The ATM Ser49Cys Variant Effects ATM Function as a Regulator of Oncogene-Induced Senescence.

An apical component of the cell cycle checkpoint and DNA damage repair response is the ataxia-telangiectasia mutated (ATM) Ser/Thr protein kinase. A variant of ATM, Ser49Cys (rs1800054; minor allele frequency = 0.011), has been associated with an elevated risk of melanoma development; however, the functional consequence of this variant is not defined. ATM-dependent signalling in response to DNA damage has been assessed in a panel of patient-derived lymphoblastoid lines and primary human melanocytic cell strains heterozygous for the ATM Ser49Cys variant allele. The ATM Ser49Cys allele appears functional for acute p53-dependent signalling in response to DNA damage. Expression of the variant allele did reduce the efficacy of oncogene expression in inducing senescence. These findings demonstrate that the ATM 146C>G Ser49Cys allele has little discernible effect on the acute response to DNA damage but has reduced function observed in the chronic response to oncogene over-expression. Analysis of melanoma, naevus and skin colour genomics and GWAS analyses have demonstrated no association of this variant with any of these outcomes. The modest loss of function detected suggest that the variant may act as a modifier of other variants of ATM/p53-dependent signalling.

Whole-genome sequencing facilitates patient-specific quantitative PCR-based minimal residual disease monitoring in acute lymphoblastic leukaemia, neuroblastoma and Ewing sarcoma.

BACKGROUND: Minimal residual disease (MRD) measurement is a cornerstone of contemporary acute lymphoblastic leukaemia (ALL) treatment. The presence of immunoglobulin (Ig) and T cell receptor (TCR) gene recombinations in leukaemic clones allows widespread use of patient-specific, DNA-based MRD assays. In contrast, paediatric solid tumour MRD remains experimental and has focussed on generic assays targeting tumour-specific messenger RNA, methylated DNA or microRNA. METHODS: We examined the feasibility of using whole-genome sequencing (WGS) data to design tumour-specific polymerase chain reaction (PCR)-based MRD tests (WGS-MRD) in 18 children with high-risk relapsed cancer, including ALL, high-risk neuroblastoma (HR-NB) and Ewing sarcoma (EWS) (n = 6 each). RESULTS: Sensitive WGS-MRD assays were generated for each patient and allowed quantitation of 1 tumour cell per 10-4 (0.01%)-10-5 (0.001%) mononuclear cells. In ALL, WGS-MRD and Ig/TCR-MRD were highly concordant. WGS-MRD assays also showed good concordance between quantitative PCR and droplet digital PCR formats. In serial clinical samples, WGS-MRD correlated with disease course. In solid tumours, WGS-MRD assays were more sensitive than RNA-MRD assays. CONCLUSIONS: WGS facilitated the development of patient-specific MRD tests in ALL, HR-NB and EWS with potential clinical utility in monitoring treatment response. WGS data could be used to design patient-specific MRD assays in a broad range of tumours.

Quantification of vincristine and tariquidar by liquid chromatography-tandem mass spectrometry in mouse whole blood using volumetric absorptive microsampling for pharmacokinetic applications.

A liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous quantification of vincristine and tariquidar in 10 µL of mouse whole blood using volumetric absorptive microsampling devices. Samples were extracted from the devices and quantified against calibrators prepared in a human blood plasma matrix. Separation of vincristine and tariquidar was achieved using a Shimpack XR ODS III C18 stationary phase and H2 O and methanol mobile phase solvents containing 0.1% formic acid, running a gradient elution at a flow rate of 0.2 mL/min over 6.0 min. The method was linear up to 1200 ng/mL (R2 > 0.99 for both analytes), with calibrator accuracy within ± 15% of the nominal concentrations and analyte coefficient of variance <15% for both vincristine and tariquidar. Pharmacokinetic assessment of both analytes was successfully applied in mice as both single-agent therapy and combination therapy over a 24-h period, and a 2.3-fold increase in vincristine drug exposure was observed in combination with tariquidar. This study validates the use of this approach for longitudinal analysis of drug exposure in animal studies.

Supporting Aboriginal and Torres Strait Islander Families to Stay Together from the Start (SAFeST Start): Urgent call to action to address crisis in infant removals.

