Human papillomavirus (HPV) infection is the cause of squamous cell carcinoma of the uterine cervix. This causative relationship has provided the rationale and incentive for development of a prophylactic vaccine. Such a vaccine, if found to be effective, could reduce the need for cervical cancer screening and have a profound effect on the incidence of cervical and other anogenital cancers. This review begins by examining the basic biological and epidemiological principles relevant to the development of HPV preventative vaccines. It then summarises studies examining the use of vaccines to prevent HPV infection in animals and humans, and, finally, discusses some of the unanswered issues surrounding vaccine development against HPV infection and cervical cancer.

Head and neck squamous cell carcinoma (HNSCC) represents frequent yet aggressive tumours that encompass complex ecosystems of stromal and neoplastic components including a dynamic population of cancer stem cells (CSCs). Recently, research in the field of CSCs has gained increased momentum owing in part to their role in tumourigenicity, metastasis, therapy resistance and relapse. We provide herein a comprehensive assessment of the latest progress in comprehending CSC plasticity, including newly discovered influencing factors and their possible application in HNSCC. We further discuss the dynamic interplay of CSCs within tumour microenvironment considering our evolving appreciation of the contribution of oral microbiota and the pressing need for relevant models depicting their features. In sum, CSCs and tumour plasticity represent an exciting and expanding battleground with great implications for cancer therapy that are only beginning to be appreciated in head and neck oncology.

Fibronectin type III domain-containing protein 5 (FNDC5) is a transmembrane protein and the precursor of irisin, which serves as a systemic exerkine/myokine with multiple origins. Since its discovery in 2012, this hormone-like polypeptide has rapidly evolved to a component significantly involved in a gamut of metabolic dysregulations and various liver diseases. After a decade of extensive investigation on FNDC5/irisin, we are still surrounded by lots of open questions regarding its diagnostic and therapeutic values. In this review, we first concentrated on the structure–function relationship of FNDC5/irisin. Next, we comprehensively summarised the current knowledge and research findings regarding pathogenic roles/therapeutic applications of FNDC5/irisin in the context of non-alcoholic fatty liver disease, fibrosis, liver injury due to multiple detrimental insults, hepatic malignancy and intrahepatic cholestasis of pregnancy. Moreover, the prominent molecules involved in the underlying mechanisms and signalling pathways were highlighted. As a result, emerging evidence reveals FNDC5/irisin may act as a proxy for diagnosing liver disease pathology, a sensitive biomarker for assessing damage severity, a predisposing factor for surveilling illness progression and a treatment option with protective/preventive impact, all of which are highly dependent on disease grading and contextually pathological features.

Helicobacter pylori (H. pylori) is a worldwide spread bacterium, co-evolving with humans for at least 100 000 years. Despite the uncertainty about the mode of H. pylori transmission, the development of intra-gastric and extra-gastric diseases is attributed to this bacterium. The morphological transformation and production of heterogenic virulence factors enable H. pylori to overcome the harsh stomach environment. Using numerous potent disease-associated virulence factors makes H. pylori a prominent pathogenic bacterium. These bacterial determinants are adhesins (e.g., blood group antigen-binding adhesin (BabA)/sialic acid-binding adhesin (SabA)), enzymes (e.g., urease), toxins (e.g., vacuolating cytotoxin A (VacA)), and effector proteins (e.g., cytotoxin-associated gene A (CagA)) involved in colonisation, immune evasion, and disease induction. H. pylori not only cleverly evades the immune system but also robustly induces immune responses. This insidious bacterium employs various strategies to evade human innate and adaptive immune responses, leading to a life-long infection. Owing to the alteration of surface molecules, innate immune receptors couldn't recognise this bacterium; moreover, modulation of effector T cells subverts adaptive immune response. Most of the infected humans are asymptomatic and only a few of them present severe clinical outcomes. Therefore, the identification of virulence factors will pave the way for the prediction of infection severity and the development of an effective vaccine. H. pylori virulence factors are hereby comprehensively reviewed and the bacterium evasion from the immune response is properly discussed.

