Cystic fibrosis (CF) is the most common autosomal recessive disorder in Caucasian populations. Individuals with CF have seen significant increases in life expectancy in the last 60 years. As a result, previously rare complications are now coming to light. The most common of these is cystic fibrosis-related diabetes (CFRD), which affects 40–50% of CF adults. CFRD significantly impacts the pulmonary function and longevity of CF patients, yet a lack of consensus on the best methods to diagnose and treat CFRD remains. We begin by reviewing our understanding of the pathogenesis of CFRD, as emerging evidence shows the cystic fibrosis transmembrane conductance regulator (CFTR) also has important roles in the release of insulin and glucagon and in the protection of β cells from oxidative stress. We then discuss how current recommended methods of CFRD diagnosis are not appropriate, as continuous glucose monitoring becomes more effective, practical, and cost-effective. Finally, we evaluate emerging treatments which have narrowed the mortality gap within the CF patient group. In the future, pharmacological potentiators and correctors directly targeting CFTR show huge promise for both CFRD and the wider CF patient groups.

Being maladaptive and frequently unresponsive to pharmacotherapy, chronic pain presents a major unmet clinical need. While an intact central nervous system is required for conscious pain perception, nociceptor hyperexcitability induced by nerve injury in the peripheral nervous system (PNS) is sufficient and necessary to initiate and maintain neuropathic pain. The genesis and propagation of action potentials is dependent on voltage-gated sodium channels, in particular, Nav1.7, Nav1.8 and Nav1.9. However, nerve injury triggers changes in their distribution, expression and/or biophysical properties, leading to aberrant excitability. Most existing treatment for pain relief acts through non-selective, state-dependent sodium channel blockage and have narrow therapeutic windows. Natural toxins and developing subtype-specific and molecular-specific sodium channel blockers show promise for treatment of neuropathic pain with minimal side effects. New approaches to analgesia include combination therapy and gene therapy. Here, we review how individual sodium channel subtypes contribute to pain, and the attempts made to develop more effective analgesics for the treatment of chronic pain.

Non-Hodgkin’s lymphoma (NHL) is the sixth-most common cancer in the UK, accounting for around 13,700 new cases every year. Until the late 1990s, treatment relied on intensive chemotherapy, such as CHOP (cyclophosphamide–doxorubicin HCl–vincristine [Oncovin]–prednisone). The use of standard CHOP therapy and its variations had resulted in poor five-year survival rates (as low as 26%), particularly in patients with aggressive NHL. Rituximab (Rituxan) was the first chimeric (mouse/human) monoclonal antibody approved for the treatment of NHL. It was approved by the US Food and Drug Administration in 1997 for indolent forms of NHL. It subsequently received EU approval in June 1998, and was licensed under the trade name Mabthera (Roche, Basel, Switzerland). It then went on to be approved for the first-line treatment of aggressive forms of NHL, such as diffuse large B-cell lymphoma (to be used in combination with CHOP or other anthracycline-based chemotherapy) in 2006. It is directed against the CD20 protein, an antigen found on the surface of B-cell lymphomas. With minimal toxicity, activity as a single-agent (for indolent forms of NHL) and safety when combined with chemotherapy (for aggressive forms), it represents great progress in this field. Here, we analyze how this antibody therapeutic was developed from basic molecular and cellular considerations through to preclinical and clinical evaluations and how it came to be a first-line treatment for NHL, and we discuss the impacts the advent of rituximab had on treatment outcomes for patients with DLBCL compared with the pre-rituximab era.

Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second most common cause of cancer death in the USA by 2030, yet progress continues to lag behind that of other cancers, with only 9% of patients surviving beyond 5 years. Long-term survivorship of PDAC and improving survival has, until recently, escaped our understanding. One recent frontier in the cancer field is the microbiome. The microbiome collectively refers to the extensive community of bacteria and fungi that colonise us. It is estimated that there is one to ten prokaryotic cells for each human somatic cell, yet, the significance of this community in health and disease has, until recently, been overlooked. This review examines the role of the microbiome in PDAC and how it may alter survival outcomes. We evaluate the possibility of employing microbiomic signatures as biomarkers of PDAC. Ultimately this review analyses whether the microbiome may be amenable to targeting and consequently altering the natural history of PDAC.

