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.

Current therapies to treat Alzheimer's disease (AD) are focused on ameliorating symptoms instead of treating the underlying causes of AD. The accumulation of amyloid β (Aβ) oligomers, whether by an increase in production or by a decrease in clearance, has been described as the seed that initiates the pathological cascade in AD. Developing therapies to target these species is a vital step in improving AD treatment. Aβ-immunotherapy, especially passive immunotherapy, is a promising approach to reduce the Aβ burden. Up to now, several monoclonal antibodies (mAbs) have been tested in clinical trials on humans, but none of them have passed Phase III. In all likelihood, these trials failed mainly because patients with mild-to-moderate AD were recruited, and thus treatment may have been too late to be effective. Therefore, many ongoing clinical trials are being conducted in patients at the prodromal stage. New structures based on antibody fragments have been engineered intending to improve efficacy and safety. This review presents the properties of this variety of developing treatments and provides a perspective on state-of-the-art of passive Aβ-immunotherapy in AD.

Spatially fractionated radiation therapy (SFRT) challenges some of the classical dogmas in conventional radiotherapy. The highly modulated spatial dose distributions in SFRT have been shown to lead, both in early clinical trials and in small animal experiments, to a significant increase in normal tissue dose tolerances. Tumour control effectiveness is maintained or even enhanced in some configurations as compared with conventional radiotherapy. SFRT seems to activate distinct radiobiological mechanisms, which have been postulated to involve bystander effects, microvascular alterations and/or immunomodulation. Currently, it is unclear which is the dosimetric parameter which correlates the most with both tumour control and normal tissue sparing in SFRT. Additional biological experiments aiming at parametrizing the relationship between the irradiation parameters (beam width, spacing, peak-to-valley dose ratio, peak and valley doses) and the radiobiology are needed. A sound knowledge of the interrelation between the physical parameters in SFRT and the biological response would expand its clinical use, with a higher level of homogenisation in the realisation of clinical trials. This manuscript reviews the state of the art of this promising therapeutic modality, the current radiobiological knowledge and elaborates on future perspectives.

Organ transplantation is the state of the art for treating end-stage organ failure. Over 25 000 organ transplants are performed in the USA each year. Survival rates following transplantation are now approaching 90% for 1 year and 75% for 5 years. Central to this success was the introduction of drugs that suppress the immune system and prevent rejection. The most commonly used class of immunosuppressing drugs are calcineurin inhibitors (CNIs). Calcineurin is a ubiquitous enzyme that is important for T-cell function. With more people taking CNIs for longer and longer periods of time the consequences of calcineurin inhibition on other organ systems – particularly the kidney – have become a growing concern. Virtually all people who take a CNI will develop some degree of kidney toxicity and up to 10% will progress to kidney failure. In the past 15 years, research into calcineurin action has identified distinct actions of the two main isoforms of the catalytic subunit of the enzyme. The α-isoform is required for kidney function whereas the β-isoform has a predominant role in the immune system. This review will discuss the current state of knowledge about calcineurin isoforms and how these new insights may reshape post-transplant immunosuppression.

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.

BAG-1 is a multifunctional protein that exists as several differentially localised and functionally distinct isoforms. BAG-1 isoforms interact with a diverse array of molecular targets and regulate a wide range of cellular processes, including proliferation, survival, transcription, apoptosis, metastasis and motility. The BAG domain of BAG-1 interacts with chaperone molecules and this is considered important for many BAG-1 functions. The ability of BAG-1 to regulate such a wide variety of cellular processes suggests it might play an important role in many cancer types. For example, regulation of nuclear hormone receptor function and susceptibility to apoptosis might have a major impact on cancer development, progression and response to therapy. There is also increasing evidence that BAG-1 expression is altered in a variety of human malignancies relative to normal cells, and with further understanding of BAG-1 function it might become a powerful prognostic/predictive marker in human cancer. This review describes the structure and function of BAG-1 isoforms and the potential clinical implications of their expression in tumour cells.

Infiltration of T cells is a key step in the pathogenesis of the inflammatory skin diseases atopic dermatitis, allergic contact dermatitis and psoriasis. Understanding the mechanisms of T cell recruitment to the skin is therefore of fundamental importance for the discovery and application of novel therapies for these conditions. Studies of both clinical samples and experimental models of skin inflammation have implicated specific adhesion molecules and chemokines in lymphocyte recruitment. In particular, recent studies using advanced in vivo imaging techniques have greatly increased our understanding of the kinetics and molecular basis of this process. In this review, we summarise the current understanding of the cellular immunology of antigen-driven dermal inflammation and the roles of adhesion molecules and chemokines. We focus on results obtained using intravital microscopy to examine the dermal microvasculature and interstitium to determine the mechanisms of T cell recruitment and migration in experimental models of T-cell-mediated skin inflammation.

