This website is using a security service to protect itself from online attacks The action you just performed triggered the security solution There are several actions that could trigger this block including submitting a certain word or phrase You can email the site owner to let them know you were blocked Please include what you were doing when this page came up and the Cloudflare Ray ID found at the bottom of this page Casa Luce is an extensive renovation of a mid-century modern home in Arizona‘s Catalina Foothills by HK Associates. Originally designed and built by Tucson architect Tom Gist, the residence featured Gist’s signature earthen walls of burnt adobe supporting a low-slung roof While the 1960s structure retained its architectural significance it required substantial updates to align with contemporary living needs The goal of the redesign was to redefine the home’s essence while respecting its historical character The home originally included a floor-to-ceiling picture window framing the distant Santa Rita Mountains to the south the home’s introverted layout centered on a closed-off The interior was further constrained by a low mechanical bulkhead and a sunken indoor terrarium both of which disrupted spatial continuity composed of a grid of painted wood beams filled with textured white plaster added to the compartmentalized feel of the home images © Ema Peter The architects at HK Associates approach the redesign of Casa Luce with the objective of enhancing natural light The transformation prioritized connecting the home’s interior to its desert surroundings creating an open transition between indoor and outdoor spaces The result is a home that is both modern and deeply respectful of its original design One of the most significant changes in Casa Luce was the removal of four masonry piers that originally supported the central roof This intervention allowed for a floating ceiling that dramatically alters the perception of space within the main living areas Achieving this required innovative engineering The removal of structural obstructions created an open-plan layout that enhances the home’s spatial fluidity Casa Luce is a mid-century modern home in Tucson renovated by HK Associates The reimagined Casa Luce incorporates a carefully curated material palette that emphasizes natural light and subtle design details Artisanal lime plaster walls and sustainable wood veneer cabinetry contribute to a minimal yet sophisticated aesthetic These materials dialogue with the home’s original elements of concrete reflecting the balance between structure and environment that defines life in the Sonoran Desert HK Associates also redefined the bedroom wing of Casa Luce enclosed corridor into a passage guided by light A frosted glass screen at the threshold to the kitchen introduces a soft while the partially exposed roof structure casts bold shadows that change with the movement of the sun These elements contribute to a dynamic interaction between light and space throughout the home the original home features burnt adobe walls and a low-slung roof The outdoor spaces are redesigned to extend the perception of the interior outward enhancing the home’s connection to its natural surroundings The panoramic view from the south-facing picture window is now amplified by the addition of an infinity-edge swimming pool which visually extends toward the distant mountains a set of long concrete steps appears to emerge from the interior functioning as amphitheater seating that invites outdoor living while framing the surrounding desert landscape the redesign focuses on introducing natural light and reorienting the home towards its desert surroundings a key transformation was the removal of four masonry piers to create a floating ceiling effect an infinity-edge swimming pool extends the home’s connection to the distant Santa Rita Mountains the formerly dark bedroom corridor now features a frosted glass screen and exposed roof structure concrete steps integrated into the landscape provide amphitheater-style outdoor seating architect: HK Associates | @hkassociatesinc photography: © Ema Peter | @emaphotographi AXOR presents three bathroom concepts that are not merely places of function but destinations in themselves — sanctuaries of style The dates displayed for an article provide information on when various publication milestones were reached at the journal that has published the article activities on preceding journals at which the article was previously under consideration are not shown (for instance submission All content on this site: Copyright © 2025 Elsevier B.V. following the Board of Directors meeting today declared: “Pirelli’s management will continue to work on finding a solution that will allow the company to adapt to the new regulations of the American market as it does in all the markets in which it operates” Please select what you would like included for printing: Copy the text below and then paste that into your favorite email application This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply Service map data © OpenStreetMap contributors New recommendations from DEFRA’s Hazardous Substances Advisory Committee (HSAC) have set out steps that could make the UK a world leader in more ethical through early adoption of a risk-based approach to regulation (also called next generation risk assessment) NAMs are modern methods of chemical testing that utilise advanced technologies to enhance the assessment and regulation of hazardous chemicals by improving the relevance speed and reliability of toxicological testing and to support a transition away from animal testing The report finds that the UK’s technological and scientific capabilities in public health and safety are substantially advanced enough to make the country a global leader in using NAMs for chemical safety assessments Professor of Environmental Nanosciences at the University of Birmingham (UoB) and Chair of the HSAC said: “The current approach to chemicals regulation has failed to keep pace with the number of chemicals on the market and has not kept pace with the advances in science that are providing new insights into the toxicology of substances and their mixtures for assessing health risks to humans and the environment The time is right for the UK to begin the transition to NAMs-based regulation.” NAMs and AI-enabled predictive models are rapidly enhancing our ability to understand and predict the effects of chemicals on humans and wildlife These new approaches are increasingly contributing to safety decision-making across different sectors while reducing the need for animal testing where alternative methods are viable achieving large-scale impact will require coordinated strategies for accelerating their adoption in regulatory settings Key Recommendations for UK Chemicals Regulation include: Professor of Environmental Genomics at the University of Birmingham and Director of the Centre for Environmental Research and Justice (CERJ) is optimistic that the technological roadblocks towards this transition are finally lifted after more than a decade of substantial public and private scientific investments “The UK is in a position to harvest from the investments of almost a billion pounds from national and European funded research by revisiting what types of evidence are needed to provide greater protection from toxic chemicals which can now be part of current legal reforms in the UK As well as the suggestion that the UK could be a world leader in NAMs if these recommendations are followed the report also argues that the strategic implementation of NAMs can significantly reduce and potentially replace the use of mammalian animals for chemical safety testing while improving hazard assessment robustness and efficiency The report concludes that a progressive regulatory framework is the essential first step in moving toward the integration of NAMs which can reduce testing costs all while improving the safety and sustainability of the chemicals industry Dr Margiotta-Casaluci is from The Institute of Pharmaceutical Science (IPS) The Institute collaborates closely with industry partners and policymakers to translate its world-leading research into real-world impact the Genetic & Environmental Toxicology Section carries out pioneering research in mechanistic and predictive toxicology dedicated to understanding the mechanisms and pathways through which chemicals and environmental contaminants cause adverse health effects in humans The Section’s ultimate goals are to leverage this cutting-edge research to enhance the protection of human and environmental health and to develop state-of-the art educational programmes that will train the next generations of toxicologists High-value saturation rate running at about 95% compared to an overall rate of 90% across Italian tire maker's facilities SpA has dedicated around one fifth of its total capex to increasing its capacity to produce high-value That's according to group CEO Andrea Casaluci who believes the current level of investment is sufficient to meet growing demand for those products the utilisation rate across Pirelli factories stands at about 90% with a saturation rate of about 95% for high-value tires The high-value rate is always above the average "because we use around 10 million of the high-value capacity to produce standard tires,” the chief executive explained allows Pirelli sufficient scope to “catch any further opportunity” from the market on the high-value side the company does not need to accelerate investment in this regard around 20% of our total capex is dedicated to capacity growth in high-value [tire production] and this is enough to balance the expected growth in demand.” Pirelli forecast capex to reach €400 million or 6.0% of sales in 2024 down from €410 million or 6.1% of sales in 2023.  Pirelli reported a “further strengthening in high value” with  ≥18” car tire volume growth of 6.8% (market +6.5%) Pirelli’s gain comprised: Replacement volumes +11.4% (versus +10.1% for the market overall); and OE volumes +0.9% (compared with +1.5% for the market overall).  