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.

Tumour hypoxia stems from impaired oxygen delivery as a result of a disorganised tumour vasculature and inadequate blood supply. Hypoxic tumours are highly resistant to chemotherapy and radiation therapy and correlate with a poor patient prognosis. Hypoxia is a powerful stimulus for the expression of genes involved in cell survival and angiogenesis. A key factor in this process is hypoxia-inducible factor (HIF), which regulates transcription of hypoxia-activated genes. Efforts are currently under way to develop targeted cancer therapeutics to hypoxia-activated pathways, and in particular to the transcription factor HIF.

Mutations that exaggerate signalling of the receptor tyrosine kinase fibroblast growth factor receptor 3 (FGFR3) give rise to achondroplasia, the most common form of dwarfism in humans. Here we review the clinical features, genetic aspects and molecular pathogenesis of achondroplasia and examine several therapeutic strategies designed to target the mutant receptor or its signalling pathways, including the use of kinase inhibitors, blocking antibodies, physiologic antagonists, RNAi and chaperone inhibitors. We conclude by discussing the challenges of treating growth plate disorders in children.

Salmonella enterica causes a range of life-threatening diseases in humans and animals worldwide. Current treatments for S. enterica infections are not sufficiently effective, and there is a need to develop new vaccines and therapeutics. An understanding of how S. enterica spreads in tissues has very important implications for targeting bacteria with vaccine-induced immune responses and antimicrobial drugs. Development of new control strategies would benefit from a more sophisticated evaluation of bacterial location, spatiotemporal patterns of spread and distribution in the tissues, and sites of microbial persistence. We review here recent studies of S. enterica serovar Typhimurium (S. Typhimurium) infections in mice, an established model of systemic typhoid fever in humans, which suggest that continuous bacterial spread to new infection foci and host phagocytes is an essential trait in the virulence of S. enterica during systemic infections. We further highlight how infections within host tissues are truly heterogeneous processes despite the fact that they are caused by the expansion of a genetically homogeneous microbial population. We conclude by discussing how understanding the within-host quantitative, spatial and temporal dynamics of S. enterica infections might aid the development of novel targeted preventative measures and drug regimens.

Humans and other vertebrates exhibit left–right (LR) asymmetric arrangement of the internal organs, and failure to establish normal LR asymmetry leads to internal laterality disorders, including situs inversus and heterotaxy. Situs inversus is complete mirror-imaged arrangement of the internal organs along LR axis, whereas heterotaxy is abnormal arrangement of the internal thoraco-abdominal organs across LR axis of the body, most of which are associated with complex cardiovascular malformations. Both disorders are genetically heterogeneous with reduced penetrance, presumably because of monogenic, polygenic or multifactorial causes. Research in genetics of LR asymmetry disorders has been extremely prolific over the past 17 years, and a series of loci and disease genes involved in situs inversus and heterotaxy have been described. The review highlights the classification, chromosomal abnormalities, pathogenic genes and the possible mechanism of human LR asymmetry disorders.

Antisense oligonucleotides as a therapeutic platform have been slow to progress since the approval of the first antisense drug in 1998. Recently, there have been several examples of convincing antisense interventions in animal models and promising clinical trial data. This review considers the factors determining the success of antisense oligonucleotides as therapeutic agents. In order to produce target knockdown after systemic delivery, antisense oligonucleotides must avoid nuclease degradation, reticuloendothelial-system uptake and rapid renal excretion, and extravasate to the target cell type outside the vasculature. They then must enter the target cell, and escape the endosome–lysosome pathway so as to be free to interact with the target mRNA. We consider the significance of these limiting factors based on the literature and our own experience using systemic administration of antisense oligonucleotides.

Angptl2 is a multifaceted protein, displaying both physiological and pathological functions, in which scientific and clinical interest is growing exponentially within the past few years. Its physiological functions are not well understood, but angptl2 was first acknowledged for its pro-angiogenic and antiapoptotic capacities. In addition, angptl2 can be considered a growth factor, since it increases survival and expansion of hematopoietic stem cells and may promote vasculogenesis. Finally, angptl2 has an important, but largely unrecognised, physiological role: in the cytosol, angptl2 binds to type 1A angiotensin II receptors and induces their recycling, with recovery of the receptor signal functions. Despite these important physiological properties, angptl2 is better acknowledged for its deleterious pro-inflammatory properties and its contribution in multiple chronic diseases such as cancer, diabetes, atherosclerosis, metabolic disorders and many other chronic diseases. This review aims at presenting an updated description of both the beneficial and deleterious biological properties of angptl2, in addition to its molecular signalling pathways and transcriptional regulation. The multiplicity of diseases in which angptl2 contributes makes it a new highly relevant clinical therapeutic target.

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.