Multiple genetic disorders can be associated with excessive signalling by mutant G-protein-coupled receptors (GPCRs) that are either constitutively active or have lost sites where phosphorylation by GPCR kinases is necessary for desensitisation by cognate arrestins. Phosphorylation-independent arrestin1 can compensate for defects in phosphorylation of the GPCR rhodopsin in retinal rod cells, facilitating recovery, improving light responsiveness, and promoting photoreceptor survival. These proof-of-principle experiments show that, based on mechanistic understanding of the inner workings of a protein, one can modify its functional characteristics to generate custom-designed mutants that improve the balance of signalling in congenital and acquired disorders. Manipulations of arrestin elements responsible for scaffolding mitogen-activated protein kinase cascades and binding other signalling proteins involved in life-or-death decisions in the cell are likely to yield mutants that affect cell survival and proliferation in the desired direction. Although this approach is still in its infancy, targeted redesign of individual functions of many proteins offers a promise of a completely new therapeutic toolbox with huge potential.

Epithelial ovarian cancer comprises several subtypes of tumours that exhibit diverse histopathological features. The intriguing assumption by many epithelial ovarian cancers of specialised features of nonovarian tissue lineages has promoted considerable debate as to whether these tumours arise from the deceptively simple surface epithelium of the ovary. This review focuses on recent molecular and pathological studies of epithelial ovarian cancers that support and challenge their surface-epithelial derivation, and discusses the findings in the context of current views of the ‘cell-of-origin’ of solid tumours.

Numerous studies have investigated specific pathways that link diabetes and high extracellular glucose exposure to glomerulosclerosis and mesangial cell extracellular matrix production. However, only in the past ten years has a role for glucose transporters in this process been addressed. Many different glucose transporters are expressed in glomeruli; of these, the GLUT1 facilitative glucose transporter is upregulated in the diabetic renal cortex and in response to glomerular hypertension, as well as in cultured mesangial cells exposed to high glucose. Transgenic mouse and cell models have recently been developed to test the role of GLUT1 in the pathogenesis of glomerulosclerosis with and without diabetes. Clinical studies of GLUT1 alleles performed in humans have identified GLUT1 susceptibility alleles for diabetic nephropathy. Studies are also currently under way to assess the potential role of GLUT1 in nondiabetic renal disorders.

The protein kinase R (PKR, also called EIF2AK2) is an interferon-inducible double-stranded RNA protein kinase with multiple effects on cells that plays an active part in the cellular response to numerous types of stress. PKR has been extensively studied and documented for its relevance as an antiviral agent and a cell growth regulator. Recently, the role of PKR related to metabolism, inflammatory processes, cancer and neurodegenerative diseases has gained interest. In this review, we summarise and discuss the involvement of PKR in several cancer signalling pathways and the dual role that this kinase plays in cancer disease. We emphasise the importance of PKR as a molecular target for both conventional chemotherapeutics and emerging treatments based on novel drugs, and its potential as a biomarker and therapeutic target for several pathologies. Finally, we discuss the impact that the recent knowledge regarding PKR involvement in metabolism has in our understanding of the complex processes of cancer and metabolism pathologies, highlighting the translational research establishing the clinical and therapeutic potential of this pleiotropic kinase.

In 2004 and 2006, two new rotavirus vaccines – Rotarix™ and RotaTeq™ – were licensed worldwide. Both are live virus vaccines and are composed of either a monovalent attenuated human rotavirus or five bovine–human reassortant rotaviruses, respectively. Studies in humans and animals have reported correlations between rotavirus antibody levels and protection, the most consistent of which has been with rotavirus IgA. Cellular immunity was also found to have a role in protection after live rotavirus immunisation, particularly in mice. However, the primary importance of CD8+ T cells may be in resolution of infection and that of CD4+ T cells may be their helper function, particularly for antibody production. CD4+ T cells have been reported to have a more direct role in protection after mucosal immunisation with non-living rotavirus vaccines, possibly because of direct or indirect effects of the cytokines they generate. Immune effectors have overlapping functions, and protection against rotavirus by either live or non-living vaccines is probably enhanced by this redundancy.

Owing to the limited regenerative capacity of cartilage tissue, cartilage repair remains a challenge in clinical treatment. Tissue engineering has emerged as a promising and important approach to repair cartilage defects. It is well known that material scaffolds are regarded as a fundamental element of tissue engineering. Novel biomaterial scaffolds formed by self-assembling peptides consist of nanofibre networks highly resembling natural extracellular matrices, and their fabrication is based on the principle of molecular self-assembly. Indeed, peptide nanofibre scaffolds have obtained much progress in repairing various damaged tissues (e.g. cartilage, bone, nerve, heart and blood vessel). This review outlines the rational design of peptide nanofibre scaffolds and their potential in cartilage tissue engineering.

The serpin superfamily encompasses hundreds of proteins, spread across all kingdoms of life, linked by a common tertiary fold. This review focuses on five diseases caused by serpin dysfunction: variants of antithrombin III lose their ability to interact with heparin; the α1-antitrypsin Pittsburgh mutation causes a change in target proteinase; the α1-antitrypsin Z mutation and neuroserpin, polymerisation of which lead to cellular cytotoxicity; and a loss of maspin expression resulting in cancer.

