The control of gene expression, and more significantly gene cohorts, requires tight transcriptional coordination and is an essential feature of probably all cells. In higher eukaryotes, the mechanisms used involve controlled modifications to both local and global DNA environments, principally through changes in chromatin structure as well as cis-element-driven mechanisms. Although the mechanisms regulating chromatin in terms of transcriptional permissiveness and the relation to developmental programmes and responses to the environment are becoming better understood for animal and fungal cells, it is only just beginning to become clear how these processes operate in other taxa, including the trypanosomatids. Recent advances are now illuminating how African trypanosomes regulate higher-order chromatin structure, and, further, how these mechanisms impact on the expression of major surface antigens that are of fundamental importance to life-cycle progression. It is now apparent that several mechanisms are rather more similar between animal and fungal cells and trypanosomes than it originally appeared, but some aspects do involve gene products unique to trypanosomes. Therefore, both evolutionarily common and novel mechanisms cohabit in trypanosomes, offering both important biological insights and possible therapeutic opportunity.

Tumour-associated macrophages (TAMs) constitute a plastic and heterogeneous cell population of the tumour microenvironment (TME) that can account for up to 50% of solid tumours. TAMs heterogeneous are associated with different cancer types and stages, different stimulation of bioactive molecules and different TME, which are crucial drivers of tumour progression, metastasis and resistance to therapy. In this context, understanding the sources and regulatory mechanisms of TAM heterogeneity and searching for novel therapies targeting TAM subpopulations are essential for future studies. In this review, we discuss emerging evidence highlighting the redefinition of TAM heterogeneity from three different directions: origins, phenotypes and functions. We notably focus on the causes and consequences of TAM heterogeneity which have implications for the evolution of therapeutic strategies that targeted the subpopulations of TAMs.

Pregnancy is a complex biological process. The establishment and maintenance of foetal–maternal interface are pivotal events. Decidual immune cells and inflammatory cytokines play indispensable roles in the foetal–maternal interface. The disfunction of decidual immune cells leads to adverse pregnancy outcome. Tumour necrosis factor (TNF)-α, a common inflammatory cytokine, has critical roles in different stages of normal pregnancy process. However, the relationship between the disorder of TNF-α and adverse pregnancy outcomes, including preeclampsia (PE), intrauterine growth restriction (IUGR), spontaneous abortion (SA), preterm birth and so on, is still indefinite. In this review, we thoroughly reviewed the effect of TNF-α disorder on pathological conditions. Moreover, we summarized the reports about the adverse pregnancy outcomes (PE, IUGR, SA and preterm birth) of using anti-TNF-α drugs (infliximab, etanercept and adalimumab, certolizumab and golimumab) currently in the clinical studies. Overall, IUGR, SA and preterm birth are the most common adverse pregnancy outcomes of anti-TNF-α drugs. Our review may provide insight for the immunological treatment of pregnancy-related complication, and help practitioners make informed decisions based on the current evidences.

In the mammalian testis, spermatogenesis is a highly coordinated process of germ cell development, which ends with the release of ‘mature’ spermatozoa. The fine regulation of spermatogenesis is strictly dependent on sex steroid hormones, which orchestrate the cellular and molecular events underlying normal development of germ cells. Sex steroids actions also rely on the control of germ cell survival, and the programmed cell death by apoptosis has been indicated as a critical process in regulating the size and quality of the germ line. Recently, oestrogens have emerged as important regulators of germ cell fate. However, the beneficial or detrimental effects of oestrogens in spermatogenesis are controversial, with independent reports arguing for their role as cell survival factors or as apoptosis-inducers. The dual behaviour of oestrogens, shifting from ‘angels to devils’ is supported by the clinical findings of increased oestrogens levels in serum and intratesticular milieu of idiopathic infertile men. This review aims to discuss the available information concerning the role of oestrogens in the control of germ cell death and summarises the signalling mechanisms driven oestrogen-induced apoptosis. The present data represent a valuable basis for the clinical management of hyperoestrogenism-related infertility and provide a rationale for the use of oestrogen-target therapies in male infertility.

The management of malignant disease remains one of the most challenging areas of modern medicine. The lifetime risk of developing cancer in the western world is estimated to be as high as 1 in 3. Traditionally, surgery, chemotherapy and radiotherapy have been the primary choice of treatment for patients with malignant tumours. Despite advances in the use and development of conventional cytotoxic agents, the cure rate remains disappointing in most patients with advanced disease of the common solid tumours. Consequently, the development of novel anti-cancer therapies is a high priority in cancer medicine. In recent years, a new generation of cancer therapies has emerged, based on a growing understanding of the molecular events that contribute to malignant transformation. A major difference between normal and cancer cells is the ability of cancer cells to multiply in an unrestricted and ungoverned fashion. In this context, there is considerable interest in elucidating the mechanisms that allow this unrestricted proliferation and that ultimately result in immortal cancer cells. It is now clear that the enzyme telomerase confers immortality on cells in most types of cancer. With the cancer cell reliant on telomerase for its survival, telomerase represents an extremely attractive mechanism-based target for the development of new cancer therapeutics.