Reducing the rate of over-representation of Aboriginal and Torres Strait Islander children in out-of-home care (OOHC) is a key Closing the Gap target committed to by all Australian governments. Current strategies are failing. The "gap" is widening, with the rate of Aboriginal and Torres Strait Islander children in OOHC at 30 June 2020 being 11 times that of non-Indigenous children. Approximately, one in five Aboriginal and Torres Strait Islander children entering OOHC each year are younger than one year. These figures represent compounding intergenerational trauma and institutional harm to Aboriginal and Torres Strait Islander families and communities. This article outlines systemic failures to address the needs of Aboriginal and Torres Strait Islander parents during pregnancy and following birth, causing cumulative harm and trauma to families, communities and cultures. Major reform to child and family notification and service systems, and significant investment to address this crisis, is urgently needed. The Family Matters Building Blocks and five elements of the Aboriginal and Torres Strait Islander Child Placement Principle (Prevention, Participation, Partnership, Placement and Connection) provide a transformative foundation to address historical, institutional, well-being and socioeconomic drivers of current catastrophic trajectories. The time for action is now.

Mouse models of high-risk neuroblastoma.

Informative and realistic mouse models of high-risk neuroblastoma are central to understanding mechanisms of tumour initiation, progression, and metastasis. They also play vital roles in validating tumour drivers and drug targets, as platforms for assessment of new therapies and in the generation of drug sensitivity data that can inform treatment decisions for individual patients. This review will describe genetically engineered mouse models of specific subsets of high-risk neuroblastoma, the development of patient-derived xenograft models that more broadly represent the diversity and heterogeneity of the disease, and models of primary and metastatic disease. We discuss the research applications, advantages, and limitations of each model type, the importance of model repositories and data standards for supporting reproducible, high-quality research, and potential future directions for neuroblastoma mouse models.

The Eyes Absent family members EYA4 and EYA1 promote PLK1 activation and successful mitosis through tyrosine dephosphorylation.

The Eyes Absent proteins (EYA1-4) are a biochemically unique group of tyrosine phosphatases known to be tumour-promoting across a range of cancer types. To date, the targets of EYA phosphatase activity remain largely uncharacterised. Here, we identify Polo-like kinase 1 (PLK1) as an interactor and phosphatase substrate of EYA4 and EYA1, with pY445 on PLK1 being the primary target site. Dephosphorylation of pY445 in the G2 phase of the cell cycle is required for centrosome maturation, PLK1 localization to centrosomes, and polo-box domain (PBD) dependent interactions between PLK1 and PLK1-activation complexes. Molecular dynamics simulations support the rationale that pY445 confers a structural impairment to PBD-substrate interactions that is relieved by EYA-mediated dephosphorylation. Depletion of EYA4 or EYA1, or chemical inhibition of EYA phosphatase activity, dramatically reduces PLK1 activation, causing mitotic defects and cell death. Overall, we have characterized a phosphotyrosine signalling network governing PLK1 and mitosis.

Healing the Past by Nurturing the Future: trauma-aware, healing-informed care to improve support for Aboriginal and Torres Strait Islander families - implementation and evaluation study protocol.

INTRODUCTION: Complex trauma can have serious impacts on the health and well-being of Aboriginal and Torres Strait Islander families. The perinatal period represents a 'critical window' for recovery and transforming cycles of trauma into cycles of healing. The Healing the Past by Nurturing the Future (HPNF) project aims to implement and evaluate a programme of strategies to improve support for Aboriginal and Torres Strait islander families experiencing complex trauma. METHOD: The HPNF programme was codesigned over 4 years to improve awareness, support, recognition and assessment of trauma. Components include (1) a trauma-aware, healing-informed training and resource package for service providers; (2) trauma-awareness resources for parents; (3) organisational readiness assessment; (4) a database for parents and service providers to identify accessible and appropriate additional support and (5) piloting safe recognition and assessment processes. The programme will be implemented in a large rural health service in Victoria, Australia, over 12 months. Evaluation using a mixed-methods approach will assess feasibility, acceptability, cost, effectiveness and sustainability. This will include service user and provider interviews; service usage and cost auditing; and an administrative linked data study of parent and infant outcomes. ANALYSIS: Qualitative data will be analysed using reflexive thematic analysis. Quantitative and service usage outcomes will be described as counts and proportions. Evaluation of health outcomes will use interrupted time series analyses. Triangulation of data will be conducted and mapped to the Consolidated Framework for Implementation Research and Reach, Effectiveness, Adoption, Implementation and Maintenance frameworks to understand factors influencing feasibility, acceptability, effectiveness, cost and sustainability. ETHICS AND DISSEMINATION: Approval granted from St Vincent's Melbourne Ethics Committee (approval no. 239/22). Data will be disseminated according to the strategy outlined in the codesign study protocol, in-line with the National Health and Medical Research Council Aboriginal and Torres Strait Islander Research Excellence criteria.

