AMP-Activated Protein Kinase:Do We Need Activators or Inhibitors to Treat or Prevent Cancer?

AMP-activated protein kinase (AMPK) is a key regulator of cellular energy balance. In response to metabolic stress, it acts to redress energy imbalance through promotion of ATP-generating catabolic processes and inhibition of ATP-consuming processes, including cell growth and proliferation. While findings that AMPK was a downstream effector of the tumour suppressor LKB1 indicated that it might act to repress tumourigenesis, more recent evidence suggests that AMPK can either suppress or promote cancer, depending on the context. Prior to tumourigenesis AMPK may indeed restrain aberrant growth, but once a cancer has arisen, AMPK may instead support survival of the cancer cells by adjusting their rate of growth to match their energy supply, as well as promoting genome stability. The two isoforms of the AMPK catalytic subunit may have distinct functions in human cancers, with the AMPK-α1 gene often being amplified, while the AMPK-α2 gene is more often mutated. The prevalence of metabolic disorders, such as obesity and Type 2 diabetes, has led to the development of a wide range of AMPK-activating drugs. While these might be useful as preventative therapeutics in individuals predisposed to cancer, it seems more likely that AMPK inhibitors, whose development has lagged behind that of activators, would be efficacious for the treatment of pre-existing cancers

Role of C-terminal phosphorylation in the regulation of the tumour suppressor IRF-1

The transcription factor Interferon Regulatory Factor-1 (IRF-1) has been demonstrated to suppress tumour growth through the regulation of many anti-oncogenic genes. Pro- and anti-apoptotic factors, cell cycle control genes, DNA damage response genes and prometastatic factors are all under the control of IRF-1, which effects both transcriptional activation and repression. In addition to these cell autonomous tumour suppressor activities, IRF-1 is also a key regulator of the immune system and, as such, mediates immune surveillance of tumours. Numerous studies have confirmed that loss or mis-regulation of IRF-1 is a key factor in several different types of cancer. Despite strong evidence for the crucial role of IRF-1 in cancer, and frequent assertions that this protein warrants further investigation as a drug target, very little is known about its regulation. Furthermore, since recent studies have linked upregulation of IRF-1 to the development of autoimmune diseases, it is particularly important that drugs be able to decouple autoimmune and anti-cancer functions of IRF-1 to avoid harmful side effects. This thesis describes how phosphorylation of IRF-1 in its regulatory C-terminal Mf1 domain modulates transactivatory and tumour suppressor activity. Phosphospecific antibodies were developed as tools to study the C-terminal phosphorylation. Using these, it was shown that treatment of cells with Interferon-γ(IFN-γ) not only causes accumulation of IRF-1 protein, but also results in phosphorylation of IRF-1 at two sites in the C-terminal Mf1 domain. Phosphomimetic mutants demonstrated that these phosphorylations enhanced the transactivatory activity of IRF-1 at various promoters, but did not affect repressor activity. Gel shift assays revealed that dual phosphorylation of IRF-1 (IRF-1 D/D) promoted DNAbinding and suggested this was through increased interaction with the cofactor/histone acetylase p300 which induces a conformational change in IRF-1, favouring DNA-binding. Acetylation by p300 appears to be important although it is not yet clear whether this directly or indirectly affects IRF-1 activity. Since the tumour suppressor activity of IRF-1 is of particular interest, the effect of phosphorylation was examined in clonogenic and invasion assays. IRF-1 D/D more efficiently suppressed colony formation in both anchorage dependent and independent assays, and may improve inhibition of invasion in Transwell assays. Thus, cell treatment with the therapeutic agent IFN-γ nduces phosphorylation of IRF-1, resulting in enhanced DNA binding of IRF-1 through improved p300 binding. In cells the outcome is more effective tumour suppression and inhibition of metastasis

Who should be prioritised for COVID-19 vaccination?