A subscription to European Rubber Journal includes: Already a subscriber? Log in here Our Standards: The Thomson Reuters Trust Principles., opens new tab , opens new tab Browse an unrivalled portfolio of real-time and historical market data and insights from worldwide sources and experts. , opens new tabScreen for heightened risk individual and entities globally to help uncover hidden risks in business relationships and human networks. © 2025 Reuters. All rights reserved Multi-center data from establishments in the South of Italy provide a general confidence in using TRT as a consolidative strategy after chemoimmunotherapy. Considering the limits of a restrospective analysis, these preliminary results support the feasibility of the approach and encourage a prospective evaluation. Volume 14 - 2023 | https://doi.org/10.3389/fimmu.2023.1289434 This article is part of the Research TopicImmunotherapy in Small Cell Lung CancerView all 5 articles Background: Consolidative thoracic radiotherapy (TRT) has been commonly used in the management of extensive-stage small cell lung cancer (ES-SCLC) phase III trials exploring first-line chemoimmunotherapy have excluded this treatment approach there is a strong biological rationale to support the use of radiotherapy (RT) as a boost to sustain anti-tumor immune responses the benefit of TRT after chemoimmunotherapy remains unclear The present report describes the real-world experiences of 120 patients with ES-SCLC treated with different chemoimmunotherapy combinations Preclinical data supporting the hypothesis of anti-tumor immune responses induced by RT are also presented Methods: A total of 120 ES-SCLC patients treated with chemoimmunotherapy since 2019 in the South of Italy were retrospectively analyzed None of the patients included in the analysis experienced disease progression after undergoing first-line chemoimmunotherapy 59 patients underwent TRT after a multidisciplinary decision by the treatment team while efficacy measured in terms of overall survival (OS) and progression-free survival (PFS) was used as the secondary endpoint Immune pathway activation induced by RT in SCLC cells was explored to investigate the biological rationale for combining RT and immunotherapy Results: Preclinical data supported the activation of innate immune pathways including the STimulator of INterferon pathway (STING) gamma-interferon-inducible protein (IFI-16) and mitochondrial antiviral-signaling protein (MAVS) related to DNA and RNA release Clinical data showed that TRT was associated with a good safety profile while no ≥ G3 radiation-induced adverse events occurred The median time for TRT onset after cycles of chemoimmunotherapy was 62 days Total radiation dose and fraction dose of TRT include from 30 Gy in 10 fractions up to definitive dose in selected patients Consolidative TRT was associated with a significantly longer PFS than systemic therapy alone (one-year PFS of 61% vs with a trend toward improved OS (one-year OS of 80% vs Conclusion: Multi-center data from establishments in the South of Italy provide a general confidence in using TRT as a consolidative strategy after chemoimmunotherapy Considering the limits of a restrospective analysis these preliminary results support the feasibility of the approach and encourage a prospective evaluation Small cell lung cancer (SCLC) is a unique subtype of lung cancer with an aggressive behavior and dismal prognosis. Approximately two-thirds of patients have extensive stage (ES)-SCLC at the diagnosis, with a five-year survival rate of <3.0% (1) While prospective data are being collected preclinical and retrospective studies represent a useful tool to guide clinical practice Using a preclinical SCLC model with H82 and H524 cells and variable basal levels of STING the present study demonstrated the activation of innate immune pathways after chemo- and radiotherapy A multi-center retrospective study was performed to characterize the outcomes and toxicities of TRT in real-world ES-SCLC patients treated with first-line chemoimmunotherapy Data for patients with treatment-naive ES-SCLC were retrospectively collected at 16 Southern Italy cancer centers between June 2020 and April 2023 All patients were treated with four cycles of chemoimmunotherapy followed by immunotherapy maintenance with or without thoracic radiation Patients with disease progression after four cycles of chemoimmunotherapy or those with disease progression prior to completion of two maintenance immunotherapy cycles were excluded A total of 120 patients with ES-SCLC treated with chemoimmunotherapy were selected Indication for TRT as a consolidative treatment after chemoimmunotherapy and the time interval between the fourth chemoimmunotherapy cycle and mediastinal RT onset were assessed. The following patient characteristics were analyzed: age, gender, and presence of hepatic, cerebral, bone, and other metastases at the diagnosis (Table 1) Table 1 Baseline patient characteristics The present study was approved by the local Ethics Committee of Istituto Tumori Giovanni Paolo II in Bari (prot 1223 CE) and conducted