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Chromatin-focused genetic and chemical screens identify BRPF1 as a targetable vulnerability in Taxol-resistant triple-negative breast cancer
Get PDFTriple-negative breast cancer (TNBC) is a particularly aggressive and frequently recurring form of breast cancer, where chemotherapy is the primary treatment approach. Unfortunately, the development of resistance to chemotherapy poses a considerable challenge, restricting the already limited therapeutic alternatives for recurrent cases. Here, we generated two Taxol-resistant TNBC cell lines with a dose-escalation method to mimic chemotherapy resistance in vitro. These cells exhibited reduced growth rates, altered morphology and evasion of apoptosis. Transcriptome analysis uncovered elevated ABCB1 expression and multidrug-resistant phenotype in these resistant cells. To comprehensively investigate the key epigenetic regulators of Taxol resistance, we conducted chromatin-focused genetic and chemical screens and pinpointed Bromodomain and PHD Finger Containing 1 (BRPF1) as a novel regulator of Taxol resistance. Knockout of BRPF1, the reader protein in the MOZ–MORF histone acetyltransferase complex, but not the other complex members, sensitized resistant cells to Taxol. In addition, BRPF1 inhibitors, PFI-4 and OF-1, in combination with Taxol significantly reduced cell viability. Transcriptome analysis upon BRPF1 loss or inhibition revealed a negative impact on ribosome biogenesis-related gene sets, resulting in a global decrease in protein translation in Taxol-resistant cells. CUT&RUN-qPCR analysis demonstrated that BRPF1 directly binds to the ABCB1 promoter, enhancing its expression toward inducing a multidrug-resistant phenotype. Conversely, knockout or inhibition of BRPF1 leads to decreased ABCB1 expression. Our findings uncover a comprehensive molecular framework, highlighting the pivotal role of epigenetic reader protein BRPF1 in Taxol resistance and providing potential avenues for therapeutic intervention in TNBC
The changing spectrum of cardiovascular diseases
Get PDFAdvances in cardiovascular disease prevention are often hailed as one of the major public health accomplishments of the past 50 years. The progress achieved is rooted in efforts challenging the inevitability of vascular events, which led to the discovery of modifiable risk factors and systematic approaches to prevent population exposure. These prevention efforts have led to steep reductions in premature vascular mortality and morbidity in many parts of the world since the 1960s.1–3 However, this downward trend seems to have reached a plateau or even reversed in several high-income countries.3–6 This trend also appears to be true for cardiovascular morbidity, with little change in the number of individuals newly diagnosed with cardiovascular disease since the mid-2000s even when accounting for population ageing.7 A rise in the prevalence of obesity, diabetes, and chronic kidney disease is thought to underpin these unfavourable trends.
Exposing binding-favourable facets of perovskites for tandem solar cells
Get PDFImproved understanding of heterojunction interfaces has enabled multijunction photovoltaic devices to achieve power conversion efficiencies that exceed the detailed-balance limit for single-junctions. For wide-bandgap perovskites, however, the pronounced energy loss across the heterojunctions of the active and charge transport layers impedes multijunction devices from reaching their full efficiency potential. Here we find that for polycrystalline perovskite films with mixed-halide compositions, the crystal termination—a factor influencing the reactivity and density of surface sites—plays a crucial role in interfacial passivation for wide-bandgap perovskites. We demonstrate that by templating the growth of polycrystalline perovskite films toward a preferred (100) facet, we can reduce the density of deep-level trap states and enhance the binding of modification ligands. This leads to a much-improved heterojunction interface, resulting in open-circuit voltages of 1.38 V for 1.77-eV single-junction perovskite solar cells. In addition, monolithic all-perovskite double-junction solar cells achieve open-circuit voltage values of up to 2.22 V, with maximum power point tracking efficiencies reaching 28.6% and 27.7% at 0.25 and 1.0 cm2 cell areas, respectively, along with improved operational and thermal stability at 85 °C. This work provides universally applicable insights into the crystalline facet-favourable surface modification of perovskite films, advancing their performance in optoelectronic applications
Variations in Methodological Approaches to Measuring Health Inequalities and Inequities: A Scoping Review of Acute Stroke Pathways
