Skeletogenesis, either during development, post-injury or for maintenance, is a carefully coordinated process reliant on the appropriate differentiation of mesenchymal stem cells. Some well described, as well as a new regulator of this process (adenosine receptors), are alike in that they signal via cyclic-AMP (cAMP). This review highlights the known contribution of cAMP signalling to mesenchymal stem cell differentiation to osteoblasts and to chondrocytes. Focus has been given to how these regulators influence the commitment of the osteochondroprogenitor to these separate lineages.

Recent genome-wide association scans (GWASs) along with several adequately powered candidate gene studies have yielded a number of risk alleles for osteoarthritis (OA). This number is now sufficiently large to allow conclusions to be drawn regarding the nature of genetic susceptibility, including the fact that the risk alleles have variable effects depending on sex, ethnicity and on the skeletal site of the disease. Several of the alleles that have emerged from the GWASs are within or close to highly plausible candidate genes, including RUNX2 and CHST11. However, the majority of risk alleles do not map to genes previously reported to play a role in musculoskeletal biology, indicating that the GWAS datasets are telling us something new about the OA disease process. Functional studies have so far revealed that effects on gene expression are likely to be one of the main mechanisms through which OA susceptibility is acting. Epigenetic mechanisms such as DNA methylation also influence OA risk, and integration of genetic, transcriptomic and epigenetic data will allow us to use the genetic discoveries for informed development of new OA biological treatments.

Polyamines are small organic cations that are essential for normal cell growth and development in eukaryotes. Under normal physiological conditions, intracellular polyamine concentrations are tightly regulated through a dynamic network of biosynthetic and catabolic enzymes, and a poorly characterised transport system. This precise regulation ensures that the intracellular concentration of polyamines is maintained within strictly controlled limits. It has frequently been observed that the metabolism of, and the requirement for, polyamines in tumours is frequently dysregulated. Elevated levels of polyamines have been associated with breast, colon, lung, prostate and skin cancers, and altered levels of rate-limiting enzymes in both biosynthesis and catabolism have been observed. Based on these observations and the absolute requirement for polyamines in tumour growth, the polyamine pathway is a rational target for chemoprevention and chemotherapeutics. Here we describe the recent advances made in the polyamine field and focus on the roles of polyamines and polyamine metabolism in neoplasia through a discussion of the current animal models for the polyamine pathway, chemotherapeutic strategies that target the polyamine pathway, chemotherapeutic clinical trials for polyamine pathway-specific drugs and ongoing clinical trials targeting polyamine biosynthesis.

Engineered tissue derived from ocular surface stem cells (SCs) are a cutting edge biotechnology for repair and restoration of severely damaged eyes as a result of ocular surface dysfunction because of SC failure. Ex-vivo SC expansion techniques have advanced significantly since the first patients were treated in the late 1990s. The techniques and clinical reports reviewed here highlight the evolution and successes of these techniques, while also revealing gaps in our understanding of ocular surface and SC biology that drives further research and development in this field. Although hurdles still remain before stem-cell-based therapies are more widely available for patients with devastating ocular surface disease, recent discoveries in the field of mesenchymal SCs and the potential of induced pluripotent SCs heralds a promising future for clinicians and our patients.

Nuclear envelope spectrin-repeat proteins (Nesprins), are a novel family of nuclear and cytoskeletal proteins with rapidly expanding roles as intracellular scaffolds and linkers. Originally described as proteins that localise to the nuclear envelope (NE) and establish nuclear-cytoskeletal connections, nesprins have now been found to comprise a diverse spectrum of tissue specific isoforms that localise to multiple sub-cellular compartments. Here, we describe how nesprins are necessary in maintaining cellular architecture by acting as essential scaffolds and linkers at both the NE and other sub-cellular domains. More importantly, we speculate how nesprin mutations may disrupt tissue specific nesprin scaffolds and explain the tissue specific nature of many nesprin-associated diseases, including laminopathies.

Systemic lupus erythematosus (SLE) is a severe multi-system autoimmune disease, whereas interferon regulatory factor (IRF) 5 belongs to the family of transcription factors that modulate immune system activities. Recently, many lines of investigations suggested that IRF5 gene polymorphisms are closely associated with the disease onset of SLE. Indeed, expressed in B cells, dendritic cells (DCs), monocytes and macrophages, IRF5 could significantly affect these immune cells participating in the pathogenesis of SLE, and numerous studies implied that this transcription factor is mechanistically linked to the disease progression. Here, we comprehensively review the updated evidence indicating the roles of IRF5 in autoimmune lupus. Hopefully, the information obtained will lead to a better understanding of the pathogenesis and development of novel therapeutic strategies for the systemic autoimmune disease.