Mitigating Contemporary Trauma Impacts Using Ancient Applications.

The COVID-19 pandemic represents the most significant global challenge in a generation. Based on extant data from previous pandemics, demographic, occupational, and psychological factors have been linked to distress and for some vulnerable members of society. COVID-19 has added to the layers of grief and distress of existing trauma. Evidence-based frameworks exist to guide our individual and collective response to reduce the trauma associated with the experience of a pandemic. Pandemic and post-pandemic measures to ameliorate impacts require a multi-disciplined approach, central to which is community connectedness, resilience, and access to support. We advocate for the acceptance and broader application of Dadirri, a healing practice held by the Ngan'gikurunggurr and Ngen'giwumirri Aboriginal people of the Daly River region in the Northern Territory, Australia. This modality engages therapeutic phases that are comparable with other practiced trauma therapies. The demonstrated therapeutic outcomes from Dadirri can be attained through an individualistic or in a relational engagement context. This practice is accessible to all ages, is non-specific to gender and is suitable for people constrained in their mobility or limited by resources, pertinent in pandemic affected settings.

Using participatory action research to co-design perinatal support strategies for Aboriginal and Torres Strait Islander parents experiencing complex trauma.

PROBLEM & BACKGROUND: Support is important for all parents but critical for those experiencing complex trauma. The The Healing the Past by Nurturing the Future project uses participatory action research to co-design effective perinatal support for Aboriginal and Torres Strait Islander parents. AIM: This research aims to identify and refine culturally appropriate support strategies for Aboriginal and Torres Strait Islander parents experiencing complex trauma. DESIGN: We presented our synthesised eight parent support goals and 60 strategies, collated from Elder and parent focus groups, previous participatory workshops, and evidence reviews, for discussion at a stakeholder workshop. Stakeholder perspectives were captured using a three-point agreement activity and, self- and scribe-recorded comments. Aboriginal and non-Aboriginal researchers analysised the qualitative data, to identify core factors which might facilitate or help enact the parenting related goals. FINDINGS: Overall, stakeholders (n = 37) strongly endorsed all eight goals. Workshop attendees (57% Aboriginal) represented multiple stakeholder roles including Elder, parent and service provider. Four core factors were identified as crucial for supporting parents to heal from complex trauma: Culture (cultural traditions, practices and strengths), Relationality (family, individual, community and services), Safety (frameworks, choice and control) and Timing (the right time socio-emotionally and stage of parenting). DISCUSSION: Context-specific support tailored to the Culture, Relationality, Safety, and Timing needs of parents is essential. These four factors are important elements to help enact or facilitate parenting support strategies. CONCLUSION: Further work is now required to develop practical resources for parents, and to implement and evaluate these strategies in perinatal care to address cumulative and compounding cycles of intergenerational trauma.

Key features of a trauma-informed public health emergency approach: A rapid review.

COVID-19 is a major threat to public safety, and emergency public health measures to protect lives (e.g., lockdown, social distancing) have caused widespread disruption. While these measures are necessary to prevent catastrophic trauma and grief, many people are experiencing heightened stress and fear. Public health measures, risks of COVID-19 and stress responses compound existing inequities in our community. First Nations communities are particularly at risk due to historical trauma, ongoing socio-economic deprivation, and lack of trust in government authorities as a result of colonization. The objective of this study was to review evidence for trauma-informed public health emergency responses to inform development of a culturally-responsive trauma-informed public health emergency framework for First Nations communities. We searched relevant databases from 1/1/2000 to 13/11/2020 inclusive, which identified 40 primary studies (and eight associated references) for inclusion in this review. Extracted data were subjected to framework and thematic synthesis. No studies reported evaluations of a trauma-informed public health emergency response. However, included studies highlighted key elements of a "trauma-informed lens," which may help to consider implications, reduce risks and foster a sense of security, wellbeing, self- and collective-efficacy, hope and resilience for First Nations communities during COVID-19. We identified key elements for minimizing the impact of compounding trauma on First Nations communities, including: a commitment to equity and human rights, cultural responsiveness, good communication, and positive leadership. The six principles guiding trauma-informed culturally-responsive public health emergency frameworks included: (i) safety, (ii) empowerment, (iii) holistic support, (iv) connectedness and collaboration, (v) compassion and caring, and (vi) trust and transparency in multi-level responses, well-functioning social systems, and provision of basic services. These findings will be discussed with First Nations public health experts, together with data on the experiences of First Nations families and communities during COVID-19, to develop a trauma-integrated public health emergency response framework or "lens" to minimize compounding trauma for First Nations communities.

