Identifying cancer driver genes in individual tumours.

Cancer is a heterogeneous disease with a strong genetic component making it suitable for precision medicine approaches aimed at identifying the underlying molecular drivers within a tumour. Large scale population-level cancer sequencing consortia have identified many actionable mutations common across both cancer types and sub-types, resulting in an increasing number of successful precision medicine programs. Nonetheless, such approaches fail to consider the effects of mutations unique to an individual patient and may miss rare driver mutations, necessitating personalised approaches to driver-gene prioritisation. One approach is to quantify the functional importance of individual mutations in a single tumour based on how they affect the expression of genes in a gene interaction network (GIN). These GIN-based approaches can be broadly divided into those that utilise an existing reference GIN and those that construct de novo patient-specific GINs. These single-tumour approaches have several limitations that likely influence their results, such as use of reference cohort data, network choice, and approaches to mathematical approximation, and more research is required to evaluate the in vitro and in vivo applicability of their predictions. This review examines the current state of the art methods that identify driver genes in single tumours with a focus on GIN-based driver prioritisation.

The role of DNA damage and repair in liver cancer.

Hepatocellular carcinoma is rapidly becoming a major cause of global mortality due to the ever-increasing prevalence of obesity. DNA damage is known to play an important role in cancer initiation, however DNA repair systems are also vital for the survival of cancer cells. Given the function of the liver and its exposure to the gut, it is likely that DNA damage and repair would be of particular importance in hepatocellular carcinoma. However, many contemporary reports have neglected the role of individual pathways of DNA damage and repair in their hypotheses. This review, therefore, aims to provide a concise overview for researchers in the field of liver cancer to understand the pathways of DNA damage and repair and their individual roles in hepatocellular carcinoma.

The effects of fructose and metabolic inhibition on hepatocellular carcinoma.

Hepatocellular carcinoma is rapidly becoming one of the leading causes of cancer-related deaths, largely due to the increasing incidence of non-alcoholic fatty liver disease. This in part may be attributed to Westernised diets high in fructose sugar. While many studies have shown the effects of fructose on inducing metabolic-related liver diseases, little research has investigated the effects of fructose sugar on liver cancer metabolism. The present study aimed to examine the metabolic effects of fructose on hepatocellular carcinoma growth in vitro and in vivo. Fructose sugar was found to reduce cell growth in vitro, and caused alterations in the expression of enzymes involved in the serine-glycine synthesis and pentose phosphate pathways. These biosynthesis pathways are highly active in cancer cells and they utilise glycolytic by-products to produce energy and nucleotides for growth. Hence, the study further investigated the efficacy of two novel drugs that inhibit these pathways, namely NCT-503 and Physcion. The study is the first to show that the combination treatment of NCT-503 and Physcion substantially inhibited hepatocellular carcinoma growth in vitro and in vivo. The combination of fructose diet and metabolism-inhibiting drugs may provide a unique metabolic environment that warrants further investigation in targeting hepatocellular carcinoma.

The CNS theory of osteoarthritis: Opportunities beyond the joint.

Osteoarthritis (OA) is a leading cause of global disability that affects more than half of the population over 65. It is not a single disease but a progressive, inflammatory- and immune-altering multi-disease that affects the whole joint. OA has many risk factors including age, obesity, gender, lifestyle, joint morphology, metabolic dysfunction and genetic disposition. A major stumbling block in treating clinical OA has been the inability to detect its early onset and disease progression. This gap in understanding may arise from our failure to recognize that the OA patient exhibits a vulnerability to dysregulation of central feedback circuits that control sympathetic tone, inflammation, circadian rhythms (central and peripheral clocks), gut microbiome, metabolic redox and whole joint pathology. Early detection of OA and slowing its progression may come from discoveries outside the joint targeting these potentially modifiable upstream targets. We argue that future treatments may benefit from moving from a knee-centric viewpoint to a more systems-based, whole-body approach. The challenge, however, will be to better characterize these key circuits and apply this knowledge to develop new therapies and interventions.