Advances in molecular biology and immunology have renewed interest in the development of vaccines for the treatment or prevention of cancer. Research over the past 10 years has focused on the identification of suitable tumour antigens to use as targets for a variety of vaccine strategies. Carcinoembryonic antigen (CEA) was one of the first tumour antigens described, and is commonly expressed by a wide range of adenocarcinomas. Recent studies have identified several human-leukocyte-antigen-restricted epitopes (short peptides) within the CEA protein that can be recognised by human T lymphocytes (T cells). Although CEA-expressing tumour cells are generally weakly recognised by the immune system, several new strategies have been used to enhance immune responses against CEA. This includes using antibodies directed against CEA; inserting the CEA gene into recombinant viruses and bacteria as viral and bacterial vaccines; pulsing the CEA protein, peptides, DNA or RNA onto dendritic cells (specialised antigen-presenting cells); and combining CEA vaccines with cytokines or co-stimulatory molecules to increase vaccine effectiveness. Other factors that might be important in establishing systemic immunity against CEA are the dose, route, timing, and choice of vector and adjuvants for vaccine administration. Further research in understanding the fundamental processes involved in tumour-cell recognition by the immune system, better animal models, and improved clinical trial designs will help to define the full potential of CEA as a target for cancer vaccine development.

The transmissible spongiform encephalopathies (TSEs) are a group of fatal neurodegenerative diseases that are also transmissible. The PrP protein is central to the disease process and has been hypothesised to be the infectious agent. Polymorphisms in the PrP gene have been linked to the incubation time of TSE disease, and mutations in the human PrP gene have been suggested to result in genetic TSE disease. Several PrP transgenic models have been developed. These models express PrP from different species, with and without PrP mutations, and at different levels of gene expression. This article discusses the contribution of these transgenic models to our present understanding of the TSE diseases.

Infertility is one of the most prevalent public health problems facing young adult males in today's society. A clear, treatable cause of infertility cannot be determined in a large number of these patients, and a growing body of evidence suggests that infertility in many of these men may be due to genetic causes. Studies using mouse knockout technology have been integral for examination of normal spermatogenesis and to identify proteins essential for this process, which in turn are candidate genes for human male infertility. Successful spermatogenesis depends on a delicate balance of local signalling factors, and this review focuses on the genes that encode these factors. Normal functioning of all testicular cell types is essential for fertility and might also be crucial to prevent germ cell oncogenesis. Analysis of these signalling processes in spermatogenesis using mouse models has provided investigators with an invaluable tool to effectively translate basic science research to the research of human disease and infertility.

Cardiac hypertrophy (CH) is an augmentation of either the right ventricular or the left ventricular mass in order to compensate for the increase of work load on the heart. Metabolic abnormalities lead to histological changes of cardiac myocytes and turn into CH. The molecular mechanisms that lead to initiate CH have been of widespread concern, hence the development of the new field of research, metabolomics: one ‘omics’ approach that can reveal comprehensive information of the paradigm shift of metabolic pathways network in contrast to individual enzymatic reaction-based metabolites, have attempted and until now only 19 studies have been conducted using experimental animal and human specimens. Nuclear magnetic resonance spectroscopy and mass spectrometry-based metabolomics studies have found that CH is a metabolic disease and is mainly linked to the harmonic imbalance of glycolysis, citric acid cycle, amino acids and lipid metabolism. The current review will summarise the main outcomes of the above mentioned 19 studies that have expanded our understanding of the molecular mechanisms that may lead to CH and eventually to heart failure.

Reactive oxygen species (ROS) play an essential role in regulating various functions of organisms such as gene transcription, signalling transduction and immune response. However, overproduction of ROS can lead to oxidative stress, which is related to various ageing diseases including eye and brain degenerative diseases. Ocular measurements have recently been suggested as potential sources of biomarkers for the early detection of brain neurodegenerative diseases. MicroRNAs (miRNAs) are useful biomarkers for various diseases including degenerative diseases. miRNAs play an important role in the oxidative stress mechanisms of ageing diseases. In this paper, the role of miRNAs related to oxidative stress mechanisms in four ageing diseases, Parkinson's disease (PD), Alzheimer's disease (AD), glaucoma and age-related macular degeneration was reviewed. The common miRNA biomarkers related to the four diseases were also discussed. The results show that these eye and brain ageing diseases share many common miRNA biomarkers. It indicates that the ocular condition may be a prognostic biomarker for PD or AD patients. When a patient's eye condition changes, this can be a warning of a change in PD or AD status.

