Neoadjuvant radiotherapy (RT) is commonly used as standard treatment for rectal cancer. However, response rates are variable and survival outcomes remain poor, highlighting the need to develop new therapeutic strategies. Research is focused on identifying novel methods for sensitising rectal tumours to RT to enhance responses and improve patient outcomes. This can be achieved through harnessing tumour promoting effects of radiation or preventing development of radio-resistance in cancer cells. Many of the approaches being investigated involve targeting the recently published new dimensions of cancer hallmarks. This review article will discuss key radiation and targeted therapy combination strategies being investigated in the rectal cancer setting, with a focus on exploitation of mechanisms which target the hallmarks of cancer.

Repulsive guidance molecule b (RGMb), a glycosylphosphatidylinositol-anchored member of the RGM family, is initially identified as a co-receptor of bone morphogenetic protein (BMP) in the nervous system. The expression of RGMb is transcriptionally regulated by dorsal root ganglion 11 (DRG11), which is a transcription factor expressed in embryonic DRG and dorsal horn neurons and plays an important role in the development of sensory circuits. RGMb is involved in important physiological processes such as embryonic development, immune response, intercellular adhesion and tumorigenesis. Furthermore, RGMb is mainly involved in the regulation of RGMb–neogenin–Rho and BMP signalling pathways. The recent discovery of programmed death-ligand 2 (PD-L2)–RGMb binding reveals that the cell signalling network and functional regulation centred on RGMb are extremely complex. The latest report suggests that down-regulation of the PD-L2–RGMb pathway in the gut microbiota promotes an anti-tumour immune response, which defines a potentially effective immune strategy. However, the biological function of RGMb in a variety of human diseases has not been fully determined, and will remain an active research field. This article reviews the properties and functions of RGMb, focusing on its role under various physiological and pathological conditions.

In mammals, the skin acts as a barrier to prevent harmful environmental stimuli from entering the circulation. CYP450s are involved in drug biotransformation, exogenous and endogenous substrate metabolism, and maintaining the normal physiological function of the skin, as well as facilitating homeostasis of the internal environment. The expression pattern of CYP450s in the skin is tissue-specific and thus differs from the liver and other organs. The development of skin topical medications, and knowledge of the toxicity and side effects of these medications require a detailed understanding of the expression and function of skin-specific CYP450s. Thus, we summarized the expression of CYP450s in the skin, their function in endogenous metabolic physiology, aberrant CYP450 expression in skin diseases and the influence of environmental variables and medications. This information will serve as a crucial foundation for future studies on the skin, as well as for the design and development of new drugs for skin diseases including topical medications.

Despite stroke being one of the major and increasing burdens to global health, therapeutic interventions in intracerebral haemorrhage (ICH) continue to be a challenge. Existing treatment methods, such as surgery and conservative treatment have shown limited efficacy in improving the prognosis of ICH. However, more and more studies show that exploring the specific process of immune response after ICH and taking corresponding immunotherapy may have a definite significance to improve the prognosis of cerebral haemorrhage. Therefore, immune interventions are currently under consideration as therapeutic interventions in the ICH. In this review, we aim to clarify unique immunological features of stroke, and consider the evidence for immune interventions. In acute ICH, activation of glial cells and cell death products trigger an inflammatory cascade that damages vessels and the parenchyma within minutes to hours of the haemorrhage. Immune interventions that ameliorate brain inflammation, vascular permeability and tissue oedema should be administered promptly to reduce acute immune destruction and avoid subsequent immunosuppression. A deeper understanding of the immune mechanisms involved in ICH is likely to lead to successful immune interventions.

Thrombocytopenia is a common symptom and one of the warning signs of dengue virus (DENV) infection. Platelet depletion is critical as it may lead to other severe dengue symptoms. Understanding the molecular events of this condition during dengue infection is challenging because of the multifaceted factors involved in DENV infection and the dynamics of the disease progression. Platelet levels depend on the balance between platelet production and platelet consumption or clearance. Megakaryopoiesis and thrombopoiesis, two interdependent processes in platelet production, are hampered during dengue infection. Conversely, platelet elimination via platelet activation, apoptosis and clearance processes are elevated. Together, these anomalies contribute to thrombocytopenia in dengue patients. Targeting the molecular events of dengue-mediated thrombocytopenia shows great potential but still requires further investigation. Nonetheless, the application of new knowledge in this field, such as immature platelet fraction analysis, may facilitate physicians in monitoring the progression of the disease.