in accordance with the international standards of good clinical practice Propensity score matching (PSM) and survival analyses and tests for equality of proportions were performed using the R v.3.6.3 environment Propensity score matching was carried out using the “MatchIt” R package Kaplan–Meier curves and Cox hazard regression analyses were implemented via the “survival” package The Mantel–Cox test used to compare the Kaplan–Meier curves was done using the “survminer” package while the “ggplot2” package was utilized to depict survival curves Based on the published data defining a subgroup of SCLC patients, where responders to immunotherapy were classified as “inflamed” (9, 10) patients that express high levels of innate immune pathway genes, such as the STING pathway, and other preclinical data supporting STING levels as potential biomarkers of a response to combination chemo- and immunotherapy (11, 12) it was hypothesized that activation of the innate immune pathways may represent a tool that can be used to investigate anti-tumor immune activity in vitro thus confirming that chemotherapy and RT sustain a direct activation of this innate pathway Figure 1 (A) H524 and (B) H82 SCLC cell lines were treated with or without cisplatin (0.5 µM) for 72 h, irradiated at 4 Gy (or not irradiated), and incubated for 24h Cell lysates were immunoblotted with the indicated antibodies (see Supplementary Material) to detect STING-mediated innate immune activation and DNA damage repair pathways GAPDH and tubulin were used to ensure equal loading Figure 2 Both (A) H524 and (B) H82 SCLC cells were treated with cisplatin (CT; 0.5 µM) for 72 h and then irradiated at 4 Gy (RT). After irradiation, both cell groups (1 × 104 cells/well) were cultured for 24 h and mRNA expression levels of innate immune activation markers in both SCLC cell lines were determined by quantitative real-time PCR (see Supplementary Material) Normalized expression data are represented as mean ± s.e.m derived from three technical replicates calculated using the comparative method of 2-^(ΔΔCt) (reference gene 18S) One-tailed unpaired Student’s t-test with 95% confidence interval (CI) Propensity score matching was used to estimate the RT effect on survival One-to-one nearest neighbor matching was used All patients who underwent RT (n=59) were matched to those who did not reaching a good balance with all standardized mean differences below 0.1 after matching excluded only two RT-untreated subjects Matched data were then used for survival analyses Figure 3 (A) Kaplan–Meier curves showing progression-free survival (B) Kaplan–Meier curves showing overall survival Figure 4 (A) Kaplan–Mier curves showing progression free survival based on radiation BED (B) Kaplan–Mier curves showing overall survival based on radiation BED the present study used preclinical SCLC cell models to show a significant positive modulation of innate immune pathway genes (STING and MAVS) accompanied by increased DNA damage with sequential chemotherapy and RT treatment in vitro These data suggest that this strategy may amplify the immune response in patients the preclinical in vitro data may not allow for consideration of the impact of the immune microenvironment thus providing only a partial estimate of the interactions between RT and immune response recently closed the recruitment due to high number of grade 5 AEs even if these AEs are not clearly tied to either immunotherapy or TRT A good safety profile for TRT in SCLC patients treated with chemoimmunotherapy was also noted A significant positive modulation of the innate immune pathway genes (STING and MAVS) was demonstrated in SCLC cell models using sequential chemotherapy and RT treatments in vitro suggesting a possible role of TRT in ES-SCLC patients treated with chemoimmunotherapy Multi-center data from Southern Italy provide a general confidence in using TRT as a consolidative strategy after chemoimmunotherapy based on a clinical multidisciplinary decision With the limit of a retrospective analysis The raw data supporting the conclusions of this article will be made available by the authors The studies involving humans were approved by Istituto Tumori Giovanni Paolo II Bari The studies were conducted in accordance with the local legislation and institutional requirements The participants provided their written informed consent to participate in this study Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article Writing – review & editing. GV: Data curation Writing – review & editing. DG: Supervision The author(s) declare financial support was received for the research This work was supported by AIRC MFAG (Project Number: 26237; PI: Carminia Maria Della Corte) The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest The author(s) declared that they were an editorial board member of Frontiers This had no impact on the peer review process and the final decision All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2023.1289434/full#supplementary-material A systematic review of survival following anti-cancer treatment for small