Dietary isoflavones are currently receiving much attention because of their potential role in preventing coronary artery disease and other chronic diseases. Accumulating evidence from cell culture and laboratory animal experiments indicates that isoflavones have the potential to prevent or delay atherogenesis. Suggested mechanisms of action include: a reduction in low-density lipoprotein (LDL) cholesterol and a potential reduction in the susceptibility of the LDL particle to oxidation; (2) an improvement in vascular reactivity; (3) an inhibition of pro-inflammatory cytokines, cell adhesion proteins and nitric oxide (NO) production; and (4) an inhibition of platelet aggregation. These mechanisms are consistent with the epidemiological evidence that a high consumption of isoflavone-rich soy products is associated with a reduced incidence of coronary artery disease. Biological effects of isoflavones are dependent on many factors, including dose consumed, duration of use, protein-binding affinity, and an individual's metabolism or intrinsic oestrogenic state. Further clinical studies are necessary to determine the potential health effects of isoflavones in specific population groups as we currently know little about age-related differences in exposure to these compounds and there are few guidelines on optimal dose for cardiovascular health benefits.

Infection of the cornea with herpes simplex virus (HSV) can result in a chronic disease called herpetic stromal keratitis (HSK). The disease represents one of the leading causes of infectious blindness in the Western world. Immune-mediated cellular damage is suspected in the pathogenesis of human HSK. The murine model has been pivotal in further establishing HSK as an immunopathological disease. This article reviews understanding of HSK, both in humans and in the mouse model, with an emphasis on possible future therapeutic strategies to counteract this blinding immunoinflammatory disease

Dendritic cells are the most potent antigen-presenting cells of the mammalian immune system and are central to the initiation and maintenance of the adaptive immune response. They are crucial for the presentation of antigen to T cells and B cells, as well as the induction of chemokines and proinflammatory cytokines, which orchestrate the balance of the cell-mediated (Th1) and antibody (Th2) response. This ability of dendritic cells to present antigen and release chemokines and cytokines also bridges the innate and adaptive immune responses by driving T cell activation. These cells thus possess key immunological functions that make them the front line of defence for the targeting and clearance of any invading pathogen and, as such, they underpin the host immune response to infection. For efficient infection, invading pathogens often need to overcome these sentinel immune functions. It is therefore not surprising that pathogens have evolved numerous mechanisms to target dendritic cell functions directly or indirectly during infection, and at least one herpesvirus – human cytomegalovirus – has evolved a life cycle that hijacks dendritic cells for its long-term persistence in the infected host.

Stem cells are unique cells exhibiting self-renewing properties and the potential to differentiate into multiple specialised cell types. Totipotent or pluripotent stem cells are generally abundant in embryonic or fetal tissues, but the use of discarded embryos as sources of these cells raises challenging ethical problems. Adult stem cells can also differentiate into a wide variety of cell types. In particular, adult adipose tissue contains a pool of abundant and accessible multipotent stem cells, designated as adipose-derived stem cells (ASCs), that are able to replicate as undifferentiated cells, to develop as mature adipocytes and to differentiate into multiple other cell types along the mesenchymal lineage, including chondrocytes, myocytes and osteocytes, and also into cells of endodermal and neuroectodermal origin, including beta-cells and neurons, respectively. An impairment in the differentiation potential and biological functions of ASCs may contribute to the development of obesity and related comorbidities. In this review, we summarise different aspects of the ASCs with special reference to the isolation and characterisation of these cell populations, their relation to the biochemical features of the adipose tissue depot of origin and to the metabolic characteristics of the donor subject and discuss some prospective therapeutic applications.

In an attempt to combat the pain and damage generated by rheumatoid arthritis (RA), new drugs are being developed to target molecular aspects of the disease process. Recently, a major development has been the use of biologicals (antibodies and soluble receptors) that neutralise the activity of tumour necrosis factor α (TNF-α) and interleukin 1 (IL-1), both of which are involved in disease progression. An increase in our understanding of cell and molecular biology has resulted in the identification and investigation of potential new targets, and also the refinement and improvement of current therapeutic modalities. This review describes therapies that are approved, in clinical trials or under pre-clinical investigation at the laboratory level, particularly focusing on cytokines, although other therapeutic targets of interest are mentioned.