Long non-coding RNAs (lncRNAs) are progressively being perceived as prominent molecular agents controlling multiple aspects of neuronal (patho)physiology. Amongst these is the HOX transcript antisense intergenic RNA, often abbreviated as HOTAIR. HOTAIR epigenetically regulates its target genes via its interaction with two different chromatin-modifying agents; histone methyltransferase polycomb-repressive complex 2 and histone demethylase lysine-specific demethylase 1. Parenthetically, HOTAIR elicits trans-acting sponging function against multiple micro-RNA species. Oncological research studies have confirmed the pathogenic functions of HOTAIR in multiple cancer types, such as gliomas and proposed it as a pro-oncological lncRNA. In fact, its expression has been suggested to be a predictor of the severity/grade of gliomas, and as a prognostic biomarker. Moreover, a propound influence of HOTAIR in other aspects of brain heath and disease states is just beginning to be unravelled. The objective of this review is to recapitulate all the relevant data pertaining to the regulatory roles of HOTAIR in neuronal (patho)physiology. To this end, we discuss the pathogenic mechanisms of HOTAIR in multiple neuronal diseases, such as neurodegeneration, traumatic brain injury and neuropsychiatric disorders. Finally, we also summarize the results from the studies incriminating HOTAIR in the pathogeneses of gliomas and other brain cancers. Implications of HOTAIR serving as a suitable therapeutic target in neuropathologies are also discussed.

Human herpesvirus 6 (HHV-6) is a T-lymphotropic herpesvirus, which infects almost all children by the age of two years and persists lifelong. Two distinct variants of HHV-6, HHV-6A and HHV-6B, have been described, and the latter has been shown to be a common cause of acute febrile illnesses in young children, including exanthem subitum (roseola). HHV-6 has also been associated with a number of neurological disorders, including encephalitis and seizures, and the virus has been postulated to play a role in acquired immunodeficiency syndrome (AIDS), multiple sclerosis (MS) and chronic fatigue immunodeficiency syndrome (CFIDS). This review provides a critical summary of research conducted on HHV-6.

Breast cancer is one of the most common causes of cancer-related mortality in women. It affects more than one in nine women over their lifetime. Although most breast cancers are sporadic, the genetics and molecular biology of the heritable forms of breast cancer have provided valuable insights into not only breast cancer but also cancers in general. Among the mutations linked to heritable breast cancers, the mutations in the breast cancer 1 (BRCA1) gene are the best characterised. The BRCA1 gene encodes a nuclear protein that is important for maintaining genome integrity. However, a growing list of BRCA1-associated proteins suggests that BRCA1 has diverse and unexpected functions.

Endometriosis originates in the uterine lining and affects ~20% of reproductive-age women. The disease often causes chronic pelvic pain, affects ovulatory function and influences fertility. Although laparoscopic diagnosis of uterine endometriosis is quite specific, direct visualisation can be difficult or inaccurate in some circumstances, and it is not useful for diagnosing extra-abdominal disease. Laparoscopy is an invasive procedure, has significant morbidity and cannot be carried out frequently to monitor efficacy of therapy and the possibility of recurrence. Thus, a specific, non-invasive diagnostic test is required. One intriguing area of research uses the technology of radioimmunotargeting, which has previously been used for cancer detection. This technique could have potential for the specific detection and eventual treatment of endometriosis. A marker, eosinophil peroxidase (EPO), has been identified that is expressed in ~90% of endometriosis specimens, and is not expressed or only weakly expressed in normal endometrium. The US Food and Drug Administration has approved a monoclonal antibody to EPO for investigation as an immunoimaging agent in cancers that exhibit eosinophilia. EPO targeting using this antibody could be useful for detecting and/or treating endometriosis.