The lymphocyte population must traverse a complex path throughout their journey to the liver. The signals which these cells must detect, including cytokines, chemokines and other soluble factors, steer their course towards further crosstalk with other hepatic immune cells, hepatocytes and biliary epithelial cells. A series of specific chemokine receptors and adhesion molecules drive not only the recruitment, migration, and retention of these cells within the liver, but also their localisation. Perturbation of these interactions and failure of self-recognition drives the development of several autoimmune liver diseases. Understanding the nature of these interactions develops our understanding of immune mediated liver disease pathogenesis, providing new opportunities for intervention to resolve uncontrolled inflammation. In this review, we provide an overview of the complex recruitment pathways and cellular interactions which position lymphocyte populations in the liver. We discuss how these are disrupted in autoimmune diseases and highlight the mechanism of immune cells inside hepatocytes (emperipolesis) in autoimmune hepatitis and immune cells inside biliary epithelial cells (intra-epithelial lymphocyte) in primary biliary cholangitis as well as avenues to manipulate these pathways for therapy. We also cover the immune mediated tissue injury mechanisms impacted by checkpoint inhibitors, leading to checkpoint inhibitor-induced liver injury (CHILI). Finally, we describe emerging immune-based therapies, including regulatory T cell, anti-cytokine and anti-chemokine therapies, cytokine supplementation such as interleukin-2 as well as numerous modalities of co-inhibitory molecule manipulation, including bispecific T cell engagers (BiTEs) and checkpoint inhibitor bispecific T cell engagers (CiTEs) and discuss their potential application in the treatment of autoimmune liver diseases. Immune-mediated liver disease encompasses two broad categories: autoimmune and inflammatory liver injury, the former resulting from a breakdown in immunological self-tolerance. These share common features, namely histologically dense immune infiltrates, autoantibody positivity and immunoglobulin elevation. Whilst well defined in their epidemiology, presentation and diagnostic evaluation, their treatment remains an unmet clinical need. Our incomplete understanding of the mechanisms leading to breakdown in immunological self-tolerance and our inability to restore immune homeostasis hampers present progress in treatment. This review summarises recent advances in our understanding of the loss of hepatic tolerance and the cellular interactions leading to this, including immune cell invasion towards hepatocytes and biliary epithelial cells, checkpoint-induced immune-mediated liver injury (CHILI) and concludes with current progress in treatment strategies.

Effective control of chronic liver diseases (CLD) requires suppression of effector T cells by CD4⁺CD25⁺CD127^low regulatory T cells (Tregs). This study investigated the role of TIGIT, a co-inhibitory receptor, in CLD by examining the phenotype, recruitment, localisation, and function of TIGIT⁺Tregs and how TIGIT augments Treg function. We also elucidated the function of TIGIT⁺effector T cells on hepatocytes. Liver infiltrating (CLD explants n = 7, donor liver n = 4) and peripheral (CLD blood n = 22, healthy control blood n = 10) TIGIT⁺Tregs and TIGIT⁺effector T cells were phenotyped by flow cytometry, and their localisation was examined by immunohistochemistry. Phenotypic and functional changes in TIGIT⁺Tregs in response to TIGIT agonism and IL-2 supplementation were also assessed. TIGIT⁺effector T cell-induced primary hepatocyte apoptosis was investigated using co-culture experiments and blocking assays. TIGIT⁺Tregs were more suppressive towards CD4⁺T cells than TIGIT^-Tregs (p = 0.04254), and their suppressive action was IL-10 dependent. TIGIT expression was highly enriched on intrahepatic Tregs compared to effector T cells (p <0.0001). TIGIT⁺Tregs and TIGIT⁺effector T cells expressed CXCR3 and VLA-4 and localised around hepatocytes which express TIGIT ligand, CD155. TIGIT⁺Tregs also exhibited significantly higher cytotoxic T lymphocyte-associated antigen-4 (CTLA-4; p = 0.0012), FoxP3 (p <0.0001), and CD39 (p <0.0001) expression than TIGIT^-Tregs. TIGIT agonism upregulated FoxP3 and CTLA-4 on Tregs, reduced proliferation, and increased TNF-α expression. Supplementing TIGIT⁺Tregs with IL-2 further enhanced FoxP3 and CTLA-4 expression. In contrast, TIGIT⁺effector T cells displayed reduced cytotoxicity towards hepatocytes, which reversed upon TIGIT blockade. TIGIT⁺Tregs are highly suppressive and can be enhanced in response to TIGIT agonism and IL-2 stimulation, demonstrating their translational therapeutic potential. However, TIGIT blockade on CD8⁺T cells induces hepatitis, caution is required when using anti-TIGIT therapy. We identified a highly suppressive subset of regulatory T cells in the liver, defined as TIGIT⁺CD39⁺CTLA-4⁺Tregs. TIGIT agonists and IL-2 enhanced the suppressive function of this cell subset. The TIGIT ligand, CD155, is expressed on inflamed hepatocytes, and TIGIT blockade in oncology could instigate checkpoint inhibitor induced liver injury (CHILI). These findings have implications for future therapy in liver disease.