The development of COVID-19 vaccines is occurring at a rapid pace, with the potential for a vaccine to be available within 6 months. So who should be prioritized for vaccination when in the first instance, there will be insufficient supply to meet demand? There is no doubt that health-care workers in all settings should be vaccinated first, but who comes next will be a complex decision based on local epidemiology, societal values, and the ability of the vaccines to prevent both severe disease and to reduce transmission thereby eliciting herd protection. The decision on who to vaccinate should be equitable, highly contextualized, and based on the property of each vaccine. In some settings, the elderly may be prioritized, in others, it may be the population most likely to get infected and responsible for community spread. To support decision-making on who to be prioritized for vaccination requires urgent additional research on the epidemiology of COVID-19; preexisting immunity and who is responsible for transmission in a variety of settings; the safety, immunogenicity, and efficacy of COVID-19 vaccines in children and pregnant women; and determining whether COVID-19 vaccines prevent asymptomatic infection and transmission

Cost and affordability of healthy food in rural South Australia

The unaffordability of healthy food, or ‘food stress’ in low SES groups is a concern, especially when this group carries the greatest burden of diet-related disease. Findings suggest that there is a need to consider both rural location and SES when developing policy responses to decrease the cost and increase the affordability of healthy foods in rural and remote areas

Cervical Cancer Prevention Through HPV Vaccination in Low- and Middle-Income Countries in Asia

Cervical cancer is ranked the first or second most common cancer in women of low- and middle-income countries (LMICs) in Asia. Cervical cancer is almost exclusively caused by human papillomavirus (HPV), and majority of the cases can be prevented with the use of HPV vaccines. The HPV vaccines have demonstrated high vaccine efficacies against HPV infection and cervical cancer precursors in clinical and post-marketing studies, and are in use in most high-income countries. However, their use in LMICs are limited mainly due to the high costs and logistics in delivering multiple doses of the vaccine. Other issues such as the safety of the vaccines, social and cultural factors, as well as poor knowledge and awareness of the virus have also contributed to the low uptake of the vaccine. This mini-review focuses on the need for HPV vaccine implementation in Asia given the substantial disease burden and underuse of HPV vaccines in LMICs in this region. In addition, the progress towards HPV vaccine introduction, and barriers preventing further rollout of these essential, life-saving vaccines are also discussed in this article

Knowledge co-production for Indigenous adaptation pathways: transform post-colonial articulation complexes to empower local decision-making

Co-production between scientific and Indigenous knowledge has been identified as useful to generating adaptation pathways with Indigenous peoples, who are attached to their traditional lands and thus highly exposed to the impacts of climate change. However, ignoring the complex and contested histories of nation-state colonisation can result in naïve adaptation plans that increase vulnerability. Here, through a case study in central Australia, we investigate the conditions under which co-production between scientific and Indigenous knowledge can support climate change adaptation pathways among place-attached Indigenous communities. A research team including scientists, Ltyentye Apurte Rangers and other staff from the Central Land Council first undertook activities to co-produce climate change presentations in the local Arrernte language; enable community members to identify potential adaptation actions; and implement one action, erosion control. Second, we reflected on the outcomes of these activities in order to unpack deeper influences. Applying the theory of articulation complexes, we show how ideologies, institutions and economies have linked Indigenous societies and the establishing Australian nation-state since colonisation. The sequence of complexes characterised as frontier, mission, pastoral, land-rights, community-development and re-centralisation, which is current, have both enabled and constrained adaptation options. We found knowledge co-production generates adaptation pathways when: (1) effective methods for knowledge co-production are used, based on deeply respectful partnerships, cultural governance and working together through five co-production tasks—prepare, communicate, discuss, bring together and apply; (2) Indigenous people have ongoing connection to their traditional territories to maintain their Indigenous knowledge; (3) the relationship between the Indigenous people and the nation-state empowers local decision-making and learning, which requires and creates consent, trust, accountability, reciprocity, and resurgence of Indigenous culture, knowledge and practices. These conditions foster the emergence of articulation complexes that enable the necessary transformative change from the colonial legacies. Both these conditions and our approach are likely to be relevant for place-attached Indigenous peoples across the globe in generating climate adaptation pathways

Measles virus causes immunogenic cell death in human melanoma

Oncolytic viruses (OV) are promising treatments for cancer, with several currently undergoing testing in randomised clinical trials. Measles virus (MV) has not yet been tested in models of human melanoma. This study demonstrates the efficacy of MV against human melanoma. It is increasingly recognised that an essential component of therapy with OV is the recruitment of host anti-tumour immune responses, both innate and adaptive. MV-mediated melanoma cell death is an inflammatory process, causing the release of inflammatory cytokines including type-1 interferons and the potent danger signal HMGB1. Here, using human in vitro models, we demonstrate that MV enhances innate antitumour activity, and that MV-mediated melanoma cell death is capable of stimulating a melanoma-specific adaptive immune response

A PAR-1–dependent orientation gradient of dynamic microtubules directs posterior cargo transport in the Drosophila oocyte

A PAR-1–mediated bias in microtubule organization in the Drosophila oocyte underlies posterior-directed mRNA transport