Seek and destroy: Targeted adeno-associated viruses for gene delivery to hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer with high incidence globally. Increasing mortality and morbidity rates combined with limited treatment options available for advanced HCC press for novel and effective treatment modalities. Gene therapy represents one of the most promising therapeutic options. With the recent approval of herpes simplex virus for advanced melanoma, the field of gene therapy has received a major boost. Adeno-associated virus (AAV) is among the most widely used and effective viral vectors today with safety and efficacy demonstrated in a number of human clinical trials. This review identifies the obstacles for effective AAV based gene delivery to HCC which primarily include host immune responses and off-target effects. These drawbacks could be more pronounced for HCC because of the underlying liver dysfunction in most of the patients. We discuss approaches that could be adopted to tackle these shortcomings and manufacture HCC-targeted vectors. The combination of transductional targeting by modifying the vector capsid and transcriptional targeting using HCC-specific promoters has the potential to produce vectors which can specifically seek HCC and deliver therapeutic gene without significant side effects. Finally, the identification of novel HCC-specific ligands and promoters should facilitate and expedite this process

Attitudes of eye health practitioners towards diagnostic tests and therapies for dry eye disease in Australasia

Introduction: The diagnosis of dry eye is challenging for eye health practitioners (EHP) and recently, a variety of new diagnostic tests have emerged. This study assesses the attitudes of EHP to dry eye and testing and compares these with attitudes in 2003. Methods: An electronic questionnaire was disseminated to EHP in Australasia between December 2020 to March 2021. Participants rated the likelihood that presenting symptoms/signs were associated with dry eye, the utility of diagnostic tests, the value of test characteristics, and their satisfaction with dry eye diagnostics. Qualitative responses were categorised into positive, negative, or neutral themes. Results: 144 responses were received, with 117 (81.3%) from Australia and 27 (18.7%) from New Zealand. Posterior blepharitis was significantly more likely to be associated with dry eye than other factors (p < 0.01). Clinical history, fluorescein staining and FBUT were judged significantly more useful in diagnosing dry eye compared to other tests (p < 0.01). Test validity was judged significantly more important in choosing a test than other qualities. Qualitative attitudes towards dry eye presentations and diagnostic tests were positive in 42.2% and 24.3%, negative in 32.4% and 41.9%, and neutral in 25.5% and 33.8% respectively. Conclusions: The opinions of EHP regarding dry eye tests were variable, but most favour history and corneal staining for diagnosis. Patterns of responses were similar to that reported by Turner et al 16-years ago, however, there is a higher satisfaction with available tests and therapeutic options. There is a need to develop a consensus amongst real-world clinicians regarding an optimum diagnostic pathway for dry eye, particularly in relation to newer diagnostic tests

Presence and prevalence of UV related genetic mutations in uveal melanoma: Similarities with cutaneous melanoma

Ultraviolet (UV) radiation is an accepted etiological factor in cutaneous melanoma (CM), however its role in Uveal Melanoma (UM) is controversial. Partly as a consequence, CM and UM are often considered to be separate conditions, and advances in the treatment of CM have not led to joint clinical trials or parallel improvements in survival of UM. This study hypothesized that a subset of UM tumors display evidence of genetic changes consistent with UV-related damage similar to that shown in CM. Analysis of the Broad Institute's Firebrowse depository of 80 UM samples and 343 CM samples, together with the Sanger Institute's Catalogue of Somatic Mutations in Cancer depository of 995 UM and 12,447 CM samples was undertaken to identify the most frequently mutated genes, mutation types and specific nucleotide variants (SNVs) in each condition. Somatic mutation data was cross-correlated and shared mutations assessed against known effects of UV radiation. The proportion of samples with C>T substitutions (a classic genetic marker of UV-related damage) was higher in UM than CM on both DNA strands (17.0% vs 13.1% , p = 0.038). The most frequently encountered cross-correlated mutated genes between UM and CM were, in order, BRAF, NRAS, TP53, CDKN2A, TERT, PTEN, ARID2 and KMT2C, with multiple common BRAF point mutations. Each cross-correlated mutation, and each common point mutation in BRAF, was associated with UV-related mechanistic changes. These findings support the hypothesis that the etiology of a substantial minority of UMs may be more UV dependent than previously recognized

The impact of ultraviolet radiation on the aetiology and development of uveal melanoma

Uveal melanoma (UM) is currently classified by the World Health Organisation as a melanoma caused by risk factors other than cumulative solar damage. However, factors relating to ultraviolet radiation (UVR) susceptibility such as light-coloured skin and eyes, propensity to burn, and proximity to the equator, frequently correlate with higher risk of UM. These risk factors echo those of the far more common cutaneous melanoma (CM), which is widely accepted to be caused by excessive UVR exposure, suggesting a role of UVR in the development and progression of a proportion of UM. Indeed, this could mean that countries, such as Australia, with high UVR exposure and the highest incidences of CM would represent a similarly high incidence of UM if UVR exposure is truly involved. Most cases of UM lack the typical genetic mutations that are related to UVR damage, although recent evidence in a small minority of cases has shown otherwise. This review therefore reassesses statistical, environmental, anatomical, and physiological evidence for and against the role of UVR in the aetiology of UM

Differences in uveal melanoma age-standardized incidence rates in two eastern states of Australia are driven by differences in rurality and ultraviolet radiation

Uveal melanoma (UM) is the second-most-common melanoma in humans and has a high age-standardized incidence rate (ASR) in Uveal melanoma (UM) is the second-most-common melanoma in humans and has a high age-standardized incidence rate (ASR) in Australia. Regional patterns of UM ASRs in Australia are unknown. The aim of this study was to determine and compare UM ASRs in two geographically disparate eastern states, Queensland (QLD) and Victoria (VIC), by using cancer registry data that was obtained from 2001 to 2013. World-standardized UM ASRs and incidence-rate ratios (IRRs) were calculated. Higher UM ASR was also observed in anterior UM compared to posterior UM ASR. UM ASR remained unchanged from 2001 to 2013 in QLD but decreased in VIC. A south-to-north latitude trend in UM ASR along the east of Australia is weakly evident, and rural populations have higher UM ASRs than major city populations in both states. Differences in ultraviolent radiation (UVR) susceptibility, indigenous populations, social behaviours, chemical exposure, and socioeconomic status could all be contributing to differences in UM rates between QLD and VIC and between rural compared to major city areas. It is possible that a minority of cases in QLD and VIC might be prevented by sun-protective behaviours. This is important, because these findings suggest that QLD, which is already known to have one of the highest cutaneous melanoma (CM) ASRs in the world, also has one of the highest UM ASRs