106 research outputs found

    Targeting DNA mismatches with rhodium metalloinsertors

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    DNA has been exploited as a biological target of chemotherapeutics since the 1940s. Traditional chemotherapeutics, such as cisplatin and DNA-alkylating agents, rely primarily on increased uptake by rapidly proliferating cancer cells for therapeutic effects, but this strategy can result in off-target toxicity in healthy tissue. Recently, research interests have shifted towards targeted chemotherapeutics, in which a drug targets a specific biological signature of cancer, resulting in selective toxicity towards cancerous cells. Here, we review a family of complexes, termed rhodium metalloinsertors, that selectively target DNA base pair mismatches, a hallmark of mismatch repair (MMR)-deficient cancers. These rhodium metalloinsertors bind DNA mismatches with high specificity and display high selectively in killing MMR-deficient versus MMR-proficient cells. This cell selectivity is unique among small molecules that bind DNA. Current generations of rhodium metalloinsertors have shown nanomolar potency along with high selectivity towards MMR-deficient cells, and show promise as a foundation for a new family of chemotherapeutics for MMR-deficient cancers

    A systematic review of self compassion and stress in parents, and an exploration of emotion regulation and psychopathology in adolescence

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    BACKGROUND: Self compassion is considered an adaptive coping strategy in the face of stress and is thought to be an important factor in parent functioning. Self compassion can also be understood within an emotion regulation framework. High levels of self compassion and effective emotion regulation have been shown to be associated with lower levels of psychopathology. The adolescent stage is thought to be an important period in the development of emotion regulation and how this relates to psychopathology. METHOD: Chapter 1 is a systematic review and meta analysis of the association between self compassion and parenting stress. Chapter 3 explored the relationship between emotion regulation and psychopathology in adolescence using a cross sectional design. RESULTS: Chapter 1 demonstrated a medium effect size for the association between self compassion and stress in parents, with high levels of self compassion being related to lower levels of stress. Chapter 3 demonstrated that in an adolescent population, dysfunctional emotion regulation is related to symptoms of anxiety and depression, and that age did not appear to moderate this relationship. CONCLUSIONS: This project explored ways of regulating emotions in parent and adolescent populations. Taken together, these findings demonstrate that emotion regulation and self compassion are important concepts in relation to understanding how individuals cope with stress and how this impacts their psychological wellbeing

    Exploring the Biological Activity of Rhodium Metalloinsertors

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    Rhodium metalloinsertors are a unique family of potential anticancer agents that have been show to bind selectively to thermodynamically destabilized DNA base pair mismatches, abasic sites, and insertions/deletions (indels) in vitro. These metalloinsertors are also able to target mismatches in cells: metalloinsertors preferentially kill mismatch repair (MMR)-deficient cancer cells, which have a relative abundance of uncorrected DNA mismatches and indels, over MMR-proficient cells, which can repair these lesions. As such, these complexes have shown great promise as a potential treatment strategy for MMR-deficient cancers, which are often resistant to classic chemotherapies. Recently, a new class of metalloinsertors that bear a rhodium-oxygen bond was synthesized and shown to have remarkable potency and selectivity towards MMR-deficient cells. We have discovered many key differences between first generation metalloinsertors and these new Rh-O metalloinsertors: (1) the MMR-selectivity of first generation metalloinsertors is heavily influenced by ancillary ligand bulk and lipophilicity, whereas the MMR-selectivity of Rh-O metalloinsertors is strong regardless of ancillary ligand properties, (2) first generation metalloinsertors have toxicities in the micromolar range while Rh-O metalloinsertors have toxicities in the nanomolar range, and (3) first generation metalloinsertors can only bind DNA via the Δ-enantiomer while Rh-O metalloinsertors can bind DNA via both the Δ- and Λ-enantiomers. Excitingly, the improved potency and selectivity of these "Rh-O" metalloinsertors brings them into a realm of clinical relevance. Here we examine the basis for the improved potency and selectivity of these new Rh-O metalloinsertors. A family of six Rh-O metalloinsertors that vary in the steric bulk and lipophilicity of an ancillary ligand was synthesized and characterized. Regardless of ancillary ligand identity, these Rh-O metalloinsertors exhibit nanomolar or low-micromolar toxicities and all preferentially target MMR-deficient cancer cells over MMR-proficient cells. Notably, the off-target accumulation of these metalloinsertors in mitochondria is very low. This cellular distribution is in stark contrast with first generation metalloinsertors in which increased ligand lipophilicity led to increased mitochondrial uptake and ultimately non-selective mitochondrial-mediated cell death. We believe robust selectivity of these complexes is retained in part due to their low off-target accumulation in the mitochondria, which is further complemented by the low dosing requirements of these potent therapeutic agents. Our studies also suggest the high potency of these complexes may be due to a difference in DNA-binding abilities, which is supported by observed differences in which enantiomers can bind to DNA mismatches, differences in ligand buckling at physiological pH, and lipophilicity of the therapeutics, with Rh-O metalloinsertors being dramatically more lipophilic than their first generation counterparts. To better understand the structural basis for this increased potency, crystallographic experiments are underway. A first generation metalloinsertor was previously crystallized with mismatched DNA, and the structure was pivotal in identifying the DNA binding mode of metalloinsertion. Using similar methods, we are working to produce a high-resolution crystal structure of an Rh-O metalloinsertor with mismatched DNA in order to gain structural insights into the increased potency of these new complexes. A significant difference in DNA binding could result in different biological activation of proteins and overall higher potency of these Rh-O metalloinsertors. Finally, as metalloinsertors are moved towards pre-clinical study, understanding their biological activity in diverse cell culture experiments is essential. We examined a metalloinsertor and the FDA approved chemotherapeutic agent cisplatin in 27 diverse colorectal cancer cell lines. The comparison of these drugs revealed the metalloinsertor to be on average five times more potent than cisplatin in this panel. The potency of the metalloinsertor in different cell lines spanned nearly three orders of magnitude and correlated with whole-cell uptake of rhodium. Additionally, a fluorescent metalloinsertor conjugate was used to quantify the number of lesions in DNA that could be targeted by metalloinsertion, a result that correlated well with the potency of a metalloinsertor across several cell lines, consistent with DNA mismatches as the effective biological target of the metalloinsertor. The experiments described within this thesis have allowed us to gain a better understanding of the biological activity of rhodium metalloinsertors. We have established that Rh-O metalloinsertors are distinct from first generation metalloinsertors, and that these new metalloinsertors can serve as highly tunable, potent, and mismatch-selective anticancer agents. Furthermore, this potency is observed across diverse cell lines and has been shown to correlate with the number of genomic DNA lesions that can be bound by metalloinsertion. The unique biological activity of these complexes makes them ideal candidates for the treatment of MMR-deficient cancers, and the potency and tunability of Rh-O metalloinsertors will allow for the development of previously unattainable diagnostic and therapeutic tools for MMR-deficiencies.</p