Get PDFBackgroundThere are a lot of advances that may affect the way treatment is delivered prehospital, including mobile stroke units and point-of-care diagnostics. These have the potential to affect populations differently and therefore affect the distribution of health outcomes.ObjectivesWe aimed to address the following research questions: (1) Which geographic and socioeconomic inequalities have been included when evaluating access to acute stroke treatment (including reperfusion therapies)? (2) How have the identified measures been considered/assessed/calculated? (3) We also report any methodological approaches that have been proposed that might further improve the way in which acute stroke care interventions are analysed, specified relating to inequalities.MethodsPubMed and Scopus electronic databases were searched for studies that included participants who underwent acute stroke treatment and included quantitative measures of geographic and/or socioeconomic inequalities or inequities in accessing/receiving treatment.ResultsOverall, sixty-six studies were included in the review. Fifty-nine included at least one measure of geographic inequalities or inequities while thirty-six included at least one measure of socioeconomic inequalities or inequities. Twenty-eight of these studies included both a geographic and socioeconomic measure of inequalities or inequities. There were no commonalities in the methods of defining, categorising and measuring the inequalities or inequities. No study provided their definition of inequality or inequity or stated any normative judgements they had made.ConclusionsIt is vital that the evaluation of programmes like acute stroke care consider impacts on inequality and inequity. Researchers and policy makers should work together to determine relevant measures of inequality/inequity and the most appropriate methods of measuring and categorising them. In addition, researchers should make it clear within their work how they are defining inequality and inequity and what (if any) normative judgements have been made
Poetry Bookshop Broadsides and Mass-Market Modernism
Get PDFThis article examines the cheaply mass-produced modernist poetry broadsides produced by Harold Monro’s Poetry Bookshop. It argues that these broadsides represented a dynamic—and remarkably successful—forgotten intervention into modern poetry publication, one which brought early modernist poetry into the homes and lives of ordinary readers. Neither antiquarian replicas nor limited-edition collectibles, the Poetry Bookshop broadsides, which flourished from 1913 to 1936, offer a new dimension to critical understandings of how modernist poetry circulated. The brightly coloured, cheap ‘Rhyme Sheets’ sold in their thousands, revealing an institution of modernist poetry deliberately seeking mass readership while also illuminating the complex temporal allegiances of early modernist aesthetics. At its close, the article offers a close reading of Ezra Pound’s Poetry Bookshop broadside ‘An Immorality’, to show how this distinctive print context could alter the experience of reading modernist poetry in the 1920s and 1930s
Distinguishing short‐term versus long‐term responses in cover‐class structured community dynamics: a test with grassland drought response
No full textClimate change is increasing the magnitude and frequency of precipitation extremes. Consequently, grassland community dynamics are destabilising and becoming harder to predict since models typically simulate long-term (asymptotic) behaviour, potentially neglecting short-term (transient) behaviour. Here, we use cover data from an experiment performed over 8 years to model short- and long-term responses of three functional groups (grasses, legumes, and non-leguminous forbs) to precipitation extremes. We use Integral Projection Models (IPMs) and pseudospectral theory to track transient grassland community dynamics driven by response lags and interannual shifts. We show that the cover-class structure and inter-cover-class interactions of functional groups make them transiently unstable but asymptotically stable, that is, disturbances are initially amplified before eventually dissipating. We also show that grasses dominate under irrigation, while legumes and forbs dominate under drought. We demonstrate that the pseudospectra of IPMs enable computationally and data-wise inexpensive assessment of whether transient dynamics drive community responses to disturbances
Primary care patients presenting with unexpected weight loss in Australian general practices: replication of a diagnostic accuracy study
Get PDFObjective: We calculate positive predictive values (PPVs) of patients presenting with unexpected weight loss (UWL) being diagnosed with cancer within 6 months, using data from a population of Australian primary care patients to replicate results from a previous UK study. Design: A diagnostic accuracy study involving calculation of the PPV for any cancer using retrospective data from routinely collected electronic healthcare records. The index date is defined as the first recorded UWL presentation and the reference standard is cancer diagnosis within 6 months of the index date. Setting: This study uses primary care data from the Patron primary care database, linked to hospital admissions data and the Victorian Cancer Registry. We include only patients who presented to their General Practitioners (GPs) at least once between 1 July 2007 and 1 February 2022. Participant: Patients were included if they were at least 18 years of age at the index date, had no previous diagnosis of cancer or previous weight loss intervention, including being prescribed medications for weight loss. 13 306 patients out of a primary care population of 1 791 051 patients were identified that met the eligibility criteria. Results: When stratified by age, sex and smoking status, we found PPVs lower than those derived in a previous UK primary care study, though still above 3% for male non-smokers over 60, female smokers over 70 and all males over 70. Patients from ages 60–79 with at least one abnormal blood test result had PPVs consistently above 3%, while overall, patients with abnormal blood test results have PPVs of up to 35%. Conclusion: We confirmed that many PPVs, while consistently below those derived in the UK study, are above clinically significant thresholds and increasing with age and the number of different abnormal blood test results
