More than 20 years have passed since the human immunodeficiency virus (HIV)-1 was identified as the cause of AIDS (acquired immune deficiency syndrome). With rapid early progress, the development of a vaccine was predicted within 2–10 years. However, over two decades later, we have seen only a single vaccine candidate complete Phase III clinical efficacy trials. These trials showed the vaccine was not able to protect the trial volunteers from HIV infection or subsequently modify the early clinical progression. It is now accepted that the initial optimism in the field was misguided, as the complexity of the problem stretched beyond the known horizons of vaccinology, immunology and retrovirology. In the intervening 20 years, unprecedented research efforts have pushed the cutting edge of these fields forward to such a degree that we are better able to put the problem of developing a vaccine for HIV-1 into context. Now it is time to examine the prospects for HIV-1 vaccines and ascertain whether real progress is being made.

The increase in the prevalence of obesity has led to an elevated risk for several associated diseases including cancer. Several studies have investigated the DNA damage in human blood samples and showed a clear trend towards increased DNA damage in obesity. Reduced genomic stability is thus one of the consequences of obesity, which may contribute to the related cancer risk. Whether this is influenced by compromised DNA repair has not been elucidated sufficiently yet. On the other hand, obesity has also been linked to reduced therapy survival and increased adverse effects during chemotherapy, although the available data are controversial. Despite some indications that obesity might alter hepatic metabolism, current literature in humans is insufficient, and results from animal studies are inconclusive. Here we have summarised published data on hepatic drug metabolism to understand the impact of obesity on cancer therapy better. Furthermore, we highlight knowledge gaps in the interrelationship between obesity and drug metabolism from a toxicological perspective.

The parasitic protozoan Toxoplasma gondii and its relatives (e.g. Plasmodium spp., which cause malaria) constitute a major global health problem. In recent years, the elucidation of biological processes in these parasites has accelerated with the application of genetic and genomic methodologies. Genetic analyses in T. gondii have revealed a remarkably stable 87 Mb (megabase) nuclear genome consisting of 11 chromosomes showing little variation across strains. Population studies demonstrate that the small amount of variation defines three clonal lineages where phenotypes such as virulence are associated with a single lineage. The random generation of cDNA (complementary DNA) sequences derived from different strains and developmental stages has highlighted the genetic differences underlying observed phenotypic variation. T. gondii also contains an extrachromosomal 35 kb (kilobase) circular DNA within an organelle with plastid-like properties. The limited coding capacity of the 35 kb organellar genome suggests that proteins responsible for organelle function(s) must be encoded by the nucleus. Scrutiny of T. gondii nuclear cDNA sequences has uncovered a number of proteins thought to carry out essential roles in the organelle (e.g. fatty acid biosynthesis). The synergism between these seemingly unrelated genomic studies has provided a greater understanding of parasite pathogenesis and has identified several new targets for chemotherapy.

Upper gastrointestinal (GI) tract malignancies, including carcinomas of the esophagus, the GI junction and the stomach, are among the most common cancers worldwide. Overall survival is poor because many patients present with locally advanced and often incurable disease. This review focuses on the pathogenesis of adenocarcinomas of the stomach. It summarises recent findings on genetic predisposition to gastric cancer, in particular in relation to germline mutations in the E-cadherin gene. It also describes the molecular basis of sporadic gastric cancer, including alterations in oncogenes, tumour suppressor genes and growth factors, and discusses how these findings might be used in the clinic for improved diagnosis and therapy.

During the past six years, great progress has been made in defining the key cellular and molecular signalling pathways that determine the fate of cardiac myocytes after ischaemia–reperfusion (IR) and consequently the severity of myocardial infarction. Among the complex network of kinases and transcription factors that mediate signals during IR is the STAT family of ‘signal transducers and activators of transcription’. During IR they are inducibly activated by Janus kinases and have the capability of transcriptionally regulating pro-survival and apoptotic gene expression. In this review we focus on recent progress made in elucidating the regulation and role of the STAT family of proteins during cardioprotective signalling events in myocardial preconditioning and during IR injury in cardiac myocyte cells and the myocardium. Moreover, we also highlight developments in understanding how this signalling pathway might be amenable to therapeutic intervention, permitting cardiac myocyte survival following IR.

Mutation and aberrant expression of the p53 tumour suppressor protein are the most frequent molecular alterations in human malignancy. Peptides derived from the p53 protein and presented by major histocompatibility complex molecules for T-cell recognition could serve as universal tumour-associated antigens for cancer immunotherapy. Because p53 normally functions as a ubiquitously expressed self-protein, controlling cell-cycle progression and apoptosis, it also represents a paradigm target molecule for tumour-reactive yet self-antigen-specific T cells. Tailoring p53-based cancer immunotherapy thus requires both interference with p53-specific self-tolerance and induction of the entire repertoire of p53-reactive T cells. Transferring selected T-cell receptor genes into human T cells offers a novel and appealing strategy to meet these requirements.