Tumour recurrence is one of the biggest challenges in breast cancer management because it affects 25–30% of women with breast cancer and the tumours are often incurable. Women with triple-negative breast cancer (TNBC – lacking expression of the oestrogen receptor, progesterone receptor and the receptor HER2/ERBB2) have the highest rates of early recurrence relative to other breast cancer subtypes. Early recurrence might be due to tumour-initiating cells (TICs), which are resistant to conventional therapies, can remain dormant and can subsequently give rise to secondary tumours. In breast cancer, TICs are identified by the cell-surface markers CD44+/CD24−/EpCAM+ and/or possess ALDH1 enzyme activity. This subpopulation has the ability to self-renew, grow as mammospheres and initiate tumour formation. Fuelling the problem of relapse is the fact that chemotherapy and radiation can induce or select for TICs; this was reported in preclinical models and more recently in women being treated for breast cancer. Thus, new therapeutic agents for TNBC are presently being sought to overcome this problem. Here we review the roles of receptor tyrosine kinases, signalling intermediates and transcription factors in sustaining the TIC subpopulation. Particular emphasis is placed on targeting these molecules in order to eliminate and/or prevent the induction of TICs and ultimately reduce the frequency of TNBC recurrence.

FLASH radiotherapy is a novel technique that has been shown in numerous preclinical in vivo studies to have the potential to be the next important improvement in cancer treatment. However, the biological mechanisms responsible for the selective FLASH sparing effect of normal tissues are not yet known. An optimal translation of FLASH radiotherapy into the clinic would require a good understanding of the specific beam parameters that induces a FLASH effect, environmental conditions affecting the response, and the radiobiological mechanisms involved. Even though the FLASH effect has generally been considered as an in vivo effect, studies finding these answers would be difficult and ethically challenging to carry out solely in animals. Hence, suitable in vitro studies aimed towards finding these answers are needed. In this review, we describe and summarise several in vitro assays that have been used or could be used to finally elucidate the mechanisms behind the FLASH effect.

Muscular dystrophy is a group of genetic disorders characterised by degeneration of muscles. Different forms of muscular dystrophy can show varying phenotypes with a wide range of age, severity and location of muscle deterioration. Many palliative care options are available for muscular dystrophy patients, but no curative treatment is available. Exon-skipping therapy aims to induce skipping of exons with disease-causing mutations and/or nearby exons to restore the reading frame, which results in an internally truncated, partially functional protein. In antisense-mediated exon-skipping synthetic antisense oligonucleotide binds to pre-mRNA to induce exon skipping. Recent advances in exon skipping have yielded promising results; the US Food and Drug Administration (FDA) approved eteplirsen (Exondys51) as the first exon-skipping drug for the treatment of Duchenne muscular dystrophy, and in vivo exon skipping has been demonstrated in animal models of dysferlinopathy, limb-girdle muscular dystrophy type 2C and congenital muscular dystrophy type 1A. Novel methods that induce exon skipping utilizing Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) are also being developed where splice site mutations are created within the genome to induce exon skipping. Challenges remain as exon-skipping agents can have deleterious non-specific effects and different in-frame deletions show phenotypic variance. This article reviews the state of the art of exon skipping for treating muscular dystrophy and discusses challenges and future prospects.

Wilms' tumour (WT; nephroblastoma), a kidney neoplasm, is one of the most frequently occurring solid tumours of childhood. It arises from the developing kidney by genetic and epigenetic changes that lead to the abnormal proliferation of renal stem cells (metanephric blastema). WT serves as a paradigm for understanding the relationship between loss of developmental control and gain of tumourigenic potential. In particular, loss of function of tumour suppressor genes has been implicated in the development of WT, and the Wilms' tumour suppressor gene WT1 (at chromosome 11p13) was the second tumour suppressor gene to be cloned, after the retinoblastoma gene RB-1. WT1 plays an essential role in kidney development, but is mutated in only approximately 20% of WTs, which suggests that further lesions and genetic loci are involved in Wilms' tumourigenesis. Other chromosomal regions associated with WT include 7p, 11p15, 16q and 17q. Although many of these loci probably contain tumour suppressor genes, imprinted genes (genes showing expression of only one parental allele) and oncogenes have also been implicated in WT. Some loci have been shown to be associated with particular clinical outcomes, suggesting that they might be used to determine prognosis, and especially to identify poor prognostic subgroups that can be targeted for aggressive and/or novel therapies.

Experimental and human studies have shown that proteinuria contributes to the progression of renal disease. Overexposure to filtered proteins promotes the expression and release of chemokines by tubular epithelial cells, thus leading to inflammatory cell recruitment and renal impairment. This review focuses on recent progress in cellular and molecular understanding of the role of chemokines in the pathogenesis of proteinuria-induced renal injury, as well as their clinical implications and therapeutic potential.