Chronic kidney disease and incident cancer risk: an individual participant data meta-analysis
Get PDFBackground Studies examining the association of chronic kidney disease (CKD) with cancer risk have demonstrated conflicting results. Methods This was an individual participant data meta-analysis including 54 international cohorts contributing to the CKD Prognosis Consortium. Included cohorts had data on albuminuria [urine albumin-to-creatinine ratio (ACR)], estimated glomerular filtration rate (eGFR), overall and site-specific cancer incidence, and established risk factors for cancer. Included participants were aged 18 years or older, without previous cancer or kidney failure. Results Among 1,319,308 individuals, the incidence rate of overall cancer was 17.3 per 1000 person-years. Higher ACR was positively associated with cancer risk [adjusted hazard ratio 1.08 (95% CI 1.06–1.10) per 8-fold increase in ACR]. No association of eGFR with overall cancer risk was seen. For site-specific cancers, lower eGFR was associated with urological cancer and multiple myeloma, whereas higher ACR was associated with many cancer types (kidney, head/neck, colorectal, liver, pancreas, bile duct, stomach, larynx, lung, hemolymphatic, leukaemia, and multiple myeloma). Results were similar in a 1-year landmark analysis. Discussion Albuminuria, but not necessarily eGFR, was independently associated with the subsequent risk of cancer. Our results warrant an investigation into mechanisms that explain the link between albuminuria and cancer
Artificial Intelligence in Digital Self-Diagnosis Tools: A Narrative Overview of Reviews
Get PDFDigital self-diagnosis tools, or symptom checkers, many of which incorporate artificial intelligence technology, are intended to provide diagnostic information and triage advice to lay users. This narrative overview of reviews explores the common themes and issues raised by existing evidence synthesis literature on these tools to establish a common ground for interdisciplinary research. We searched 3 bibliographic databases (PubMed, Scopus and Web of Science) and Google Scholar using keyword combinations of artificial, self-diagnosis, intelligence, and machine learning for publications from 2019 to 2023. We included systematic reviews, meta-analyses, scoping reviews, narrative syntheses, and opinion pieces that discussed tools where users proactively entered personal health information to acquire a predicted diagnosis of their symptoms or triage advice. This overview reveals significant gaps in understanding the key areas of development, implementation, impact, and oversight of digital self-diagnosis tools. Additionally, the terminology used to describe these tools and their underlying technologies varies widely, encompassing technologies ranging from simple branching logic algorithms to complex deep neural networks. Our interdisciplinary analysis identified gaps and critical areas for future research across all stages of the lifecycles of these tools. The diverse challenges uncovered highlight the necessity for multiagency and multidisciplinary efforts promoting responsible development and implementation
Testing autonomous vehicles and AI: perspectives and challenges from cybersecurity, transparency, robustness and fairness
Get PDFThis study aims to comprehensively explore the complexities of integrating Artificial Intelligence (AI) into Autonomous Vehicles (AVs), examining the challenges introduced by AI components and their impact on testing procedures. The research focuses on essential requirements for trustworthy AI, including cybersecurity, transparency, robustness, and fairness. We first analyse the role of AI at the most relevant operational layers of AVs, and discuss the implications of the EU’s AI Act on AVs, highlighting the importance of the concept of a safety component. Using an expert opinion-based methodology, involving an interdisciplinary workshop with 21 academics and a subsequent in-depth analysis by a smaller group of experts, this study provides a state-of-the-art overview of the current landscape of vehicle regulation and standards, including ex-ante, post-hoc, and accident investigation processes, highlighting the need for new testing methodologies for both Advanced Driver Assistance Systems (ADAS) and Automated Driving Systems (ADS). The study also provides a detailed analysis of cybersecurity audits, explainability in AI decision-making processes and protocols for assessing the robustness and ethical behaviour of predictive systems in AVs. The analysis highlights significant challenges and suggests future directions for research and development of AI in AV technology, emphasising the need for multidisciplinary expertise. The study’s conclusions have relevant implications for the development of trustworthy AI systems, vehicle regulations, and the safe deployment of AVs