MoA Studies of the TEAD P-Site Binding Ligand MSC-4106 and Its Optimization to TEAD1-Selective Amide M3686.

Taking the structural information into account, we were able to tune the TEAD selectivity for a specific chemotype. However, different TEAD selectivity profiles did not affect the compound potency or efficacy in the NCI-H226 viability assay. Amides based on or analogues showed improved viability efficacy compared with the corresponding acids.

Discovery of reversible and covalent TEAD 1 selective inhibitors MSC-1254 and MSC-5046 based on one scaffold.

The Transcriptional Enhanced Associated Domain (TEAD) family of transcription factors are key components of the Hippo signalling family which play a crucial role in the regulation of cell proliferation, differentiation and apoptosis. The identification of inhibitors of the TEAD transcription factors are an attractive strategy for the development of novel anticancer therapies. A HTS campaign identified hit 1, which was optimised using structure-based drug design, to deliver potent TEAD1 selective inhibitors with both a reversible and covalent mode of inhibition.

Clinical Outcomes and Healthcare Resource Utilization for Patients With Lower-Risk Myelodysplastic Syndromes Treated With Erythropoiesis-Stimulating Agents.

Introduction: Real-world studies of lower-risk myelodysplastic syndromes (LR-MDS) are limited. We evaluated treatment patterns, clinical outcomes, and healthcare resource utilization (HCRU) among patients with LR-MDS treated with erythropoiesis-stimulating agents (ESAs) in the United States.

Patients And Methods: This retrospective study included patients with LR-MDS who initiated treatment with ESAs between January 1, 2016 and June 30, 2019.

Neurological outcome following out of hospital cardiac arrest: Evaluation of performance of existing risk prediction models in a UK cohort.

Introduction: Out of hospital cardiac arrest (OHCA) is a common problem. Rates of survival are low and a proportion of survivors are left with an unfavourable neurological outcome. Four models have been developed to predict risk of unfavourable outcome at the time of critical care admission - the Cardiac Arrest Hospital Prognosis (CAHP), MIRACLE, Out of Hospital Cardiac Arrest (OHCA), and Targeted Temperature Management (TTM) models.

Air pollution mortality benefits of sustained COVID-19 mobility restrictions in Australian cities.

Objectives: Emissions from road traffic, power generation and industry were substantially reduced during pandemic lockdown periods globally. Thus, we analysed reductions in traffic-related air pollution in Australian capital cities during March-April 2020 and then modelled the mortality benefits that could be realised if similar reductions were sustained by structural policy interventions.

Study Design: Satellite, air pollution monitor and land use observations were used to estimate ground-level nitrogen dioxide (NO) concentrations in all Australian capital cities during: (a) a typical year with no prolonged air pollution events; (b) a hypothetical sustained reduction in NO equivalent to the COVID-19 lockdowns.

Acute health effects of bushfire smoke on mortality in Sydney, Australia.

Background: Bushfire smoke is a major ongoing environmental hazard in Australia. In the summer of 2019-2020 smoke from an extreme bushfire event exposed large populations to high concentrations of particulate matter (PM) pollution. In this study we aimed to estimate the effect of bushfire-related PM of less than 2.

Epidemiology of interstitial lung disease in patients with metastatic breast cancer at baseline and after treatment with HER2-directed therapy: a real-world data analysis.

Purpose: Using real-world data, interstitial lung disease (ILD) prevalence before and after HER2-directed therapy was estimated. Potential ILD risk factors in patients receiving HER2-directed therapy for metastatic breast cancer (mBC) were evaluated.

Methods: Adults with HER2-directed therapy for mBC initiated between September 25, 1998, and February 22, 2020 were, included.

Optimization of TEAD P-Site Binding Fragment Hit into In Vivo Active Lead .

The dysregulated Hippo pathway and, consequently, hyperactivity of the transcriptional YAP/TAZ-TEAD complexes is associated with diseases such as cancer. Prevention of YAP/TAZ-TEAD triggered gene transcription is an attractive strategy for therapeutic intervention. The deeply buried and conserved lipidation pocket (P-site) of the TEAD transcription factors is druggable.

Real-World Treatment Patterns and Clinical Effectiveness of Palbociclib Plus an Aromatase Inhibitor as First-Line Therapy in Advanced/Metastatic Breast Cancer: Analysis from the US Syapse Learning Health Network.

This retrospective single-arm study assessed real-world treatment patterns and clinical outcomes in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced/metastatic breast cancer (A/MBC) who received palbociclib plus an aromatase inhibitor as first-line therapy in US community health systems. Using electronic health records from the Syapse Learning Health Network, 242 patients were identified as having received first-line palbociclib plus an aromatase inhibitor between 3 February 2015, and 31 July 2019 (data cutoff 1 February 2020) resulting in a minimum potential 6-month follow-up period. In total, 56.

Retrospective epidemiological analysis of SARS-CoV-2 wastewater surveillance and case notifications data - New South Wales, Australia, 2020.

This epidemiological study analysed SARS-CoV-2 wastewater surveillance and case notifications data to inform evidence-based public health action in NSW. We investigated measures of association between SARS-CoV-2 RNA fragments detected in wastewater samples (n = 100) and case notifications (n = 1,367, as rates per 100,000 population) within wastewater catchment areas (n = 6); and evaluated the performance of wastewater testing as a population-level diagnostic tool. Furthermore, we modelled SARS-CoV-2 RNA fragment detection in wastewater given the case notification rate using logistic regression.