During the past 30 years, organ transplantation has developed from a highly experimental procedure into an important part of routine clinical practice. This is reflected by the fact that graft survival times, which were once considered in terms of days or weeks, are now measured in terms of years or decades, with enormous corresponding benefits for the patient. Much of this improvement is due to the development of sophisticated immunosuppressive drugs that inhibit the rejection response mediated by the immune system of the recipient. However, almost without exception, all of the grafts that are transplanted from one genetically disparate individual to another are eventually rejected. The Holy Grail in transplantation is the development of protocols that lead to transplantation tolerance and provide stable graft function without long-term drug therapy. In this article, we have discussed the need for alternatives to current immunosuppression and reviewed the results of animal models, which suggest that long-term stable tolerance is an achievable goal.

Microbiome, the study of microbial communities in specific environments, has developed significantly since the Human Microbiome Project began. Microbiomes have been associated with changes within environmental niches and the development of various diseases. The development of high-throughput technology such as next-generation sequencing has also allowed us to perform transcriptome studies, which provide accurate functional profiling data. Metabolome studies, which analyse the metabolites found in the environment, are the most direct environmental condition indicator. Although each dataset provides valuable information on its own, the integration of multiple datasets provides a deeper understanding of the relationship between the host, agent and environment. Therefore, network analysis using multiple datasets might give a clearer understanding of disease pathogenesis.

Complex tumour ecosystem comprising tumour cells and its associated tumour microenvironment (TME) constantly influence the tumoural behaviour and ultimately impact therapy failure, disease progression, recurrence and poor overall survival of patients. Crosstalk between tumour cells and TME amplifies the complexity by creating metabolic changes such as hypoxic environment and nutrient fluctuations. These changes in TME initiate stem cell-like programmes in cancer cells, contribute to tumoural heterogeneity and increase tumour robustness. Recent studies demonstrate the multifaceted role of autophagy in promoting fibroblast production, stemness, cancer cell survival during longer periods of dormancy, eventual growth of metastatic disease and disease resistance. Recent ongoing studies examine autophagy/mitophagy as a powerful survival strategy in response to environmental stress including nutrient deprivation, hypoxia and environmental stress in TME. It prevents irreversible senescence, promotes dormant stem-like state, induces epithelial–mesenchymal transition and increases migratory and invasive potential of tumour cells. The present review discusses various theories and mechanisms behind the autophagy-dependent induction of cancer stem cell (CSC) phenotype. Given the role of autophagic functions in CSC aggressiveness and therapeutic resistance, various mechanisms and studies based on suppressing cellular plasticity by blocking autophagy as a powerful therapeutic strategy to kill tumour cells are discussed.

Oral cancer survival rates have seen little improvement over the past few decades. This is mainly due to late detection and a lack of reliable markers to predict disease progression in oral potentially malignant disorders (OPMDs). There is a need for highly specific and sensitive screening tools to enable early detection of malignant transformation. Biochemical alterations to tissues occur as an early response to pathological processes; manifesting as modifications to molecular structure, concentration or conformation. Raman spectroscopy is a powerful analytical technique that can probe these biochemical changes and can be exploited for the generation of novel disease-specific biomarkers. Therefore, Raman spectroscopy has the potential as an adjunct tool that can assist in the early diagnosis of oral cancer and the detection of disease progression in OPMDs. This review describes the use of Raman spectroscopy for the diagnosis of oral cancer and OPMDs based on ex vivo and liquid biopsies as well as in vivo applications that show the potential of this powerful tool to progress from benchtop to chairside.