cell lung cancer Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer N Engl J Med (2018) 379(23):2220–9 Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised Adebrelimab or placebo plus carboplatin and etoposide as first-line treatment for extensive-stage small-cell lung cancer (CAPSTONE-1): a multicentre Effect of first-line serplulimab vs placebo added to chemotherapy on survival in patients with extensive-stage small cell lung cancer: the ASTRUM-005 randomized clinical trial Phase I trial of pembrolizumab and radiation therapy after induction chemotherapy for extensive-stage small cell lung cancer 8. NRG-LU007. Available at: https://clinicaltrials.gov/study/NCT04402788 Google Scholar Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities Cancer Cell (2021) 39(3):346–360.e7 Combination treatment of the oral CHK1 inhibitor and low-dose gemcitabine enhances the effect of programmed death ligand 1 blockade by modulating the immune microenvironment in SCLC J Thorac Oncol (2019) 14(12):2152–63 Targeting DNA damage response promotes antitumor immunity through STING-mediated T-cell activation in small cell lung cancer STING pathway expression identifies non-small cell lung cancers with an immune-responsive phenotype J Thorac Oncol (2020) pii:S1556–0864(20)30030-7 Role of consolidative thoracic radiation in extensive-stage small-cell lung cancer with first-line chemoimmunotherapy: a retrospective study from a single cancer center Real-world outcomes of PD-L1 inhibitors combined with thoracic radiotherapy in the first-line treatment of extensive stage small cell lung cancer Use of radiation therapy among patients with Extensive-stage Small-cell lung cancer receiving Immunotherapy: Canadian consensus recommendations Radiation therapy for small cell lung cancer: an ASTRO clinical practice guideline Pract Radiat Oncol (2020) 10(3):158–73 Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials Lancet Respir Med (2021) 9(5):467–75 Is consolidative thoracic radiotherapy of extensive-stage small cell lung cancer still beneficial in the era of immunotherapy Strahlenther Onkol (2023) 199(7):668–75 Which patients with ES-SCLC are most likely to benefit from more aggressive radiotherapy: A secondary analysis of the Phase III CREST trial 1988MO Recruitment discontinuation in TREASURE trial (thoracic radiotherapy with atezolizumab in small cell lung cancer extensive disease) due tounexpected safety data Annals of Oncol (2023) 34:SupplementS 1060 Thoracic radiotherapy may improve the outcome of extensive stage small cell lung carcinoma patients treated with first-line immunotherapy plus chemotherapy Anticancer Drugs (2022) 33(10):e842–9 Galetta D and Vitiello F (2024) Consolidative thoracic radiation therapy for extensive-stage small cell lung cancer in the era of first-line chemoimmunotherapy: preclinical data and a retrospective study in Southern Italy Received: 05 September 2023; Accepted: 18 December 2023;Published: 18 January 2024 distribution or reproduction in other forums is permitted provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited in accordance with accepted academic practice distribution or reproduction is permitted which does not comply with these terms *Correspondence: Vito Longo, dml0by5sb25nbzc5QHRpc2NhbGkuaXQ=; Carminia Maria Della Corte, Y2FybWluaWFtYXJpYS5kZWxsYWNvcnRlQHVuaWNhbXBhbmlhLml0 †These authors have contributed equally to this work and share first authorship Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher 94% of researchers rate our articles as excellent or goodLearn more about the work of our research integrity team to safeguard the quality of each article we publish The Pirelli & C. SpA Board of Directors that was nominated on 31 July met for the first time yesterday. During this meeting, board members nominated Marco Tronchetti Provera to the position of Executive Vice Chairman and Andrea Casaluci as Chief Executive Officer Tronchetti Provera holds authority in areas related to general strategies as well as relations with shareholders and institutions He will also supervise the implementation of Pirelli’s industrial plan is responsible for Pirelli’s operational management chairman of Pirelli’s new Board of Directors becomes the firm’s legal representative and assumes powers specified by current company byelaws After examining available information and statements from interested parties, the Board of Directors evaluated whether the nine independent directors met the requirements for independence as mandated by Legislative Decree 58/1998 and the Code of Corporate Governance for listed companies The nine directors in question are: Michele Carpinelli The following directors make up the new Pirelli & C SpA Board of Directors: Jiao Jian (Chairman) Marco Tronchetti Provera (Executive Vice Chairman) Roberto Diacetti (independent); Paola Boromei (independent) and Giovanni Lo Storto (independent) As announced on 28 June 2023 the Board has appointed Francesco Tanzi Pirelli’s Corporate General Manager Taking the new composition of the Board into account members nominated