A Culturally Responsive Trauma-Informed Public Health Emergency Framework for Aboriginal and Torres Strait Islander Communities in Australia, Developed during COVID-19.

The Coronavirus Disease 2019 (COVID-19) pandemic impacted peoples' livelihoods and mental wellbeing. Aboriginal and Torres Strait Islander peoples in Australia continue to experience intergenerational trauma associated with colonization and may experience trauma-related distress in response to government responses to public health emergencies. We aimed to develop a culturally responsive trauma-informed public health emergency response framework for Aboriginal and Torres Strait Islander peoples. This Aboriginal and Torres Strait Islander-led study involved: (i) a review of trauma-informed public health emergency responses to develop a draft framework (ii) interviews with 110 Aboriginal and Torres Strait Islander parents about how COVID-19 impacted their lives, and (iii) a workshop with 36 stakeholders about pandemic experiences using framework analysis to refine a culturally responsive trauma-informed framework. The framework included: an overarching philosophy (cultural humility, safety and responsiveness); key enablers (local leadership and Eldership); supporting strategies (provision of basic needs and resources, well-functioning social systems, human rights, dignity, choice, justice and ethics, mutuality and collective responsibility, and strengthening of existing systems); interdependent core concepts (safety, transparency, and empowerment, holistic support, connectedness and collaboration, and compassion, protection and caring); and central goals (a sense of security, resilience, wellbeing, self- and collective-efficacy, hope, trust, resilience, and healing from grief and loss).

"You Can't Replace That Feeling of Connection to Culture and Country": Aboriginal and Torres Strait Islander Parents' Experiences of the COVID-19 Pandemic.

This Aboriginal-led study explores Aboriginal and Torres Strait Islander parents' experiences of COVID-19. 110 Aboriginal and Torres Strait Islander parents were interviewed between October 2020 and March 2022. Participants were recruited through community networks and partner health services in South Australia, Victoria, and Northern Territory, Australia. Participants were predominantly female (89%) and based in Victoria (47%) or South Australia (45%). Inductive thematic analysis identified three themes: (1) Changes to daily living; (2) Impact on social and emotional wellbeing; and (3) Disconnection from family, community, and culture. COVID-19 impacted Aboriginal and Torres Strait Islander families. Disruption to cultural practice, and disconnection from country, family, and community was detrimental to wellbeing. These impacts aggravated pre-existing inequalities and may continue to have greater impact on Aboriginal and Torres Strait Islander parents and communities due to intergenerational trauma, stemming from colonisation, violence and dispossession and ongoing systemic racism. We advocate for the development of a framework that ensures an equitable approach to future public health responses for Aboriginal and Torres Strait Islander people.

Healing the Past by Nurturing the Future: Aboriginal parents' views of what helps support recovery from complex trauma.

