acid receptors (RARα, RARβ and RARγ) and retinoid X receptors (RXRα, RXRβ and RXRγ) – which themselves act as ligand-dependent transcription factors. Retinoids are of special interest in cancer research owing to their antiproliferative and cancer-preventative properties. They have been used successfully to cure acute promyelocytic leukaemia (APL) and can suppress carcinogenesis in a variety of tissue types (e.g. skin, lung, breast and oral cancers). Extensive research efforts have been dedicated to elucidating the molecular and cellular networks that are induced by retinoids, and this has recently yielded novel insights into how retinoids can both prevent and combat cancer.