Alongside advancements in gene therapy for inherited immune disorders, the need for effective alternative therapeutic options for other conditions has resulted in an expansion in the field of research for T cell gene therapy. T cells are easily obtained and can be induced to divide robustly ex vivo, a characteristic that allows them to be highly permissible to viral vector-mediated introduction of transgenes. Pioneering clinical trials targeting cancers and infectious diseases have provided safety and feasibility data and important information about persistence of engineered cells in vivo. Here, we review clinical experiences with γ-retroviral and lentiviral vectors and consider the potential of integrating transposon-based vectors as well as specific genome editing with designer nucleases in engineered T cell therapies.

The nuclear factor of κ-light chain of enhancer-activated B cells (NF-κB) signaling pathway, which is conserved in invertebrates, plays a significant role in human diseases such as inflammation-related diseases and carcinogenesis. Angiogenesis refers to the growth of new capillary vessels derived from already existing capillaries and postcapillary venules. Maintaining normal angiogenesis and effective vascular function is a prerequisite for the stability of organ tissue function, and abnormal angiogenesis often leads to a variety of diseases. It has been suggested that NK-κB signalling molecules under pathological conditions play an important role in vascular differentiation, proliferation, apoptosis and tumourigenesis by regulating the transcription of multiple target genes. Many NF-κB inhibitors are being tested in clinical trials for cancer treatment and their effect on angiogenesis is summarised. In this review, we will summarise the role of NF-κB signalling in various neovascular diseases, especially in tumours, and explore whether NF-κB can be used as an attack target or activation medium to inhibit tumour angiogenesis.

Inflammation and immune evasion are major key players in breast cancer (BC) progression. Recently, the FDA approved the use of anti-programmed death-ligand 1 antibody (anti-PD-L1) and phosphoinositide 3-kinase (PI3K) inhibitors against aggressive BC. Despite the paradigm shift in BC treatments, patients still suffer from resistance, recurrence and serious immune-related adverse events. These obstacles require unravelling of the hidden molecular contributors for such therapy failure hence yielding therapeutics that are at least as efficient yet safer. Inflammasome pathway is activated when the pattern recognition receptor senses danger signals (danger-associated molecular patterns) from damagedRdying cells or pathogen-associated molecular patterns found in microbes, leading to secretion of the active pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18). It has been shown throughout numerous studies that inflammasome pathway enhanced invasion, metastasis, provoked BC progression and therapy resistance. Additionally, inflammasomes upregulated the proliferative index ki67 and enhanced PD-L1 expression leading to immunotherapy resistance. IL-1β contributed to significant decrease in oestrogen receptor levels and promoted BC chemo-resistance. High levels of IL-18 in sera of BC patients were associated with worst prognosis. Stimulation of purinergic receptors and modulation of adipokines in obese subjects activated inflammasomes that evoked radiotherapy resistance and BC progression. The micro RNA miR-223-3p attenuated the inflammasome over-expression leading to lowered tumour volume and lessened angiogenesis in BC. This review sheds the light on the molecular pathways of inflammasomes and their impacts in distinct BC subtypes. In addition, it highlights novel strategies in treatment and prevention of BC.

Strategies for non-invasive biomarker discovery in early detection of cancer are an urgent need. Extracellular vesicles (EVs) have generated increasing attention from the scientific community and are under intensive investigations due to their unique biological profiles and their non-invasive nature. EVs are membrane-enclosed vesicles with variable sizes and function. Such vesicles are actively secreted from multiple cell types and are considered as key vehicles for inter-cellular communications and signalling. The stability and potential to easily cross biological barriers enable EVs for exerting durable effects on target cells. These along with easy access to such vesicles, the consistent secretion from tumour during all stages of tumorigenesis and their content providing a reservoir of molecules as well as mirroring the identity of the cell of origin are virtues that have made EVs appealing to be assessed in liquid biopsy approaches and for using as a promising resource of biomarkers in cancer diagnosis and therapy and monitoring targeted cancer therapy. Early detection of EVs will guide time-scheduled personalised therapy. Surveying reliable and sensitive methods for rapid isolation of EVs from biofluids, the purity of isolated vesicles and their molecular profiling and marker specification for clinical translation in patients with cancer are issues in the area and the hot topics of many recent studies. Here, the focus is over methods for EV isolation and stratification for digging more information about liquid biopsy-based diagnosis. Extending knowledge regarding EV-based strategies is a key to validate independent patient follow-up for cancer diagnosis at early stages and inspecting the efficacy of therapeutics.