Periodontitis is a chronic inflammatory condition of the periodontium involving interactions between bacterial products, numerous cell populations and inflammatory mediators. It is generally accepted that periodontitis is initiated by complex and diverse microbial biofilms which form on the teeth, i.e. dental plaque. Substances released from this biofilm such as lipopolysaccharides, antigens and other virulence factors, gain access to the gingival tissue and initiate an inflammatory and immune response, leading to the activation of host defence cells. As a result of cellular activation, inflammatory mediators, including cytokines, chemokines, arachidonic acid metabolites and proteolytic enzymes collectively contribute to tissue destruction and bone resorption. This review summarises recent studies on the pathogenesis of periodontitis, with the main focus on inflammatory mediators and their role in periodontal disease.

Elastic fibres are insoluble components of the extracellular matrix of dynamic connective tissues such as skin, arteries, lungs and ligaments. They are laid down during development, and comprise a cross-linked elastin core within a template of fibrillin-based microfibrils. Their function is to endow tissues with the property of elastic recoil, and they also regulate the bioavailability of transforming growth factor β. Severe heritable elastic fibre diseases are caused by mutations in elastic fibre components; for example, mutations in elastin cause supravalvular aortic stenosis and autosomal dominant cutis laxa, mutations in fibrillin-1 cause Marfan syndrome and Weill–Marchesani syndrome, and mutations in fibulins-4 and -5 cause autosomal recessive cutis laxa. Acquired elastic fibre defects include dermal elastosis, whereas inflammatory damage to fibres contributes to pathologies such as pulmonary emphysema and vascular disease. This review outlines the latest understanding of the composition and assembly of elastic fibres, and describes elastic fibre diseases and current therapeutic approaches.

Accumulative evidence demonstrates the crucial role of evolutionary conserved Toll-like receptors (TLRs) in identifying microbial or viral compounds. TLRs are also able to recognise endogenous molecules which are released upon cell damage or stress and have been shown to play a key role in numerous autoimmune diseases including systemic sclerosis (SSc). A classic feature of SSc, is vascular injury manifested as Raynaud's phenomenon and ischaemia of the skin, resulting in the release of endogenous TLR ligands during inflammation and local tissue damage. These locally released TLR ligands bind TLRs possibly complexed to autoantibodies, and initiate intracellular signalling pathways and may be one of the mechanisms that initiate and drive autoimmunity and subsequent fibrosis. Activation of the immune system results in interferon (IFN) sensitive gene transcription. There is also an IFN gene signature in SSc peripheral blood. TLRs may represent the link between immune activation, common in SSc, and tissue fibrosis. Therefore, a better understanding of the mechanisms of TLR-mediated pathogenesis and therapies targeting individual TLRs, may provide a more specific approach of treating multi-systemic autoimmune diseases. This review aims to integrate the current knowledge of TLR function in the autoimmune disorders with particular emphasis on SSc. We suggest the TLR system as a new therapeutic target.

Resveratrol (RSV) is a natural polyphenol produced by plants and is proposed to have multiple beneficial effects on health. In recent years, the interest in this molecule has increased nearly exponentially following the major findings that RSV (I) is chemo-preventive in some cancer models, (II) is cardio-protective and (III) has positive effects on metabolism in mammals and increases lifespan in lower organisms. Mechanistic target of rapamycin (mTOR) is a central controller of cell growth, proliferation, metabolism and angiogenesis. As a part of the mTORC1 and mTORC2 complexes, the mTOR kinase plays a key role in several pathways involved in cancer and metabolic diseases. Recent studies suggest that modulation of the mTOR signalling pathway could play an important role in mediating the beneficial effects of RSV. Therefore, this review summarises the current findings regarding RSV and its inhibition/activation of the proteins in the mTOR pathway, and thereby propose the proteins of the mTOR cascade to be primary targets for RSV. RSV affects many different targets related to mTOR, and it is not clear which is most relevant. However, most frequently, RSV is found to inhibit the activity of the mTOR pathway proteins, and to activate AMPK and LKB1, which can suppress mTOR signalling. Thus, it appears that RSV plays a role in modulation of proteins of the mTOR pathway although more research is still needed to fully understand the interaction.