This review discusses mechanisms that link allelic variants of major histocompatibility complex (MHC) class II molecules (MHCII) to immune pathology. We focus on HLA (human leukocyte antigen)-DQ (DQ) alleles associated with celiac disease (CD) and type 1 diabetes (T1D) and the role of the murine DQ-like allele, H2-Ag7 (I-Ag7 or Ag7), in murine T1D. MHCII molecules bind peptides, and alleles vary in their peptide-binding specificity. Disease-associated alleles permit binding of disease-inducing peptides, such as gluten-derived, Glu-/Pro-rich gliadin peptides in CD and peptides from islet autoantigens, including insulin, in T1D. In addition, the CD-associated DQ2.5 and DQ8 alleles are unusual in their interactions with factors that regulate their peptide loading, invariant chain (Ii) and HLA-DM (DM). The same alleles, as well as other T1D DQ risk alleles (and Ag7), share nonpolar residues in place of Asp at β57 and prefer peptides that place acidic side chains in a pocket in the MHCII groove (P9). Antigen-presenting cells from T1D-susceptible mice and humans retain CLIP because of poor DM editing, although underlying mechanisms differ between species. We propose that these effects on peptide presentation make key contributions to CD and T1D pathogenesis.

Ovarian carcinomas show more morphological heterogeneity than adenocarcinomas of any other body site. It has recently become clear that the morphologically defined subtypes of ovarian carcinoma are distinct diseases, with different risk factors, molecular events during oncogenesis, likelihood of spread, responses to chemotherapy, and outcomes. This review focuses on molecular abnormalities (in genes expressing BRCA1/2, TP53 and RB1/CCND1/CDKN2A/E2F) found in high-grade serous carcinomas of the ovary, which account for most ovarian cancer deaths. These highly aggressive but chemosensitive tumours are associated with perturbation of molecular pathways leading to genomic instability and extreme mutability and present unique challenges in oncological research and practice.

The protozoan parasite Entamoeba histolytica is the causative agent of amoebic dysentery. It is prevalent in developing countries that cannot prevent its fecal–oral spread and ranks second in worldwide causes of morbidity by parasitic infection. Improvements in sanitation would help curb disease spread. However, a lack of significant progress in this area has resulted in the need for a better understanding of the molecular and cellular biology of pathogenesis in order to design novel methods of disease treatment and prevention. Recent insight into the cellular mechanisms regulating virulence of E. histolytica has indicated that processes such as endocytosis, secretion, host cell adhesion and encystation play major roles in the infectious process. This review focuses on components of the molecular machinery that govern these cellular processes and their role in virulence, and discusses how an understanding of this might reveal opportunities to interfere with E. histolytica infection.

Recent advances in surgical techniques have made it possible to study the changes that are known as degeneration of the intervertebral disc (IVD) in greater depth than ever before. This is an important area of study because degeneration of the lumbar IVDs is associated, perhaps causally, with low back pain: one of the most common and debilitating conditions in the western world. The term degeneration implies an inevitable progression that is characteristic of wear-and-tear-associated conditions. However, modern research on human tissue has shown that this is not the case. Here, disruption of the micro-anatomy that is described as degeneration is an active process, which is probably regulated by locally produced cytokines. This one observation opens up the possibility of inhibiting or even reversing the processes of degeneration. The immediate question is how can the slowly progressive changes of degeneration be treated, particularly as connective tissue repair is thought to be a slow and highly regulated process. In this review, the possibility of using gene therapy as a single-shot, long-lasting therapeutic strategy is discussed, together with an outline of developments in this area to date.

A wide range of viruses, including many human and animal pathogens representing various taxonomic groups, contain genomes that are enclosed in lipid envelopes. These envelopes are generally acquired in the final stages of assembly, as viruses bud from regions of the membrane of the infected cell at which virally encoded membrane proteins have accumulated. The viruses procure their membranes during this process and mature particles ‘pinch off’ from the cellular membranes. Under most circumstances, initiation of another round of infection is dependent on two critical functions supplied by the envelope proteins. The virus must bind to cell-surface receptors of a new host cell, and fusion of the viral and cellular membranes must occur to transfer the viral genome into the cell. Enveloped viruses have evolved a variety of mechanisms to execute these two basic functions. Owing to their relative simplicity, studies of binding and fusion using enveloped viruses and their components have contributed significantly to the overall understanding of receptor–ligand interactions and membrane fusion processes – fundamental activities involved in a plethora of biological functions.

Atherosclerosis is a pathological process that takes place in the major arteries and is the underlying cause of heart attacks, stroke and peripheral artery disease. The earliest detectable lesions, called fatty streaks, contain macrophage foam cells that are derived from recruited monocytes. More-advanced atherosclerotic lesions, called fibro-fatty plaques, are the result of continued monocyte recruitment and smooth muscle cell migration and proliferation. Variable numbers of CD4+ T cells are found in atherosclerotic lesions, and cytokines secreted by T helper 1 (Th1)- or Th2-type cells can have a profound influence on macrophage gene expression within atherosclerotic plaques. This review briefly addresses the key features of macrophage biology and discusses the factors that influence the growth and development of atherosclerotic lesions (atherogenesis). It then considers the potential role of chemokines in mediating monocyte recruitment and macrophage differentiation within atherosclerotic lesions.

