Kayani Kayani

Background: Normothermic machine perfusion of donor livers has become standard practice in the field of transplantation, allowing the assessment of organs and safe extension of preservation times. Alongside its clinical uses, there has been expanding interest in extended normothermic machine perfusion (eNMP) of livers as a potential vehicle for medical research. Reproducible extended normothermic machine perfusion has remained elusive due to its increased complexity and monitoring requirements. We set out to develop a reproducible protocol for the extended normothermic machine perfusion of whole human livers. Methods: Human livers declined for transplantation were perfused using a blood-based perfusate at 36 °C using the Liver Assist device (XVIVO, Sweden), with continuous veno-venous haemofiltration in-parallel. We developed the protocol in a stepwise fashion. Results: Perfusion techniques utilised included: targeted physiological vascular flows, phosphate replacement (to prevent hypophosphataemia), N-acetylcysteine (to prevent methaemoglobin accumulation), and the utilisation of sodium lactate as both a nutritional source and real-time measure of hepatocyte function. All five human livers perfused with the developed protocol showed preserved function with a median perfusion time of 168 h (range 120–184 h), with preserved viability throughout. Conclusions: Livers can be reproducibly perfused in excess of 120 (range 121–184) hours with evidence of preserved hepatocyte and cholangiocyte function.

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.

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.