The integration of molecular information in clinical decision making is becoming a reality. These changes are shaping the way clinical research is conducted, and as reality sets in, the challenges in conducting, managing and organising multi-disciplinary research become apparent. Clinical trials provide a platform to conduct translational research (TR) within the context of high quality clinical data accrual. Integrating TR objectives in trials allows the execution of pivotal studies that provide clinical evidence for biomarker-driven treatment strategies, targeting early drug development trials to a homogeneous and well defined patient population, supports the development of companion diagnostics and provides an opportunity for deepening our understanding of cancer biology and mechanisms of drug action. To achieve these goals within a clinical trial, developing translational research infrastructure and capabilities (TRIC) plays a critical catalytic role for translating preclinical data into successful clinical research and development. TRIC represents a technical platform, dedicated resources and access to expertise promoting high quality standards, logistical and operational support and unified streamlined procedures under an appropriate governance framework. TRIC promotes integration of multiple disciplines including biobanking, laboratory analysis, molecular data, informatics, statistical analysis and dissemination of results which are all required for successful TR projects and scientific progress. Such a supporting infrastructure is absolutely essential in order to promote high quality robust research, avoid duplication and coordinate resources. Lack of such infrastructure, we would argue, is one reason for the limited effect of TR in clinical practice beyond clinical trials.

Testicular cancer is the most frequent solid malignant tumour type in men 20–40 years of age. At the time of diagnosis up to 50% of the patients suffer from metastatic disease. In contrast to most other metastatic solid tumours, the majority of metastatic testicular cancer patients can be cured with highly effective cisplatin-based chemotherapy. This review aims to summarise the current knowledge on response to chemotherapy and the biological basis of cisplatin-induced apoptosis in testicular cancer. The frequent presence of wild-type TP53 and the low levels of p53 in complex with the p53 negative feed-back regulator MDM2 contribute to cisplatin sensitivity. Moreover, the high levels of the pluripotency regulator Oct4 and as a consequence of Oct4 expression high levels of miR-17/106b seed family and pro-apoptotic Noxa and the low levels of cytoplasmic p21 (WAF1/Cip1) appear to be causative for the exquisite sensitivity to cisplatin-based therapy of testicular cancer. However, resistance of testicular cancer to cisplatin-based therapy does occur and can be mediated through aberrant levels of the above mentioned key players. Drugs targeting these key players showed, at least pre-clinically, a sensitising effect to cisplatin treatment. Further clinical development of such treatment strategies will lead to new treatment options for platinum-resistant testicular cancers.

In recent years, there have been many new developments in the field of regulatory T cells (Treg), challenging the consensus on their behaviour, classification and role(s) in disease. The role Treg might play in autoimmune disease appears to be more complex than previously thought. Here, we discuss the current knowledge of regulatory T cells through animal and human research and illustrate the recent developments in childhood autoimmune arthritis (juvenile idiopathic arthritis (JIA)). Furthermore, this review summarises our understanding of the fields and assesses current and future implications for Treg in the treatment of JIA.

Integrase (IN) is required for lentivirus replication and is a proven drug target for the prevention of AIDS in HIV-1-infected patients. While clinical strand transfer inhibitors disarm the IN active site, allosteric inhibition of enzyme activity through the disruption of IN–IN protein interfaces holds great therapeutic potential. A promising class of allosteric IN inhibitors (ALLINIs), 2-(quinolin-3-yl) acetic acid derivatives, engage the IN catalytic core domain dimerisation interface at the binding site for the host integration co-factor LEDGF/p75. ALLINIs promote IN multimerisation and, independent of LEDGF/p75 protein, block the formation of the active IN–DNA complex, as well as inhibit the IN–LEDGF/p75 interaction in vitro. Yet, rather unexpectedly, the full inhibitory effect of these compounds is exerted during the late phase of HIV-1 replication. ALLINIs impair particle core maturation as well as reverse transcription and integration during the subsequent round of virus infection. Recapitulating the pleiotropic phenotypes observed with numerous IN mutant viruses, ALLINIs provide insight into underlying aspects of IN biology that extend beyond its catalytic activity. Therefore, in addition to the potential to expand our repertoire of HIV-1 antiretrovirals, ALLINIs afford important structural probes to dissect the multifaceted nature of the IN protein throughout the course of HIV-1 replication.