We aimed to understand support needs for Aboriginal and Torres Strait Islander parents experiencing complex trauma.Becoming a parent is an exciting yet challenging transition, particularly for parents who have experienced past hurt in their own childhood which can have long lasting effects, including complex trauma. Complex trauma-related distress can make it harder to care for a baby, but the parenting transition offers unique opportunities for recovery.This formative research is part of a community-based participatory action research project which aims to co-design perinatal awareness, recognition, assessment and support strategies for Aboriginal and Torres Strait Islander parents experiencing complex trauma. We used an Indigenist approach and grounded theory methods. Aboriginal and Torres Strait Islander parents who were pregnant and/or have children up to two years old were recruited through perinatal care services and community networks in three Australian sites (Alice Springs, Adelaide and Melbourne). Parents were offered a group discussion or individual interview, facilitated by Aboriginal researchers. Third-person scenarios and visual tools were used to facilitate reflections about the impact of past experiences, what keeps parents strong, hopes and dreams, and what is needed to achieve those dreams. Parents were also shown themes from a previous systematic review of parents' experiences as a prompt to identify any additional key issues.Seventeen Aboriginal and Torres Strait Islander parents participated in August to September 2019. Most were mothers (n = 15).  The study's grounded theory methods provided the foundation of a theoretical supposition that positions the transformation of the compounding cycle of trauma, to a reinforcing cycle of nurturing at the intersection of: 1) parents' connectedness; 2) social and emotional wellbeing; and 3) the transition to parenting. Unique opportunities and challenges situated at the interface are bound to the compounding or reinforcing nature of the intersecting factors. Findings reveal complexity, differing experiences by gender and age, as well as within and between communities.

Community Perspectives of Complex Trauma Assessment for Aboriginal Parents: 'Its Important, but How These Discussions Are Held Is Critical'.

BACKGROUND AND PURPOSE: Becoming a parent can be an exciting and also challenging transition, particularly for parents who have experienced significant hurt in their own childhoods, and may be experiencing 'complex trauma.' Aboriginal and Torres Strait Islander (Aboriginal) people also experience historical trauma. While the parenting transition is an important time to offer support for parents, it is essential to ensure that the benefits of identifying parents experiencing complex trauma outweigh any risks (e.g., stigmatization). This paper describes views of predominantly Aboriginal stakeholders regarding (1) the relative importance of domains proposed for complex trauma assessment, and (2) how to conduct these sensitive discussions with Aboriginal parents. SETTING AND METHODS: A co-design workshop was held in Alice Springs (Central Australia) as part of an Aboriginal-led community-based participatory action research project. Workshop participants were 57 predominantly Aboriginal stakeholders with expertise in community, clinical, policy and academic settings. Twelve domains of complex trauma-related distress had been identified in existing assessment tools and through community consultation. Using story-telling and strategies to create safety for discussing complex and sensitive issues, and delphi-style methods, stakeholders rated the level of importance of the 12 domains; and discussed why, by whom, where and how experiences of complex trauma should be explored. MAIN FINDINGS: The majority of stakeholders supported the importance of assessing each of the proposed complex trauma domains with Aboriginal parents. However, strong concerns were expressed regarding where, by whom and how this should occur. There was greater emphasis and consistency regarding 'qualities' (e.g., caring), rather than specific 'attributes' (e.g., clinician). Six critical overarching themes emerged: ensuring emotional and cultural safety; establishing relationships and trust; having capacity to respond appropriately and access support; incorporating less direct cultural communication methods (e.g., yarning, dadirri); using strengths-based approaches and offering choices to empower parents; and showing respect, caring and compassion. CONCLUSION: Assessments to identify Aboriginal parents experiencing complex trauma should only be considered when the prerequisites of safety, trusting relationships, respect, compassion, adequate care, and capacity to respond are assured. Offering choices and cultural and strengths-based approaches are also critical. Without this assurance, there are serious concerns that harms may outweigh any benefits for Aboriginal parents.

EGFR and Prion protein promote signaling via FOXO3a-KLF5 resulting in clinical resistance to platinum agents in colorectal cancer.

Epidermal growth factor receptor (EGFR) supports colorectal cancer progression via oncogenic signaling. Anti-EGFR therapy is being investigated as a clinical option for colorectal cancer, and an observed interaction between EGFR and Prion protein has been detected in neuronal cells. We hypothesized that PrPC expression levels may regulate EGFR signaling and that detailed understanding of this signaling pathway may enable identification of resistance mechanisms and new actionable targets in colorectal cancer. We performed molecular pathway analysis following knockdown of PrPC or inhibition of EGFR signaling via gefitinib to identify changes in expression of key signaling proteins that determine cellular sensitivity or resistance to cisplatin. Expression of these proteins was examined in matched primary and metastatic patient samples and was correlated for resistance to therapy and progression of disease. Utilizing three colorectal cancer cell lines, we observed a correlation between high expression of PrPC and resistance to cisplatin. Investigation of molecular signaling in a resistant cell line revealed that PrPC contributed to signaling via colocalization with EGFR, which could be overcome by targeting p38 mitogen-activated protein kinases (p38 MAPK). We revealed that the level of Krüppel-like factor 5 (KLF5), a target downstream of p38 MAPK, was predictive for cell line and patient response to platinum agents. Further, high KLF5 expression was observed in BRAF-mutant colorectal cancer. Our study indicates that the EGFR to KLF5 pathway is predictive of patient progression on platinum-based therapy.

