It is now well established that epigenetic phenomena and aberrant gene regulation play a major role in carcinogenesis. These include aberrant gene silencing by imposing inactive histone marks on promoters, aberrant methylation of DNA at CpG islands, and the active repression of promoters by oncoproteins. In addition, many malignant cells also show aberrant gene activation due to constitutively active signalling. The next frontier in cancer research will be to examine how, at the molecular level, small mutations that alter the regulatory phenotype of a cell give rise after a number of cell divisions to the vast deregulation phenomena seen in malignant cells. This review outlines recent insights into how normal cell differentiation in the haematopoietic system is subverted in leukaemia and it introduces the molecular players involved in this process. It also summarises the results of recent clinical trials trying to reverse aberrant epigenetic regulation by employing agents influencing global epigenetic regulators.

Repeat-expansion mutations cause 13 autosomal dominant neurodegenerative disorders falling into three groups. Huntington's disease (HD), dentatorubral pallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA), and spinocerebellar ataxias (SCAs) types 1, 2, 3, 7 and 17 are each caused by a CAG repeat expansion that encodes polyglutamine. Convergent lines of evidence demonstrate that neurodegeneration in these diseases is a consequence of the neurotoxic effects of abnormally long stretches of glutamines. How polyglutamine induces neurodegeneration, and why neurodegeneration occurs in only select neuronal populations, remains a matter of intense investigation. SCA6 is caused by a CAG repeat expansion in CACNA1A, a gene that encodes a subunit of the P/Q-type calcium channel. The threshold length at which the repeat causes disease is much shorter than in the other polyglutamine diseases, and neurodegeneration may arise from expansion-induced change of function in the calcium channel. Huntington's disease-like 2 (HDL2) and SCAs 8, 10 and 12 are rare disorders in which the repeats (CAG, CTG or ATTCT) are not in protein-coding regions. Investigation into these diseases is still at an early stage, but it is now reasonable to hypothesise that the net effect of each expansion is to alter gene expression. The different pathogenic mechanisms in these three groups of diseases have important implications for the development of rational therapeutics.

Autoimmune diseases of the central nervous system (CNS) involve the migration of abnormal numbers of self-directed leukocytes across the blood–brain barrier that normally separates the CNS from the immune system. The cardinal lesion associated with neuroinflammatory diseases is the perivascular infiltrate, which comprises leukocytes that have traversed the endothelium and have congregated in a subendothelial space between the endothelial-cell basement membrane and the glial limitans. The exit of mononuclear cells from this space can be beneficial, as when virus-specific lymphocytes enter the CNS for pathogen clearance, or might induce CNS damage, such as in the autoimmune disease multiple sclerosis when myelin-specific lymphocytes invade and induce demyelinating lesions. The molecular mechanisms involved in the movement of lymphocytes through these compartments involve multiple signalling pathways between these cells and the microvasculature. In this review, we discuss adhesion, costimulatory, cytokine, chemokine and signalling molecules involved in the dialogue between lymphocytes and endothelial cells that leads to inflammatory infiltrates within the CNS, and the targeting of these molecules as therapies for the treatment of multiple sclerosis.

The fate of a forming thrombus is determined through the delicate balance between the coagulation cascade, favouring clot formation, and the fibrinolytic system, favouring clot lysis. These processes occur simultaneously, and enhancement of fibrinolysis has been shown to reduce occlusive thrombus formation in animal models. This review examines the roles of the major fibrinolytic factors involved in clot lysis. The regulation of plasmin activity by plasminogen activators, α-2-antiplasmin, plasminogen activator inhibitor 1, and thrombin-activatable fibrinolysis inhibitor, and their effects on thrombus formation in vivo are discussed. Since alterations in fibrinolytic capacity appear to affect thrombus formation in animal models, there is considerable interest in the pharmacological manipulation of fibrinolysis.

Despite the fact that insulin injection can protect diabetic patients from developing diabetes-related complications, recent meta-analyses indicate that rapid and long-acting insulin analogues only provide a limited benefit compared with conventional insulin regarding glycemic control. As insulin deficiency is the main sequel of type-1 diabetes (T1D), transfer of the insulin gene-by-gene therapy is becoming an attractive treatment modality even though T1D is not caused by a single genetic defect. In contrast to human insulin and insulin analogues, insulin gene therapy targets to supplement patients not only with insulin but also with C-peptide. So far, insulin gene therapy has had limited success because of delayed and/or transient gene expression. Sustained insulin gene expression is now feasible using current gene-therapy vectors providing patients with basal insulin coverage, but management of postprandial hyperglycaemia is still difficult to accomplish because of the inability to properly control insulin secretion. Enteroendocrine cells of the gastrointestinal track (K cells and L cells) may be ideal targets for insulin gene therapy, but cell-targeting difficulties have limited practical implementation of insulin gene therapy for diabetes treatment. Therefore, recent gene transfer technologies developed to generate authentic beta cells through transdifferentiation are also highlighted in this review.