    HARMONY: a pragmatic cluster randomised controlled trial of a culturally competent systems intervention to prevent and reduce domestic violence among migrant and refugee families in general practice:study protocol

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    INTRODUCTION: Domestic violence and abuse (DVA) is prevalent, harmful and more dangerous among diaspora communities because of the difficulty accessing DVA services, language and migration issues. Consequently, migrant/refugee women are common among primary care populations, but evidence for culturally competent DVA primary care practice is negligible. This pragmatic cluster randomised controlled trial aims to increase DVA identification and referral (primary outcomes) threefold and safety planning (secondary outcome) among diverse women attending intervention vs comparison primary care clinics. Additionally, the study plans to improve recording of DVA, ethnicity, and conduct process and economic evaluations. METHODS AND ANALYSIS: Recruitment of ≤28 primary care clinics in Melbourne, Australia with high migrant/refugee communities. Eligible clinics need ≥1 South Asian general practitioner (GP) and one of two common software programmes to enable aggregated routine data extraction by GrHanite. Intervention staff undertake three DVA training sessions from a GP educator and bilingual DVA advocate/educator. Following training, clinic staff and DVA affected women 18+ will be supported for 12 months by the advocate/educator. Comparison clinics are trained in ethnicity and DVA data entry and offer routine DVA care. Data extraction of DV identification, safety planning and referral from routine GP data in both arms. Adjusted regression analysis by intention-to-treat by staff blinded to arm. Economic evaluation will estimate cost-effectiveness and cost-utility. Process evaluation interviews and analysis with primary care staff and women will be framed by Normalisation Process Theory to maximise understanding of sustainability. Harmony will be the first primary care trial to test a culturally competent model for the care of diverse women experiencing DVA. ETHICS AND DISSEMINATION: Ethical approval from La Trobe University Human Ethics Committee (HEC18413) and dissemination by policy briefs, journal articles and conference and community presentations. TRIAL REGISTRATION NUMBER: ANZCTR- ACTRN12618001845224; Pre-results

    Relationship Between Non-Hodgkin's Lymphoma and Blood Levels of Epstein-Barr Virus in Children in North-Western Tanzania: A Case Control Study.