The ongoing global pandemic of coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and significantly impacts the world economy and daily life. Symptoms of COVID-19 range from asymptomatic to fever, dyspnoea, acute respiratory distress and multiple organ failure. Critical cases often occur in the elderly and patients with pre-existing conditions. By binding to the angiotensin-converting enzyme 2 receptor, SARS-CoV-2 can enter and replicate in the host cell, exerting a cytotoxic effect and causing local and systemic inflammation. Currently, there is no specific treatment for COVID-19, and immunotherapy has consistently attracted attention because of its essential role in boosting host immunity to the virus and reducing overwhelming inflammation. In this review, we summarise the immunopathogenic features of COVID-19 and highlight recent advances in immunotherapy to illuminate ideas for the development of new potential therapies.

Retinoblastoma (Rb) is the most common primary ocular malignancy of children and is caused by a mutation in the gene RB1. Approximately 40% of cases are associated with one or more constitutional mutations, and are therefore heritable, whereas the other 60% are sporadic. Rb is exclusively found in young children. In some cases, Rb tumours metastasise to extraocular organs including bone, lung and brain. Although there is no effective treatment for metastatic disease, non-metastatic cases can be cured by removal of the eye (enucleation). Newer treatment strategies emphasise salvaging the affected eye whenever possible. Animal models of Rb have been developed with xenograft and transgenic techniques. Each model has both strengths and weaknesses for exploring the mechanisms of disease development and progression and the efficacy of new treatment strategies.

Patients with the autoimmune rheumatic disease systemic lupus erythematosus (SLE or ‘lupus’) develop a wide variety of clinical and serological manifestations including the presence of antibodies to double-stranded DNA (dsDNA), which are often diagnostic and potentially pathogenic. In this review, we have examined the links between the structure and function of anti-dsDNA antibodies, emphasising their clinical associations. We have also reviewed studies involving animal models, the analysis of human antibody sequences and studies of, and using, computer modelling and crystal structure.

Primary pulmonary hypertension (PPH) is defined clinically by sustained elevation of pulmonary arterial pressure without a demonstrable cause, and is a progressive, often-fatal disease. PPH can be associated with ingestion of appetite suppressants, human immunodeficiency virus infection and certain autoimmune diseases. Familial PPH is known to account for 6% of all cases. Mutations in the gene encoding the bone morphogenetic protein (BMP) type II receptor have been identified in 72% of affected families and 26% of apparently sporadic cases. BMPs are members of the transforming growth factor β superfamily and affect intracellular signalling via Smads and mitogen-activated protein kinases. Evidence supports a ‘two-hit’ hypothesis in which PPH is triggered by accumulation of genetic and environmental insults in a susceptible individual. Elucidation of the precise molecular and cellular mechanisms underlying PPH will provide a powerful basis for the development of novel therapeutic strategies in the treatment of this devastating condition.

The maintenance of a healthy mitochondrial network and the ability to adjust organelle population in response to internal or external stimuli are essential for the function and the survival of eukaryotic cells. Over the last two decades several studies have demonstrated the paramount importance of mitophagy, a selective form of autophagy that removes damaged and/or superfluous organelles, in organismal physiology. Post-mitotic neuronal cells are particularly vulnerable to mitochondrial damage, and mitophagy impairment has emerged as a causative factor in multiple neurodegenerative pathologies, including Alzheimer's disease and Parkinson's disease among others. Although mitochondrial turnover is a multifaceted process, neurons have to tackle additional complications, arising from their pronounced bioenergetic demands and their unique architecture and cellular polarisation that render the degradation of distal organelles challenging. Mounting evidence indicates that despite the functional conservation of mitophagy pathways, the unique features of neuronal physiology have led to the adaptation of compartmentalised solutions, which serve to ensure seamless mitochondrial removal in every part of the cell. In this review, we summarise the current knowledge concerning the molecular mechanisms that mediate mitophagy compartmentalisation and discuss their implications in various human pathologies.

The current COVID-19 pandemic contributed by the SARS-CoV-2 has put in place an urgent need for new and promising antiviral therapeutics. The viral RNA-dependent RNA polymerase (RdRp) enzyme plays a vital role in viral replication for all RNA viruses, including SARS-CoV-2, thereby making it a prime and promising candidate for novel antiviral targeting. Interestingly, the human telomerase reverse transcriptase (hTERT), a common catalytic subunit of the telomerase enzyme in many cancers, has also been identified with structural and functional similarities to the viral RdRp. Therefore, it becomes essential to evaluate and consider anticancer drugs that target hTERT towards antiviral RdRp activity, and vice versa. For instance, Floxuridine, an hTERT inhibitor, and VX-222, a hepatitis C virus RdRp inhibitor, are now gaining recognition as a potential antiviral against SARS-CoV-2 and anti-hTERT for cancer, simultaneously. While limited studies on hTERT inhibitors for use as viral RdRp, and anti-RdRp inhibitors as hTERT inhibitors are available, in this review, we aim at bringing to light this close structural and functional relationship between both these enzymes. We punctuate this idea with specific examples on how potential anticancer inhibitors can effectively be brought to use as inhibitors against the SARS-CoV-2 virus, a relatively new pathogen, compared to the very well-studied field of cancer research.