individuals to serve on the various Board Committees They confirmed existing committees and also established a new Sustainability Committee which will focus on sustainability-related issues related to the company’s operations The Committees are now composed as follows: – Remuneration Committee: Grace Tang (Chairman) Risks and Corporate Governance Committee: Fan Xiaohua (Chairman) – Nomination and Succession Committee: Marco Tronchetti Provera (Chairman) – Strategies Committee: Marco Tronchetti Provera (Chairman) – Related Parties Committee: Marisa Pappalardo (Chairman) – Sustainability Committee: Marco Tronchetti Provera (Chairman) with the prior approval of the Board of Statutory Auditors has reappointed Fabio Bocchio as the designated manager responsible for preparing the company’s accounting documents the Board of Directors confirmed Carlo Secchi (Chairman) and Alberto Bastanzio as members of the Supervisory Board These appointments continue from their prior mandate which expired together with the previous Board If you would like the latest news from the Chinese tyre industry in Chinese, visit our partner site TyrepressChina.com MEMBERS OF BOARD COMMITTEES AND SUPERVISORY BOARDNOMINATED AND NEW SUSTAINABILITY COMMITTEE INSTITUTED INSTITUTES CORPORATE GENERAL MANAGEMENT ENTRUSTED TO FRANCESCO TANZI 3 August 2023 – The Board of Directors of Pirelli & C nominated on 31July  and meeting today for the first time nominated Marco Tronchetti Provera as Executive Vice Chairman investing him with the powers relative to general strategies and the supervision of the implementation of the industrial plan and powers relative to communication as well as relations with shareholders and institution and Andrea Casaluci as Chief Executive Officer (CEO) investing him with the powers for the operational management of Pirelli The Chairman Jiao Jian will be attributed legal representation of the Company and the other powers foreseen in the current Bylaws on the basis of the available information and statements from the interested parties the existence of the requisites needed of board members to hold the role of independence (both in accordance with Legislative Decree 58/1998 and the Code of Corporate Governance for listed companies) of the nine independent directors: Michele Carpinelli The Board is therefore thus composed: Jiao Jian (Chairman) Roberto Diacetti (independent); Paola Boromei (independent) e Giovanni Lo Storto (independet) in line with that which was announced to the market on 28 June 2023 instituted the Corporate General Management the Board itself proceeded to nominate the components of the Board Committees – confirming all previous committees and introducing the Sustainability Committee with a focus on sustainability matters connected with the execution of the company’s activities – which are composed as follows:   - Remuneration Committee: Grace Tang (Chairman) - Nomination and Succession Committee: Marco Tronchetti Provera (Chairman) - Strategies Committee: Marco Tronchetti Provera (Chairman) - Related Parties Committee: Marisa Pappalardo (Chairman) - Sustainability Committee: Marco Tronchetti Provera (Chairman) confirmed Fabio Bocchio as the manager indicated for the preparation of the company accounting documents and Carlo Secchi (Chairman) Antonella Carù and Alberto Bastanzio as components of thesupervisory board in continuation with the previous mandate which expired together with that Board that had nominated it Essential digital access to quality FT journalism on any device Complete digital access to quality FT journalism with expert analysis from industry leaders Complete digital access to quality analysis and expert insights complemented with our award-winning Weekend Print edition Terms & Conditions apply Discover all the plans currently available in your country See why over a million readers pay to read the Financial Times Metrics details A Corrigendum to this article was published on 20 June 2016 This article has been updated The Adverse Outcome Pathway (AOP) framework represents a valuable conceptual tool to systematically integrate existing toxicological knowledge from a mechanistic perspective to facilitate predictions of chemical-induced effects across species its application for decision-making requires the transition from qualitative to quantitative AOP (qAOP) Here we used a fish model and the synthetic glucocorticoid beclomethasone dipropionate (BDP) to investigate the role of chemical-specific properties and internal exposure dynamics in the development of qAOPs We generated a qAOP network based on drug plasma concentrations and focused on immunodepression disruption of gluconeogenesis and reproductive performance We showed that internal exposure dynamics and chemical-specific properties influence the development of qAOPs and their predictive power Comparing the effects of two different glucocorticoids we highlight how relatively similar in vitro hazard-based indicators can lead to different in vivo risk This discrepancy can be predicted by their different uptake potential