Inherited bone marrow failure syndromes provide extremely useful genetic models for understanding leukaemogenesis because the initial genetic defect can be identified and the risk of leukaemia is very high. Shwachman–Diamond syndrome is one of the most common inherited bone marrow failure syndromes and an example of such a model. Here, I describe the malignant features of Shwachman–Diamond syndrome and discuss the potential molecular mechanisms that can lead to leukaemia.

Translational research is about transforming progress in basic research into products that benefit patients. Here I discuss some of the key obstacles to effective translational research in oncology that have previously received limited attention. Basic research often does not go far enough for straightforward clinical translation, and long-term, high-risk endeavours to fill these key gaps have not been adequately addressed either by industry or by the culture of investigator-initiated research. These key gaps include the identification of causative oncogenic mutations and new approaches to regulating currently undruggable targets such as tumour suppressor genes. Even where an inhibitor of a key target has been identified, new approaches to clinical development are needed. The current approach of treating broad populations of patients based primarily on primary cancer site is not well suited to the development of molecularly targeted drugs. Although developing drugs with predictive diagnostics makes drug development more complex, it can improve the success rate of development, as well as provide benefit to patients and the economics of healthcare. I review here some prospective Phase III designs that have been developed for transition from the era of correlative science to one of reliable predictive and personalised oncology.

Atopic dermatitis (AD) is a strongly heritable, chronic relapsing dermatosis that frequently co-occurs with other atopic phenotypes including asthma and allergic rhinitis (the so-called atopic triad disorders). However, despite high levels of co-morbidity, relatively low levels of genomic co-incidence have been observed between atopic triad disorders. Conversely, current mapping data have revealed a striking pattern of co-localisation between AD disease loci and those mapped using another chronic dermatological disease – psoriasis. In this review, we examine the evidence for co-localisation between AD and a range of atopic, infectious, inflammatory and autoimmune diseases, and consider the implications of these data for the AD disease concept and future research in the field.

Alveolar macrophages (AMs) are lung-resident myeloid cells that sit at the interface of the airway and lung tissue. Under homeostatic conditions, their primary function is to clear debris, dead cells and excess surfactant from the airways. They also serve as innate pulmonary sentinels for respiratory pathogens and environmental airborne particles and as regulators of pulmonary inflammation. However, they have not typically been viewed as primary therapeutic targets for respiratory diseases. Here, we discuss the role of AMs in various lung diseases, explore the potential therapeutic strategies to target these innate cells and weigh the potential risks and challenges of such therapies. Additionally, in the context of the COVID-19 pandemic, we examine the role AMs play in severe disease and the therapeutic strategies that have been harnessed to modulate their function and protect against severe lung damage. There are many novel approaches in development to target AMs, such as inhaled antibiotics, liposomal and microparticle delivery systems, and host-directed therapies, which have the potential to provide critical treatment to patients suffering from severe respiratory diseases, yet there is still much work to be done to fully understand the possible benefits and risks of such approaches.

Fragile X mental retardation 1 (FMR1) full-mutation expansion causes fragile X syndrome. Trans-generational fragile X syndrome transmission can be avoided by preimplantation genetic diagnosis (PGD). We describe a robust PGD strategy that can be applied to virtually any couple at risk of transmitting fragile X syndrome. This novel strategy utilises whole-genome amplification, followed by triplet-primed polymerase chain reaction (TP-PCR) for robust detection of expanded FMR1 alleles, in parallel with linked multi-marker haplotype analysis of 13 highly polymorphic microsatellite markers located within 1 Mb of the FMR1 CGG repeat, and the AMELX/Y dimorphism for gender identification. The assay was optimised and validated on single lymphoblasts isolated from fragile X reference cell lines, and applied to a simulated PGD case and a clinical in vitro fertilisation (IVF)-PGD case. In the simulated PGD case, definitive diagnosis of the expected results was achieved for all ‘embryos’. In the clinical IVF-PGD case, delivery of a healthy baby girl was achieved after transfer of an expansion-negative blastocyst. FMR1 TP-PCR reliably detects presence of expansion mutations and obviates reliance on informative normal alleles for determining expansion status in female embryos. Together with multi-marker haplotyping and gender determination, misdiagnosis and diagnostic ambiguity due to allele dropout is minimised, and couple-specific assay customisation can be avoided.

