Karonudib is a promising anticancer therapy in hepatocellular carcinoma

Background: Hepatocellular carcinoma (HCC) is the most common form of liver cancer and is generally caused by viral infections or consumption of mutagens, such as alcohol. While liver transplantation and hepatectomy is curative for some patients, many relapse into disease with few treatment options such as tyrosine kinase inhibitors, for example, sorafenib or lenvatinib. The need for novel systemic treatment approaches is urgent. Methods: MTH1 expression profile was first analyzed in a HCC database and MTH1 mRNA/protein level was determined in resected HCC and paired paracancerous tissues with polymerase chain reaction (PCR) and immunohistochemistry. HCC cancer cell lines were exposed in vitro to MTH1 inhibitors or depleted of MTH1 by siRNA. 8-oxoG was measured by the modified comet assay. The effect of MTH1 inhibition on tumor growth was explored in HCC xenograft in vivo models. Results: MTH1 protein level is elevated in HCC tissue compared with paracancerous liver tissue and indicates poor prognosis. The MTH1 inhibitor Karonudib (TH1579) and siRNA effectively introduce toxic oxidized nucleotides into DNA, 8-oxoG, and kill HCC cell lines in vitro. Furthermore, we demonstrate that HCC growth in a xenograft mouse model in vivo is efficiently suppressed by Karonudib. Conclusion: Altogether, these data suggest HCC relies on MTH1 for survival, which can be targeted and may open up a novel treatment option for HCC in the future

Tailor-made inflammation: how neutrophil serine proteases modulate the inflammatory response

Neutrophil granulocytes are important mediators of innate immunity, but also participate in the pathogenesis of (auto)inflammatory diseases. Neutrophils express a specific set of proteolytic enzymes, the neutrophil serine proteases (NSPs), which are stored in cytoplasmic granules and can be secreted into the extra- and pericellular space upon cellular activation. These NSPs, namely cathepsin G (CG), neutrophil elastase (NE), and proteinase 3 (PR3), have early been implicated in bacterial defense. However, NSPs also regulate the inflammatory response by specifically altering the function of cytokines and chemokines. For instance, PR3 and NE both inactivate the anti-inflammatory mediator progranulin, which may play a role in chronic inflammation. Here, we provide a concise update on NSPs as modulators of inflammation and discuss the biological and pathological significance of this novel function of NSPs. Mounting evidence support an important proinflammatory function for PR3, which may have been underestimated in the past

Targeting OGG1 arrests cancer cell proliferation by inducing replication stress

Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting in oxidative DNA damage, e.g. 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise and excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target to exploit reactive oxygen species (ROS) elevation in cancer. Although OGG1 depletion is well tolerated in non-transformed cells, we report here that OGG1 depletion obstructs A3 T-cell lymphoblastic acute leukemia growth in vitro and in vivo, validating OGG1 as a potential anti-cancer target. In line with this hypothesis, we show that OGG1 inhibitors (OGG1i) target a wide range of cancer cells, with a favourable therapeutic index compared to non-transformed cells. Mechanistically, OGG1i and shRNA depletion cause S-phase DNA damage, replication stress and proliferation arrest or cell death, representing a novel mechanistic approach to target cancer. This study adds OGG1 to the list of BER factors, e.g. PARP1, as potential targets for cancer treatment

2014 Report Northern Territory

Made available by the Northern Territory Library via the Publications (Legal Deposit) Act 2004 (NT).'This report gives the latest information on how Aboriginal and Torres Strait Islander people in the Northern Territory are faring according to a range of measures of health status and outcomes, determinants of health and health system performance. Indicators are based on the Aboriginal and Torres Strait Islander Health Performance Framework. The report highlights the main areas of improvement and continuing concern.' - Back coverSummary -- Introduction -- Demographic information -- Structure of this report -- Housing -- Antenatal care -- Appendix 1 - Data sources -- Reference

Acute management of skin tears with mesh grafting: a prospective study and cost-benefit analysis

**Background**: Skin tears cause a significant burden to the patient and healthcare system. Acute management has traditionally comprised of operative debridement and formal skin grafting, which is costly, invasive and often followed by admission for five to seven days. In a 2014 pilot study by Vandervord and colleagues, a protocol for re-laying the skin tear as a meshed skin graft (mesh protocol) was proposed, which has not been validated to date. Our study aims to compare a prospective cohort to the original pilot study to determine validity in clinical practice and provide an updated cost-benefit analysis. **Method**: All patients who presented with acutely sustained skin tears at Northern Beaches Hospital, NSW, Australia, were prospectively entered into the mesh protocol as described by Vandervord and colleagues. An updated cost-benefit analysis was performed using a national hospital cost data collection report produced by the Independent Hospital Pricing Authority (IHPA). **Results**: We enrolled 53 patients onto the protocol who had sustained a total of 64 discrete skin tears, with 11 patients sustaining more than one skin tear. The average age of patients was 86, and the most common location of the skin tear was pretibial, followed by forearm/hand. Only one patient required a return to theatre for debridement and formal skin grafting, and three patients required long-term dressings for partial mesh graft loss. The cost to the healthcare system is consistent with the pilot study, with a significant difference between discharge from the emergency department post-procedure and formal grafting and admission for five to seven days. **Conclusion**: Use of the mesh protocol creates wound coverage and prevents the need for formal skin grafting, and reduces costs associated with formal operations and hospital admissions

Modeling the performance of accommodating intraocular lenses

Pseudo-accommodating intra-ocular lenses (P-IOL) have been available for some time and the availability of accommodating IOL (A-IOL) is imminent. While these types of devices have been tested empirically, few studies have addressed the fundamental parameters governing their performance limits. We modelled the amplitude of accommodation of A-IOLs and P-IOLs to analyse parameters controlling their performance. Two types of two-element A-IOLs (those with a mobile anterior optical element, or a mobile posterior element) were modelled. Paraxial models were developed to identify key controlling parameters and potential optimal configurations, followed by finite modelling using computer assisted ray-tracing employing equi-convex/concave optical elements. A range of configurations representing varying focal lengths of front and back optical elements were tested. Degenerate cases representing P-IOLs were also tested. P-IOLs have limited rate of pseudo-accommodation with axial shift (approximately 1.2D/mm). For A-IOLs, configurations with positive power front elements returned best rate of accommodation (up to approximately 3.0D/mm when the front element focal length is 25 mm). Considering the maximum potential amounts of axial shifts available, P-IOLs were predicted to provide less than 1D of accommodation whereas A-IOLs may provide up to 3-4D of accommodation, depending on design configuration