Ageing is known to be the primary risk factor for most neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and Huntington's disease. They are currently incurable and worsen over time, which has broad implications in the context of lifespan and healthspan extension. Adding years to life and even to physical health is suboptimal or even insufficient, if cognitive ageing is not adequately improved. In this review, we will examine how interventions that have the potential to extend lifespan in animals affect the brain, and if they would be able to thwart or delay the development of cognitive dysfunction and/or neurodegeneration. These interventions range from lifestyle (caloric restriction, physical exercise and environmental enrichment) through pharmacological (nicotinamide adenine dinucleotide precursors, resveratrol, rapamycin, metformin, spermidine and senolytics) to epigenetic reprogramming. We argue that while many of these interventions have clear potential to improve cognitive health and resilience, large-scale and long-term randomised controlled trials are needed, along with studies utilising washout periods to determine the effects of supplementation cessation, particularly in aged individuals.

Transforming growth factor-beta (TGF-β) is a double-edged sword in cancer treatment because of its pivotal yet complex and roles played during cancer initiation/development. Current anti-cancer strategies involving TGF-β largely view TGF-β as an onco-therapeutic target that not only substantially hinders its full utilisation for cancer control, but also considerably restricts innovations in this field. Thereby, how to take advantages of therapeutically favourable properties of TGF-β for cancer management represents an interesting and less investigated problem. Here, by categorising cancer hallmarks into four critical transition events and one enabling characteristic controlling cancer initiation and progression, and delineating TGF-β complexities according to these cancer traits, we identify the suppressive role of TGF-β in tumour initiation and early-stage progression and its promotive functionalities in cancer metastasis as well as other cancer hallmarks. We also propose the feasibility and possible scenarios of combining cold atmospheric plasma (CAP) with onco-therapeutics utilising TGF-β for cancer control given the intrinsic properties of CAP against cancer hallmarks.

Deviations from the precisely coordinated programme of human head development can lead to craniofacial and orofacial malformations often including a variety of dental abnormalities too. Although the aetiology is still unknown in many cases, during the last decades different intracellular signalling pathways have been genetically linked to specific disorders. Among these pathways, the RAS/extracellular signal-regulated kinase (ERK) signalling cascade is the focus of this review since it encompasses a large group of genes that when mutated cause some of the most common and severe developmental anomalies in humans. We present the components of the RAS/ERK pathway implicated in craniofacial and orodental disorders through a series of human and animal studies. We attempt to unravel the specific molecular targets downstream of ERK that act on particular cell types and regulate key steps in the associated developmental processes. Finally we point to ambiguities in our current knowledge that need to be clarified before RAS/ERK-targeting therapeutic approaches can be implemented.

Preterm birth (PTB) is one of the leading causes of deaths in infants under the age of five. Known risk factors of PTB include genetic factors, lifestyle choices or infection. Identification of omic biomarkers associated with PTB could aid clinical management of women at high risk of early labour and thereby reduce neonatal morbidity. This systematic literature review aimed to identify and summarise maternal omic and multi-omic (genomics, transcriptomics, proteomics and metabolites) biomarker studies of PTB. Original research articles were retrieved from three databases: PubMed, Web of Science and Science Direct, using specified search terms for each omic discipline. PTB studies investigating genomics, transcriptomics, proteomics or metabolomics biomarkers prior to onset of labour were included. Data were collected and reviewed independently. Pathway analyses were completed on the biomarkers from non-targeted omic studies using Reactome pathway analysis tool. A total of 149 omic studies were identified; most of the literature investigated proteomic biomarkers. Pathway analysis identified several cellular processes associated with the omic biomarkers reported in the literature. Study heterogeneity was observed across the research articles, including the use of different gestation cut-offs to define PTB. Infection/inflammatory biomarkers were identified across majority of papers using a range of targeted and non-targeted approaches.

Coronavirus disease 2019 (COVID-19) is a serious respiratory disease mediated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The worldwide spread of COVID-19 has caused millions of confirmed cases and morbidity, and the crisis has greatly affected global economy and daily life and changed our attitudes towards life. The reproductive system, as a potential target, is at a high risk of SARS-CoV-2 infection, and females are more vulnerable to viral infection compared with males. Therefore, female fertility and associated reproductive health care in the COVID-19 era need more attention. This review summarises the mechanism of SARS-CoV-2 infection in the female reproductive system and discusses the impact of the COVID-19 crisis on female fertility. Studies have proven that COVID-19 might affect female fertility and interfere with assisted reproductive technology procedures. The side effects of vaccines against the virus on ovarian reserve and pregnancy have not yet been well investigated. In the future, the female fertility after SARS-CoV-2 infection and vaccination needs more attention because of the uncertainty of COVID-19.