Breast cancer was the most commonly diagnosed cancer worldwide in 2020. Greater understanding of the factors which promote tumour progression, metastatic development and therapeutic resistance is needed. In recent years, a distinct microbiome has been detected in the breast, a site previously thought to be sterile. Here, we review the clinical and molecular relevance of the oral anaerobic bacterium Fusobacterium nucleatum in breast cancer. F. nucleatum is enriched in breast tumour tissue compared with matched healthy tissue and has been shown to promote mammary tumour growth and metastatic progression in mouse models. Current literature suggests that F. nucleatum modulates immune escape and inflammation within the tissue microenvironment, two well-defined hallmarks of cancer. Furthermore, the microbiome, and F. nucleatum specifically, has been shown to affect patient response to therapy including immune checkpoint inhibitors. These findings highlight areas of future research needed to better understand the influence of F. nucleatum in the development and treatment of breast cancer.

The adhesion of cells to their surrounding extracellular matrix has vital roles in embryonic development, inflammatory responses, wound healing and adult tissue homeostasis. Cells attach to extracellular matrix by specific cell-surface receptors, of which the integrins and transmembrane proteoglycans are major representatives. The engagement of adhesion receptors triggers assembly of functional matrix contacts, in which bound matrix components, adhesion receptors and associated intracellular cytoskeletal and signalling molecules form large, localised multiprotein complexes. This review discusses the functional categories of matrix contacts, examples of the biological roles of matrix contacts in normal physiology, and examples of the ways in which abnormalities of matrix contacts are associated with major human diseases.

Cancers are a complex set of proliferative diseases that arise in most cases through multi-step pathways involving an accumulation of genetic and epigenetic changes. These steps include inactivation of tumour suppressor genes and activation of oncogenes. However, in addition to genetic mutations in the tumour cells themselves, the local host environment can act as a critical modulator of cancer progression, having either tumour-suppressive or tumour-promoting effects depending on the stage and site of cancer development. Because stromal cells can have these opposing functions during cancer development and progression, a recurring theme throughout this review will be that of balance: maintaining the normal functions of these co-opted cells, yet selectively inhibiting their pro-tumourigenic functions. To achieve this equilibrium, we need to understand the molecular mechanisms by which normal cells become modified by cancer cells before we can hope to target these functions selectively. Here, we will discuss recent efforts to address these key challenges and offer perspectives on the translation of discoveries made in model systems to the clinic.

The introduction of cyclin-dependent kinase 4/6 inhibitors (CKIs) has marked a major development in the standard treatment of advanced breast cancer. Extensive preclinical, translational and clinical research efforts into CKI agents are ongoing, and clinical application of this class of systemic anti-cancer therapy is anticipated to expand beyond metastatic breast cancer treatment. Emerging evidence indicates that mechanisms by which CKI agents exert their therapeutic effect transcend their initially expected impacts on cell cycle control into the realms of cancer immunology and metabolism. The recent expansion in our understanding of the multifaceted impact of CKIs on tumour biology has the potential to improve clinical study design, therapeutic strategies and ultimately patient outcomes. This review contextualises the current status of CKI therapy by providing an overview of the original and emerging insights into mechanisms of action and the evidence behind their current routine use in breast cancer management. Recent preclinical and clinical studies into CKIs across tumour types are discussed, including a synthesis of the more than 300 clinical trials of CKI-combination treatments registered as of November 2020. Key challenges and opportunities anticipated in the 2020s are explored, including treatment resistance, combination therapy strategies and potential biomarker development.

With the increasing incidence and mortality of cancer worldwide, there is an urgent need for new therapeutic approaches. Gene therapy is one such approach and preliminary data are promising. Viral and nonviral vector systems for gene delivery are available, but most of the current systems suffer from disadvantages such as low transfection efficiencies, in vivo instability, targeting problems, mutagenic potential and immunogenicity. Viruses of the Parvoviridae family, which are characterised by their oncotropism, oncosuppression, long-term gene expression and human apathogenicity, potentially offer advantages as viral vectors. This article evaluates their usefulness in gene therapy strategies for cancer.