Evolution of the Cancer Registrar in the Era of Informatics.

The cancer registrar reports accurate, complete, and timely abstracted cancer data to various healthcare agencies. The data are used for understanding the incidence of cancer, evaluating the effectiveness of public health efforts in the prevention of new cases and improving patient care outcomes and survival. There are increasing demands placed on registrars for additional data points with real-time submission to reporting agencies.

TET2 is a component of the estrogen receptor complex and controls 5mC to 5hmC conversion at estrogen receptor cis-regulatory regions.

Estrogen receptor-α (ER) drives tumor development in ER-positive (ER+) breast cancer. The transcription factor GATA3 has been closely linked to ER function, but its precise role in this setting remains unclear. Quantitative proteomics was used to assess changes to the ER complex in response to GATA3 depletion.

Avoidable Mortality Attributable to Anthropogenic Fine Particulate Matter (PM) in Australia.

Ambient fine particulate matter <2.5 µm (PM) air pollution increases premature mortality globally. Some PM is natural, but anthropogenic PM is comparatively avoidable.

IL6/STAT3 Signaling Hijacks Estrogen Receptor α Enhancers to Drive Breast Cancer Metastasis.

The cytokine interleukin-6 (IL6) and its downstream effector STAT3 constitute a key oncogenic pathway, which has been thought to be functionally connected to estrogen receptor α (ER) in breast cancer. We demonstrate that IL6/STAT3 signaling drives metastasis in ER breast cancer independent of ER. STAT3 hijacks a subset of ER enhancers to drive a distinct transcriptional program.

The mortality effect of PM sources in the Greater Metropolitan Region of Sydney, Australia.

We describe an assessment of the impact on mortality of eight major sources of PM in the Greater Metropolitan Region of Sydney, Australia (GMR). We modeled exposure to PM for the year July 2010 to June 2011 and estimated the burden of current mortality attributable to these sources. We also estimated the number of life-years that would be produced if emissions from wood heaters and power stations, the two largest emissions sources, were reduced.

Impact of emergency department occupancy on waiting times, rates of admission and representation, and length of stay when hospitalised: A data linkage study.

Objectives: To assess the association between ED occupancy and relevant outcomes including ED waiting times, rates of admission and representation and length of stay when hospitalised.

Methods: Retrospective study of all ED presentations by New South Wales (NSW), Australia, residents to 15 NSW public, principal referral or paediatric specialist hospitals between 1 January to 31 December 2015 (N = 935 282). ED data were linked longitudinally (to ED data) and cross-sectionally to hospital admissions data.

Lessons Learnt From Exercise Celestial Navigation: The Application of a Geographic Information System to Inform Legionnaires' Disease Control Activity.

Geographic information systems (GIS) have emerged in the past few decades as a technology capable of assisting in the control of infectious disease outbreaks. A Legionnaires' disease cluster investigation in May 2016 in Sydney, New South Wales (NSW), Australia, demonstrated the importance of using GIS to identify at-risk water sources in real-time for field investigation to help control any immediate environmental health risk, as well as the need for more staff trained in the use of this technology. Sydney Local Health District Public Health Unit (PHU) subsequently ran an exercise (based on this investigation) with 11 staff members from 4 PHUs across Sydney to further test staff capability to use GIS across NSW.

The inhibition of human lung fibroblast proliferation and differentiation by Gs-coupled receptors is not predicted by the magnitude of cAMP response.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrotic lung disease for which there is no cure. Current therapeutics are only able to slow disease progression, therefore there is a need to explore alternative, novel treatment options. There is increasing evidence that the 3', 5' cyclic adenosine monophosphate (cAMP) pathway is an important modulator in the development of fibrosis, with increasing levels of cAMP able to inhibit cellular processes associated with IPF.

Age and cause-of-death contributions to area socioeconomic, sex and remoteness differences in life expectancy in New South Wales, 2010-2012.

Objectives: To determine age group- and cause-of-death-specific contributions to area socioeconomic status (SES), sex and remoteness life expectancy inequalities.

Methods: Mortality and estimated residential population data from New South Wales, Australia, over 2010-2012 was used to calculate life expectancy. Inequalities by sociodemographic groups were partitioned into age group- and cause-of-death-specific contributions.

The health impacts and economic value of wildland fire episodes in the U.S.: 2008-2012.

Introduction: Wildland fires degrade air quality and adversely affect human health. A growing body of epidemiology literature reports increased rates of emergency departments, hospital admissions and premature deaths from wildfire smoke exposure.

Objective: Our research aimed to characterize excess mortality and morbidity events, and the economic value of these impacts, from wildland fire smoke exposure in the U.

Patterns of low acuity patient presentations to emergency departments in New South Wales, Australia.

Objective: To explore the patterns of low acuity patient (LAP) presentations to EDs in New South Wales (NSW), Australia.

Methods: Retrospective study of NSW public hospital ED presentations between January 2013 and December 2014 that were registered in the NSW Emergency Department Data Collection (n = 409 035). LAPs were defined according to the Australian Institute of Health and Welfare (AIHW), Sprivulis and multiple ACEM methods.