Ovarian cancer is the most lethal female reproductive system tumour. Despite the great advances in surgery and systemic chemotherapy over the past two decades, almost all patients in stages III and IV relapse and develop resistance to chemotherapy after first-line treatment. Ovarian cancer has an extraordinarily complex immunosuppressive tumour microenvironment in which immune checkpoints negatively regulate T cells activation and weaken antitumour immune responses by delivering immunosuppressive signals. Therefore, inhibition of immune checkpoints can break down the state of immunosuppression. Indeed, Immune checkpoint inhibitors (ICIs) have revolutionised the therapeutic landscape of many solid tumours. However, ICIs have yielded modest benefits in ovarian cancer. Therefore, a more comprehensive understanding of the mechanistic basis of the immune checkpoints is needed to improve the efficacy of ICIs in ovarian cancer. In this review, we systematically introduce the mechanisms and expression of immune checkpoints in ovarian cancer. Moreover, this review summarises recent updates regarding ICI monotherapy or combined with other small-molecule-targeted agents in ovarian cancer.

Acquired drug resistance limits the efficacy of cytotoxics used in the management of haematological and solid tumours and is responsible for the declining clinical benefit following successive treatment regimens in metastatic cancers. Treatment failure has a major impact on quality of life and survival in advanced disease. Defining pathways of intrinsic and acquired drug resistance may provide new targets to prolong drug efficacy and time to disease progression. Predicting the intrinsic drug sensitivity of human tumours in advance of cytotoxic therapy is of paramount importance in order to limit unnecessary toxicity and optimise treatment outcome. RNA interference (RNAi) provides a powerful tool to annotate gene function and systematically define drug-resistance pathways. High-throughput screening RNAi technology has provided evidence for drug-specific resistance pathways as well as novel pathways implicated in multidrug sensitivity. The challenge is how to integrate these data with biological samples to define relevant drug-resistant pathways in vivo.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by gradual memory loss and declining cognitive and executive functions. AD is the most common cause of dementia, affecting more than 50 million people worldwide, and is a major health concern in society. Despite decades of research, the cause of AD is not well understood and there is no effective curative treatment so far. Therefore, there is an urgent need to increase understanding of AD pathophysiology in the hope of developing a much-needed cure. Dissecting the cellular and molecular mechanisms of AD pathogenesis has been challenging as the most commonly used model systems such as transgenic animals and two-dimensional neuronal culture do not fully recapitulate the pathological hallmarks of AD. The recent advent of three-dimensional human brain organoids confers unique opportunities to study AD in a humanised model system by encapsulating many aspects of AD pathology. In the present review, we summarise the studies of AD using human brain organoids that recapitulate the major pathological components of AD including amyloid-β and tau aggregation, neuroinflammation, mitochondrial dysfunction, oxidative stress and synaptic and circuitry dysregulation. Additionally, the current challenges and future directions of the brain organoids modelling system are discussed.

Toxoplasma gondii is a protozoan parasite that is uniquely adapted for penetrating and surviving within a wide range of host cells. This parasite invades mammalian cells by an active actin-dependent mechanism, and after entry establishes a vacuole with the assistance of products secreted by the parasite's apical organelles. Simultaneously, Toxoplasma sets about gaining access to cellular nutrients by forming pores in the vacuolar membrane. In this manner it enjoys a rich and comfortable lifestyle at the host cell's expense. Understanding the Toxoplasma–host interaction may reveal unusual mechanisms for exploiting host cell pathways and diverting host organelle functions. These novel modifications could also be potential targets for new drugs.

Biological complexity, inaccessible anatomical location, nonspecific symptoms, lack of a screening biomarker, advanced disease at presentation and drug resistance epitomise pancreatic ductal adenocarcinoma (PDA) as a poor-prognosis, lethal disease. Twenty-five years of research (basic, translational and clinical) have barely made strides to improve survival, mainly because of a fundamental lack of knowledge of the biological processes initiating and propagating PDA. However, isolation of pancreas cancer stem cells or progenitors, whole-genome sequencing for driver mutations, advances in functional imaging, mechanistic dissection of the desmoplastic reaction and novel targeted therapies are likely to shed light on how best to treat PDA. Here we summarise current knowledge and areas where the field is advancing, and give our opinion on the research direction the field should be focusing on to better deliver promising therapies for our patients.