MicroRNAs (miRNAs) are short noncoding RNAs that act as post-transcriptional regulators. The low complementarity required between the sequences of a miRNA and its target mRNA enables a single miRNA to act on a large range of targets. Thus miRNAs have an intersecting complex effect that spans a multiplicity of pathways and processes. In this review, the different roles of a vital miRNA, miR-181a, in physiological and pathological developments are collated in an attempt to highlight the intersections of such processes and to show how the deregulation of miR-181a could in one context drive malignancy, whereas in another it can lead to autoimmunity. Such deregulation could be related to the faulty levels of one of its own targets, p53, which was recently reported to control an array of miRNAs, one of which is miR-181a. This sheds light on a hidden loop of chaos behind chronic diseases such as autoimmunity and cancer.

ErbB receptor tyrosine kinases are membrane-bound receptors that possess intrinsic, ligand-activated, tyrosine kinase activity. Binding of growth factors to these receptors induces the formation of ErbB homo- and heterodimers and initiates a signalling cascade that traverses the cytoplasm to communicate with the nucleus and the cytoskeleton. The effect of this cascade is the regulation of cellular proliferation, differentiation, apoptosis, migration and adhesion. Although ErbB signalling is important for normal growth and development in the breast, a dysregulation of ErbB activity can lead to tumourigenesis. This review will focus on the role of ErbB signalling in both normal mammary gland development and breast cancer, with an emphasis on the mechanisms behind receptor activation and the therapeutic agents designed to inhibit ErbB activity.

Corneal allotransplantation is the most common and successful form of solid organ transplantation in humans. In uncomplicated cases, the two-year graft survival rate is over 90%. This extraordinary success can be attributed in part to various features of the normal cornea and anterior segment that together account for their ‘immune-privileged’ status. However, despite this success, a significant number of corneal grafts fail and immunological rejection remains by far the leading cause of graft failure. Studies on animal models of corneal transplantation have yielded a wealth of information on the molecular and cellular features of graft rejection, and have established that this process is mediated primarily by CD4+ T cells of the T helper 1 (Th1) phenotype. In addition, studies have elucidated that certain facets of allosensitisation differ between corneal and other solid organ transplants. On the basis of these findings, novel experimental strategies selectively targeting the afferent or efferent arms of corneal alloimmunity have provided promising results in preventing corneal allograft rejection in the laboratory. Finally, because of the global shortage of human donor corneas, there is currently renewed interest in the possibility of using corneas from other species for transplantation into human eyes (xenotransplantation). Preliminary studies on animal models of corneal xenotransplantation have documented both antibody-mediated and cell-mediated responses that might play important roles in the accelerated rejection observed in corneal xenotransplants. This review synthesises the principal concepts emerging from studies of the molecular mechanisms in corneal transplant immunology.

Triple-negative breast cancer (TNBC) is a heterogeneous group of tumours characterised by lack of expression of oestrogen-, progesterone- and human epidermal growth factor receptors. TNBC, which represents approximately 15% of all mammary tumours, has a poor prognosis because of an aggressive behaviour and the lack of specific treatment. Accordingly, TNBC has become a major focus of research into breast cancer and is now classified into several molecular subtypes, each with a different prognosis. Pathological angiogenesis occurs at a late stage in the proliferation of TNBC and is associated with invasion and metastasis; there is an association with metabolic syndrome. Semaphorins are a versatile family of proteins with multiple roles in angiogenesis, tumour growth and metastasis and may represent a clinically useful focus for therapeutic targeting in this type of breast cancer. Another important field of investigation into the control of pathological angiogenesis is related to the expression of noncoding RNA (ncRNA) – these molecules can be considered as a therapeutic target or as a biomarker. Several molecular agents for intervening in the activity of different signalling pathways are being explored in TNBC, but none has so far proved effective in clinical trials and the disease continues to pose a defining challenge for clinical management as well as innovative cancer research.

Cardiovascular autonomic neuropathy (CAN), in which patients present with damage of autonomic nerve fibres, is one of the most common complications of diabetes. CAN leads to abnormalities in heart rate and vascular dynamics, which are features of diabetic heart failure. Dysregulated neurohormonal activation, an outcome of diabetic neuropathy, has a significant pathophysiological role in diabetes-associated cardiovascular disease. Key players in neurohormonal activation include cardioprotective neuropeptides and their receptors, such as substance P (SP), neuropeptide Y (NPY), calcitonin-gene-related peptide (CGRP), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). These neuropeptides are released from the peripheral or autonomic nervous system and have vasoactive properties. They are further implicated in cardiomyocyte hypertrophy, calcium homeostasis, ischaemia-induced angiogenesis, protein kinase C signalling and the renin–angiotensin–aldosterone system. Therefore, dysregulation of the expression of neuropeptides or activation of the neuropeptide signalling pathways can negatively affect cardiac homeostasis. Targeting neuropeptides and their signalling pathways might thus serve as new therapeutic interventions in the treatment of heart failure associated with diabetes. This review discusses how neuropeptide dysregulation in diabetes might affect cardiac functions that contribute to the development of heart failure.