Vitiligo is a depigmenting disorder characterised by the loss of melanocytes from the cutaneous epidermis. Although the exact aetiology of vitiligo has not yet been established, the abnormal immune responses frequently observed in vitiligo patients have led to the suggestion that, in some cases, the condition has an autoimmune component. Briefly, circulating autoantibodies and autoreactive T cells that recognise pigment cell antigens have been detected in the sera of a significant proportion of vitiligo patients compared with healthy individuals. In addition, vitiligo is often associated with other disorders that have an autoimmune origin, including Hashimoto's thyroiditis, Graves' disease, type 1 insulin-dependent diabetes mellitus and Addison's disease. Furthermore, effective use of immunosuppressive therapies to treat vitiligo, the association of vitiligo with certain major histocompatibility complex antigens, and evidence from animal models of the disease have all added credence to the hypothesis that immune reactions play a role in vitiligo pathogenesis. This review presents and discusses the evidence for immunological pathomechanisms in vitiligo.

The prevalence of oropharyngeal candidiasis continues to be high, mainly because of an increasing population of immunocompromised patients. Traditional treatment of oropharyngeal candidiasis has relied on the use of antimicrobial drugs. However, unsatisfactory results with drug monotherapy and the emergence of resistant strains have prompted investigations into the potential use of adjunctive immunoenhancing therapies for the treatment of these infections. Here we review the host-recognition systems of Candida albicans, the immune and inflammatory response to infection, and antifungal effector mechanisms. The potential of immune modulation as a therapeutic strategy in oropharyngeal candidiasis is also discussed.

Cancer metastasis occurs through local invasion of circulating tumour cells (CTCs), intravasation, transportation to distant sites, and their extravasation followed by colonisation at secondary sites. Epithelial–mesenchymal transition (EMT) is a normal developmental phenomenon, but its aberrant activation confers tumour cells with enhanced cell motility, metastatic properties, resistant to therapies and cancer stem cell (CSC) phenotype in epithelium-derived carcinoma.

Experimental studies from various research papers have been reviewed to determine the factors, which interlink cancer stemness and cellular plasticity with EMT. Although existence of CSCs has been linked with EMT, nevertheless, there are controversies with the involvement of type of tumour cells, including cells with E (epithelial) and M (mesenchymal) phenotype alone or hybrid E/M phenotype in different types of cancers. Studies on CTCs with hybrid E/M phenotypes during different stages of cancer metastasis reveal strong association with tumour -initiation potential, cellular plasticity and types of cancer cells. Cells with the hybrid E/M state are strictly controlled by phenotypic stability factors coupled to core EMT decision-making circuits, miR200/ZEB and miR-34/Snail.

Understanding the regulatory functions of EMT program in cancer metastasis can help us to characterise the biomarkers of prognostic and therapeutic potential. These biomarkers when targeted may act as metastatic suppressors, inhibit cellular plasticity and stemness ability of tumour cells and can block metastatic growth.

Amyotrophic lateral sclerosis (ALS) is a severe neuromuscular disease characterised by a progressive loss of motor neurons that usually results in paralysis and death within 2 to 5 years after disease onset. The pathophysiological mechanisms involved in ALS remain largely unknown and to date there is no effective treatment for this disease. Here, we review clinical and experimental evidence suggesting that dysregulation of copper homeostasis in the central nervous system is a crucial underlying event in motor neuron degeneration and ALS pathophysiology. We also review and discuss novel approaches seeking to target copper delivery to treat ALS. These novel approaches may be clinically relevant not only for ALS but also for other neurological disorders with abnormal copper homeostasis, such as Parkinson's, Huntington's and Prion diseases.

Attention deficit hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder with complex genetic aetiology. The identification of candidate intermediate phenotypes may facilitate the detection of susceptibility genes and neurobiological mechanisms underlying the disorder. Electroencephalography (EEG) is an ideal neuroscientific approach, providing a direct measurement of neural activity that demonstrates reliability, developmental stability and high heritability. This systematic review evaluates the utility of a subset of electrophysiological measures as potential intermediate phenotypes for ADHD: quantitative EEG indices of arousal and intraindividual variability, and functional investigations of attention, inhibition and performance monitoring using the event-related potential (ERP) technique. Each measure demonstrates consistent and meaningful associations with ADHD, a degree of genetic overlap with ADHD and potential links to specific genetic variants. Investigations of the genetic and environmental contributions to EEG/ERP and shared genetic overlap with ADHD might enhance molecular genetic studies and provide novel insights into aetiology. Such research will aid in the precise characterisation of the clinical deficits seen in ADHD and guide the development of novel intervention and prevention strategies for those at risk.

Chemokines are small, chemotactic cytokines that direct migration of leukocytes, activate inflammatory responses and participate in many other pleiotropic functions, including regulation of tumour growth. Chemokines modulate tumour behaviour by three important mechanisms: regulation of tumour-associated angiogenesis, activation of a host tumour-specific immunological response, and direct stimulation of tumour cell proliferation in an autocrine fashion. All of these mechanisms are promising points of cancer intervention, and preclinical mouse models suggest that chemokine antagonists and agonists could become important in the development of new anticancer therapies.