Life expectancy has increased exponentially in the last century accompanied by disability, poor quality of life, and all-cause mortality in older age due to the high prevalence of obesity and physical inactivity in older people. Biologically, the aging process reduces the cell’s metabolic and functional efficiency, and disrupts the cell’s anabolic and catabolic homeostasis, predisposing older people to many dysfunctional conditions such as cardiovascular disease, neurodegenerative disorders, cancer, and diabetes. In the immune system, aging also alters cells' metabolic and functional efficiency, a process known as ‘immunosenescence’, where cells become more broadly inflammatory and their functionality is altered. Notably, autophagy, the conserved and important cellular process that maintains the cell’s efficiency and functional homeostasis may protect the immune system from age-associated dysfunctional changes by regulating cell death in activated CD4+ T cells. This regulatory process increases the delivery of the dysfunctional cytoplasmic material to lysosomal degradation while increasing cytokine production, proliferation, and differentiation of CD4+ T cell-mediated immune responses. Poor proliferation and diminished responsiveness to cytokines appear to be ubiquitous features of aged T cells and may explain the delayed peak in T cell expansion and cytotoxic activity commonly observed in the ‘immunosenescence’ phenotype in the elderly. On the other hand, physical exercise stimulates the expression of crucial nutrient sensors and inhibits the mechanistic target of the rapamycin (mTOR) signaling cascade which increases autophagic activity in cells. Therefore, in this perspective review, we will first contextualize the overall view of the autophagy process and then, we will discuss how body adiposity and physical fitness may counteract autophagy in naïve CD4+ T cells in aging.

Over the past decade, the prevailing view for the molecular and cellular pathogenesis of Alzheimer's disease (AD) has centred on the β-amyloid (Aβ) peptide that accumulates in vulnerable brain areas in the disease. The amyloid cascade hypothesis postulates that the build up of Aβ in the brain causes damage to neurons, leading to dysfunction and loss of neurons, and the clinical phenotype of the amnestic dementia characteristic of AD. All known mutations that result in autosomal dominant forms of early-onset familial AD cause increased production of Aβ42, a form of Aβ that is particularly relevant in AD. Other proteins that are crucial to the pathogenesis of AD are the presenilins 1 and 2, which are intimately involved with Aβ production and when mutated in familial forms of AD cause increases in Aβ42. Currently, challenges in AD research include determining the earliest pathological effects of Aβ42, how the important AD risk factor apolipoprotein E affects the disease process, whether presenilin is the elusive γ-secretase, and how levels of Aβ can be effectively reduced therapeutically.

It was suggested by Ronald Fisher in 1931 that genes that benefit the male (including those required for spermatogenesis) would accumulate on the Y chromosome. Following the discovery that microdeletions of the Y chromosome were associated with diverse spermatogenic phenotypes, at least three intervals that contain one or more genes controlling male germ-cell differentiation have been identified in humans. These intervals, named AZFa, AZFb and AZFc, have been mapped, cloned and examined in detail for the presence of functional genes. In this review, I have discussed the genes that map to the AZF intervals and the evidence indicating which ones are the most likely candidates underlying Y-linked male infertility. In addition, I have considered the analysis of key intervals on the mouse Y chromosome, where it provides comparative data supporting the role of a candidate gene in an infertility phenotype.

This review discusses current research on acute paediatric leukaemia, the leukaemic bone marrow (BM) microenvironment and recently discovered therapeutic opportunities to target leukaemia–niche interactions. The tumour microenvironment plays an integral role in conferring treatment resistance to leukaemia cells, this poses as a key clinical challenge that hinders management of this disease. Here we focus on the role of the cell adhesion molecule N-cadherin (CDH2) within the malignant BM microenvironment and associated signalling pathways that may bear promise as therapeutic targets. Additionally, we discuss microenvironment-driven treatment resistance and relapse, and elaborate the role of CDH2-mediated cancer cell protection from chemotherapy. Finally, we review emerging therapeutic approaches that directly target CDH2-mediated adhesive interactions between the BM cells and leukaemia cells.