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    Non-Hodgkin's Lymphomas (NHL) are common in African children, with endemic Burkitt's lymphoma (BL) being the most common subtype. While the role of Epstein-Barr Virus (EBV) in endemic BL is known, no data are available about clinical presentations of NHL subtypes and their relationship to Human Immunodeficiency Virus (HIV) infection and Epstein Barr Virus (EBV) load in peripheral blood of children in north-western, Tanzania. A matched case control study of NHL subtypes was performed in children under 15 years of age and their respective controls admitted to Bugando Medical Centre, Sengerema and Shirati district designated hospitals in north-western, Tanzania, between September 2010 and April 2011. Peripheral blood samples were collected on Whatman 903 filter papers and EBV DNA levels were estimated by multiplex real-time PCR. Clinical and laboratory data were collected using a structured data collection tool and analysed using chi-square, Fisher and Wilcoxon rank sum tests where appropriate. The association between NHL and detection of EBV in peripheral blood was assessed using conditional logistic regression model and presented as odds ratios (OR) and 95% confidence intervals (CI). A total of 35 NHL cases and 70 controls matched for age and sex were enrolled. Of NHLs, 32 had BL with equal distribution between jaw and abdominal tumour, 2 had large B cell lymphoma (DLBCL) and 1 had NHL-not otherwise specified (NHL-NOS). Central nervous system (CNS) presentation occurred only in 1 BL patient; 19 NHLs had stage I and II of disease. Only 1 NHL was found to be HIV-seropositive. Twenty-one of 35 (60%) NHL and 21 of 70 (30%) controls had detectable EBV in peripheral blood (OR = 4.77, 95% CI 1.71 - 13.33, p = 0.003). In addition, levels of EBV in blood were significantly higher in NHL cases than in controls (p = 0.024). BL is the most common childhood NHL subtype in north-western Tanzania. NHLs are not associated with HIV infection, but are strongly associated with EBV load in peripheral blood. The findings suggest that high levels of EBV in blood might have diagnostic and prognostic relevance in African children

    Effects of Environmental Exposures on Fetal and Childhood Growth Trajectories

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    Delayed fetal growth and adverse birth outcomes are some of the greatest public health threats to this generation of children worldwide because these conditions are major determinants of mortality, morbidity, and disability in infancy and childhood and are also associated with diseases in adult life. A number of studies have investigated the impacts of a range of environmental conditions during pregnancy (including air pollution, endocrine disruptors, persistent organic pollutants, heavy metals) on fetal and child development. The results, while provocative, have been largely inconsistent. This review summarizes up to date epidemiologic studies linking major environmental pollutants to fetal and child development and suggested future directions for further investigation

    How can students-as-partners work address challenges to student, faculty, and staff mental health and well-being?

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    Leakage-Resilient Inner-Product Functional Encryption in the Bounded-Retrieval Model

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    We propose a leakage-resilient inner-product functional encryption scheme (IPFE) in the bounded-retrieval model (BRM). This is the first leakage-resilient functional encryption scheme in the BRM. In our leakage model, an adversary is allowed to obtain at most ll-bit knowledge from each secret key. And our scheme can flexibly tolerate arbitrarily leakage bound ll, by only increasing the size of secret keys, while keeping all other parts small and independent of ll. Technically, we develop a new notion: Inner-product hash proof system (IP-HPS). IP-HPS is a variant of traditional hash proof systems. Its output of decapsulation is an inner-product value, instead of the encapsulated key. We propose an IP-HPS scheme under DDH-assumption. Then we show how to make an IP-HPS scheme to tolerate l2˘7l\u27-bit leakage, and we can achieve arbitrary large l2˘7l\u27 by only increasing the size of secret keys. Finally, we show how to build a leakage-resilient IPFE in the BRM with leakage bound l=l2˘7nl=\frac{l\u27}{n} from our IP-HPS scheme

    How can students-as-partners work address challenges to student, faculty, and staff mental health and well-being?

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    Mental health has emerged as a critical area of attention in higher education, and educational research over the last 15 years has focused increasingly on emotions and wellbeing at all stages of education (Hill et al., 2021). While definitions of well-being vary, most are premised on “good quality of life” (Nair et al., 2018, p. 69). Within the last few years, we have experienced an intersection of several forces that undermine or threaten good quality of life. These include the uncertainties prompted by the COVID-19 pandemic (Hews et al., 2022, U.S. Surgeon General, n.d.), climate change (Charlson et al., 2021), racism and social injustices (Williams & Etkins, 2021), the cost-of-living crisis (Montacute, 2023), and the lack of motivation and higher incidence of mental health issues associated with growing concerns about job prospects and income (Chowdhury et al., 2022). This fifth iteration of Voices from the Field explores some of the ways in which students-as-partners work can address challenges to the mental health and well-being of students, faculty, and staff. This focus, proposed by members of the IJSaP Editorial Board, both responds to the intersecting realities named above and remains true to the goal of this section of the journal, which is to offer a venue for a wide range of contributors to address important questions around and aspects of students-as-partners work without going through the intensive submission, peer-review, and revision processes. The prompt we included in the call for this iteration of Voices was: “In what ways can students-as-partners work address challenges to the mental health and well-being of students, staff, and faculty posed by the current realities in the wider world (socio-political, environmental, economic, etc.) that affect higher education?
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