The single-pass transmembrane protein KCNE2 or MIRP1 was once thought to be the missing accessory protein that combined with hERG to fully recapitulate the cardiac repolarising current IKr. As a result of this role, it was an easy next step to associate mutations in KCNE2 to long QT syndrome, in which there is delayed repolarisation of the heart. Since that time however, KCNE2 has been shown to modify the behaviour of several other channels and currents, and its role in the heart and in the aetiology of long QT syndrome has become less clear. In this article, we review the known interactions of the KCNE2 protein and the resulting functional effects, and the effects of mutations in KCNE2 and their clinical role.

Glioblastoma (GBM) is the most common and aggressive primary brain tumour, yet little progress has been made towards providing better treatment options for patients diagnosed with this devastating condition over the last few decades. The complex nature of the disease, heterogeneity, highly invasive potential of GBM tumours and until recently, reduced investment in research funding compared with other cancer types, are contributing factors to few advancements in disease management. Survival rates remain low with less than 5% of patients surviving 5 years. Another important contributing factor is the use of preclinical models that fail to fully recapitulate GBM pathophysiology, preventing efficient translation from the lab into successful therapies in the clinic. This review critically evaluates current preclinical GBM models, highlighting advantages and disadvantages of using such models, and outlines several emerging techniques in GBM modelling using animal-free approaches. These novel approaches to a highly complex disease such as GBM show evidence of a more truthful recapitulation of GBM pathobiology with high reproducibility. The resulting advancements in this field will offer new biological insights into GBM and its aetiology with potential to contribute towards the development of much needed improved treatments for GBM in future.

The mitogen-activated protein kinase (MAPK) pathway has been implicated in the pathophysiology of many cancers. Under normal physiologic conditions, the RAS–RAF–mitogen-activated protein kinase kinase (MEK)–mitogen-activated protein kinase (ERK) signalling cascade interaction is initiated by ligation of a receptor-linked tyrosine kinase by its cognate growth factor. It has been demonstrated in many systems that aberrant autocrine or paracrine stimulation of growth factor receptors is pathogenic in large part because of MAPK activation. As one of the key downstream effector pathways of mutated RAS (KRAS, NRAS and HRAS), pharmacologic inhibition of components of the MAPK pathway has been pursued as a means to indirectly inhibit RAS, which remains a technical challenge for direct pharmacologic inhibition. RAF and MEK are the two non-membrane-bound, serine–threonine and tyrosine–threonine kinases, within the pathway that have been most extensively explored as drug targets. The discovery of activating BRAF mutations in cancer clarified which cancer types and subsets of certain cancers are most dependent on activation of the MAPK pathway for growth and survival. Now, with the successful translation of selective BRAF and MEK inhibitors into validated therapies for BRAF mutant melanoma, the field seeks to resolve the role for these agents in cancers harbouring RAS mutations or those driven by aberrant growth factor receptor activation.

Within the past decade, many oncolytic viruses (OVs) have been studied as potential treatments for pancreatic cancer and some of these are currently under clinical trials. The applicability of certain OVs, such as adenoviruses, herpesviruses and reoviruses, for the treatment of pancreatic cancer has been intensively studied for several years, whereas the applicability of other more recently investigated OVs, such as poxviruses and parvoviruses, is only starting to be determined. At the same time, studies have identified key characteristics of pancreatic cancer biology that provide a better understanding of the important factors or pathways involved in this disease. This review aims to summarise the different replication-competent OVs proposed as therapeutics for pancreatic cancer. It also focuses on the unique biology of these viruses that makes them exciting candidate virotherapies for pancreatic cancer and discusses how they could be genetically manipulated or combined with other drugs to improve their efficacy based on what is currently known about the molecular biology of pancreatic cancer.

Malaria remains one of the biggest health problems in large parts of the world. In sub-Saharan Africa alone, it is currently estimated that there are more than 150 million clinical cases annually, and that about 2 million people die from the disease every year. The bulk of malaria-related morbidity and mortality in an endemic setting (malaria is regularly found) is concentrated in children below the age of five years, and the increasing resistance to infection and disease with age is conventionally thought to reflect a slow and gradual acquisition of protective immunity. Many recent and comprehensive reviews of malarial immunity exist; rather than attempting to add another, this review summarises some of the recent evidence on how protective immunity is acquired in humans and what precipitates clinical disease, specifically as it relates to populations living in areas where the disease is endemic. It is becoming increasingly clear that naturally acquired protective immunity depends largely on responses directed against highly variable parasite antigens. This implies that a successful blood-stage vaccine against this disease must be able to either induce protective responses against many of these variants, or artificially initiate protective immune responses that do not normally occur following natural exposure to the parasites. Such protective immune responses might either rely on a different immunological mechanism, or be directed against other antigens, other than those seen in naturally acquired protective immunity. It remains to be seen whether it will be possible to induce protective responses such as these by ‘artificially’ immunising humans.