Healing the Past by Nurturing the Future-co-designing perinatal strategies for Aboriginal and Torres Strait Islander parents experiencing complex trauma: framework and protocol for a community-based participatory action research study.

INTRODUCTION: Child maltreatment and other traumatic events can have serious long-term physical, social and emotional effects, including a cluster of distress symptoms recognised as 'complex trauma'. Aboriginal and Torres Strait Islander (Aboriginal) people are also affected by legacies of historical trauma and loss. Trauma responses may be triggered during the transition to parenting in the perinatal period. Conversely, becoming a parent offers a unique life-course opportunity for healing and prevention of intergenerational transmission of trauma. This paper outlines a conceptual framework and protocol for an Aboriginal-led, community-based participatory action research (action research) project which aims to co-design safe, acceptable and feasible perinatal awareness, recognition, assessment and support strategies for Aboriginal parents experiencing complex trauma. METHODS AND ANALYSIS: This formative research project is being conducted in three Australian jurisdictions (Northern Territory, South Australia and Victoria) with key stakeholders from all national jurisdictions. Four action research cycles incorporate mixed methods research activities including evidence reviews, parent and service provider discussion groups, development and psychometric evaluation of a recognition and assessment process and drafting proposals for pilot, implementation and evaluation. Reflection and planning stages of four action research cycles will be undertaken in four key stakeholder workshops aligned with the first four Intervention Mapping steps to prepare programme plans. ETHICS AND DISSEMINATION: Ethics and dissemination protocols are consistent with the National Health and Medical Research Council Indigenous Research Excellence criteria of engagement, benefit, transferability and capacity-building. A conceptual framework has been developed to promote the application of core values of safety, trustworthiness, empowerment, collaboration, culture, holism, compassion and reciprocity. These include related principles and accompanying reflective questions to guide research decisions.

Secreted cellular prion protein binds doxorubicin and correlates with anthracycline resistance in breast cancer.

Anthracyclines are amongst the most effective chemotherapeutics ever developed, but they produce grueling side-effects, serious adverse events and resistance often develops over time. We found that these compounds can be sequestered by secreted cellular Prion protein (PrPC), blocking their cytotoxic activity. This effect was dose-dependent using either cell line-conditioned medium or human serum as a source of PrPC. Genetic depletion of PrPC or inhibition of binding via chelation of ionic copper prevented the interaction and restored cytotoxic activity. This was more pronounced for doxorubicin than its epimer, epirubicin. Investigating the relevance to breast cancer management, we found that the levels of PRNP transcript in pre-treatment tumor biopsies stratified relapse-free survival after neoadjuvant treatment with anthracyclines, particularly amongst doxorubicin-treated patients with residual disease at surgery (p=2.8E-08). These data suggest that local sequestration could mediate treatment resistance. Consistent with this, tumor cell expression of PrPC protein correlated with poorer response to doxorubicin but not epirubicin in an independent cohort analyzed by immunohistochemistry, particularly soluble isoforms released into the extracellular environment by shedding (p=0.015). These findings have important potential clinical implications for frontline regimen decision-making. We suggest there is warranted utility for prognostic PrPC/PRNP assays to guide chemo-sensitization strategies that exploit an understanding of PrPC-anthracycline-copper ion complexes.

Prion protein scrapie and the normal cellular prion protein.

Prions are infectious proteins and over the past few decades, some prions have become renowned for their causative role in several neurodegenerative diseases in animals and humans. Since their discovery, the mechanisms and mode of transmission and molecular structure of prions have begun to be established. There is, however, still much to be elucidated about prion diseases, including the development of potential therapeutic strategies for treatment. The significance of prion disease is discussed here, including the categories of human and animal prion diseases, disease transmission, disease progression and the development of symptoms and potential future strategies for treatment. Furthermore, the structure and function of the normal cellular prion protein (PrP(C)) and its importance in not only in prion disease development, but also in diseases such as cancer and Alzheimer's disease will also be discussed.