Tamoxifen is commonly prescribed for preventing recurrence in patients with breast cancer. However, the responses of the patients on tamoxifen treatment are variable. Cytochrome P450 genetic variants have been reported to have a significant impact on the clinical outcomes of tamoxifen treatment but no tangible conclusion can be made up till now. The present review attempts to provide a comprehensive review on the associative relationship between genetic polymorphisms in cytochrome P450 enzymes and survival in breast cancer patients on adjuvant tamoxifen therapy. The literature search was conducted using five databases, resulting in the inclusion of 58 studies in the review. An appraisal of the reporting quality of the included studies was conducted using the assessment tool from the Effective Public Health Practice Project (EPHPP). Meta-analyses were performed on CYP2D6 studies using Review Manager 5.3 software. For other studies, descriptive analyses were performed. The results of meta-analyses demonstrated that shorter overall survival, disease-free survival and relapse-free survival were found in the patients with decreased metabolisers when compared to normal metabolisers. The findings also showed that varying and conflicting results were reported by the included studies. The possible explanations for the variable results are discussed in this review.

Limb-girdle muscular dystrophy type 2A (LGMD2A) is characterised by muscle wasting and progressive degeneration of proximal muscles because of mutations in the CAPN3 gene. However, the underlying pathophysiological mechanisms of muscle degeneration are still not well understood. The objective of this study was to assess the relevance of genes with differential expression in the muscle of LGMD2A patients. For this purpose, we analysed their in vitro expression in primary cultures of human myoblasts and myotubes. Abnormal fusion was observed in the myotubes of these patients, which may be explained by the lack of physiological replacement of integrin β1D. Owing to this observation, we focused on deregulated genes coding proteins that directly interact with integrin, ITGB1BP2 and CD9, as well as FRZB gene, because of its in vitro upregulation in myotubes. Silencing studies established that these genes are closely regulated, CD9 and FRZB being positive regulators of the expression of ITGB1BP2, and in turn, this gene being a negative regulator of the expression of FRZB. Interestingly, we observed that FRZB regulates integrin β1D expression, its silencing increasing integrin β1D expression to levels similar to those in controls. Finally, the administration of LiCl, an enhancer of the Wnt-signalling pathway showed similar experimentally beneficial effects, suggesting FRZB silencing or LiCl administration as potential therapeutic targets, though further studies are required.

Poliomyelitis is a paralytic disease of the motor neurones of the central nervous system, which is caused by poliovirus. The virus is transmitted by the faecal–oral route, and if virus replication is confined to the gut, it is harmless. Poliomyelitis is an ancient human disease, but was rare until the beginning of the 20th century, when children began to be exposed to the virus at older ages and were, therefore, no longer protected by maternal antibody, which had already been lost. Inactivated polio vaccines are increasingly being used in those countries in which poliomyelitis has been brought under control; however, live vaccines are still the most widely used types and the World Health Organization (WHO) have set the goal of using such vaccines to eliminate the wild-type virus throughout the world by the year 2000. Substantial progress has been made to this end; however, the strains of poliovirus that are used as vaccines are able to adapt rapidly to the human gut, losing their attenuated (weakened) character within a few weeks. Currently, there is urgent debate about the best method of stopping vaccination against poliomyelitis once the wild-type poliovirus has been eliminated completely, so that the vaccine-strain virus will also be eliminated. Proposed strategies include the abrupt cessation of vaccination with the live virus worldwide, followed by the optional use of inactivated vaccines for an appropriate period. Further information about both the epidemiology and the pathogenesis of the disease is required before an informed choice can be made. The topics covered in this article include a brief history of studies of the disease, its pathogenesis and its control by vaccination, the molecular biology of the live vaccines, which have been extremely successful in controlling poliomyelitis so far, and the concerns that are raised as the eradication of the wild-type virus approaches.

at the present growth rate, the world population is estimated to reach a phenomenal 8.9 billion people by the year 2050, posing a great risk of overpopulation. therefore, new strategies of contraception are required. a novel contraceptive strategy that is receiving considerable attention is that of immunocontraception. spermatozoa have proteins that are unique, cell specific, immunogenic and accessible to antibodies. the targeting of antibodies to gamete-specific antigens implicated in sperm function, sperm–egg binding and fertilisation could block sperm binding and thus fertilisation. the present review highlights the current status, relative merits and future directions for various sperm-based candidate antigens with regard to the development of a contraceptive vaccine.