The term ‘autophagy’ literally translates to ‘self-eating’ and alterations to autophagy have been identified as one of the several molecular changes that occur with aging in a variety of species. Autophagy and aging, have a complicated and multifaceted relationship that has recently come to light thanks to breakthroughs in our understanding of the various substrates of autophagy on tissue homoeostasis. Several studies have been conducted to reveal the relationship between autophagy and age-related diseases. The present review looks at a few new aspects of autophagy and speculates on how they might be connected to both aging and the onset and progression of disease. Additionally, we go over the most recent preclinical data supporting the use of autophagy modulators as age-related illnesses including cancer, cardiovascular and neurodegenerative diseases, and metabolic dysfunction. It is crucial to discover important targets in the autophagy pathway in order to create innovative therapies that effectively target autophagy. Natural products have pharmacological properties that can be therapeutically advantageous for the treatment of several diseases and they also serve as valuable sources of inspiration for the development of possible new small-molecule drugs. Indeed, recent scientific studies have shown that several natural products including alkaloids, terpenoids, steroids, and phenolics, have the ability to alter a number of important autophagic signalling pathways and exert therapeutic effects, thus, a wide range of potential targets in various stages of autophagy have been discovered. In this review, we summarised the naturally occurring active compounds that may control the autophagic signalling pathways.

The effectiveness of anti-cancer chemotherapy can be limited by acute suppression of the bone marrow (myelosuppression). There is also a risk of therapy-related secondary haematopoietic malignancy as well as acute and longer term effects in other tissues. Clinical strategies have been established to address some of these problems, particularly toxic effects on the bone marrow (acute myelotoxicity); however, there is still substantial scope for improving the management of chronic toxicity and mutagenicity to haematopoietic cells and collateral damage to non-haematopoietic cells during chemotherapy. In this review, we have discussed a novel strategy that involves the transfer and expression of drug-resistance functions into haematopoietic stem cells and more-mature blood progenitor cells, to overcome both the acute and long-term deleterious effects of anti-tumour treatment in bone marrow. The potential advantages of this approach include: (1) the in vivo selection of protected cell populations, which offers the possibility of intensification or escalation of chemotherapeutic drug doses; (2) a reduction in the frequency of therapy-related leukaemia and (3) tumour sensitisation to chemotherapy at the same time as haematopoietic protection.

Cystic fibrosis (CF) is a common and fatal recessive disease, which is caused by dysfunction of a chloride ion channel, termed the CF transmembrane conductance regulator (CFTR). The CF gene was cloned in 1989; subsequently, several mouse models have been created using gene targeting within embryonic stem cells. This report describes how such animal models provide the opportunity to elucidate disease pathogenesis, correlate genotype with phenotype and develop novel therapies. The current models encompass mice with a complete knockout of CFTR function, with residual CFTR function, and with precise mutations corresponding to those in humans that precipitate CF. All the CF mice demonstrate the characteristic CF ion-transport defect and show some evidence of intestinal disease, but they have a variable level of survival. Genetic background has also been shown to affect the intestinal phenotype of CF mice and this has allowed identification of a genetic modifier locus of CF in humans. Lung disease in human CF is the major cause of death in early adulthood. This is not entirely reproduced in CF mice, but repeat exposure of the lung to clinical pathogens does reveal a significantly abnormal pathogen-related response in the residual-function mice. CF mice have been successfully used to investigate the safety and efficacy of various pharmacological and gene-therapy protocols. As new cloning techniques become available, the models can be refined to ensure that in vivo models continue to be an essential tool for studying CF.

Human neurodevelopment is a complex process vulnerable to disruptions, particularly during the prenatal period. Maternal viral infections represent a significant environmental factor contributing to a spectrum of congenital defects with profound and enduring impacts on affected offspring. The advent of induced pluripotent stem cell (iPSC)-derived three-dimensional (3D) human brain organoids has revolutionised our ability to model prenatal viral infections and associated neurodevelopmental disorders. Notably, human brain organoids provide a distinct advantage over traditional animal models, whose brain structures and developmental processes differ markedly from those of humans. These organoids offer a sophisticated platform for investigating viral pathogenesis, infection mechanisms and potential therapeutic interventions, as demonstrated by their pivotal role during the 2016 Zika virus outbreak. This review critically examines the utilisation of brain organoids in elucidating the mechanisms of TORCH viral infections, their impact on human brain development and contribution to associated neurodevelopmental disorders.