pharmacokinetic (PK) and pharmacodynamic (PD) profiles We recommend that the development phase of qAOPs should include the application of species-specific uptake and physiologically-based PK/PD models This integration will significantly enhance the predictive power enabling a more accurate assessment of the risk and the reliable transferability of qAOPs across chemicals will allow the full exploitation of the AOP predictive potential IVIVE is highly relevant to drive risk assessment since the risk of effects at levels of organization higher than those considered in the in vitro assay has very narrow limits of tolerance in other cases a certain level of risk is accepted and the attention is focused instead on risk management the modulation of a molecular target (or pathway) does not automatically imply that the potential consequent effects will be adverse or adverse enough to be not tolerable Examples of risk management and tolerated chemical-induced effects are determination of drug safety margins in humans and effects in wildlife that do not affect population dynamics AOPs are relevant for risk management since they are intended to cover all levels of biological organization risk can be assessed on the basis of the most relevant part of the pathway (e.g molecular level vs population level) for different target-species (e.g humans vs wildlife) and the most relevant exposure route Synthetic glucocorticoids are able to modulate the GR and are widely prescribed to treat together with the ability of some synthetic glucocorticoids to interact also with other steroid receptors (i.e Our study aimed at disentangling the complexity of in vivo responses to chronic exposure to synthetic glucocorticoids and to synthesise this information into a predictive qAOP network We focused on three major pathways leading to perturbation of blood glucose homeostasis We demonstrated how internal exposure dynamics and chemical-specific PK/PD properties have profound implications for the occurrence of multi-scale effects We propose that the explicit consideration of PK and PD during the development phase will enhance the predictive power of qAOPs and their transferability across chemicals and across species Mean measured water concentrations in the 10 and 1000 ng/L groups were Log D7.4 and measured water concentrations of BDP on sampling day as inputs (c,d) Predicted plasma concentrations for fish exposed to 1000 ng BDP/L (nominal concentration) in Experiment 1 and Experiment 2 Fish in the two experiments were exposed to the same peak concentrations of BDP (Cmax) but to different total drug concentration over time (AUCs) The predicted internal exposure profile was used to calculate time-integrated plasma concentrations expressed as AUC values Average drug plasma concentration in fish exposed to 10 ng BDP/L in Experiment 2 was within the Human Therapeutic Plasma Concentrations (HTPC) range expressed as Cmax (0.8–1.4 ng/mL) whereas plasma concentrations fish exposed to 1000 ng BDP/L were approximately 50-fold higher than the HTPC range suggesting the likelihood of significant toxicological effects it is predicted that drug plasma concentration in fish exposed to 10 ng BDP/L in Experiment 1 reached the HTPC range once every 4 days whereas in the same 4-day period it oscillated between 1- and 10-fold HTPC in the group exposed to 100 ng BDP/L and between 10-and 100-fold HTPC in the group exposed to 1000 ng BDP/L (a) Relationship between PEPCK gene expression and increase of blood glucose in fish exposed to increasing plasma concentrations of BDP Best-fit regression curves are shown for PEPCK gene expression measured in the liver (solid black curve) and blood glucose concentration (solid red curve) Effect magnitude was calculated for each individual sample as fold-changes versus the control mean value (b) Highly significant correlations were observed between PEPCK and GR gene expression and (c) between PEPCK gene expression and blood glucose concentrations The solid red line represents the linear regression curve the dashed lines the 95% confidence interval White blood cells were analysed by flow-cytometry and changes in the percentages of lymphocytes precursors and granulocytes were quantified in each individual fish (a) Percentage of lymphocytes in fish exposed to oscillating (oscill.) or sustained (sust.) concentrations of BDP for 21 days (n = 30–36) (b) Percentage of precursor cells and (c) granulocytes in fish exposed to sustained concentrations of BDP (1 and 60 ng·h/mL) for 21 days (n = 30–36) (d–f) Representative forward scatter (FSC) versus side scatter (SSC) profile of white blood cells in control fish and in fish exposed to sustained concentrations (1 and 60 ng·h/mL) of BDP for 21 days Note the concentration-dependent changes in the components of white blood cells populations Best-fit regression curves for GR gene expression (solid black curve) and decrease of lymphocyte (lymphocytopenia solid red curve) expressed as effect magnitude at increasing plasma concentrations of BDP (expressed as AUC) Note the changes in the two curves in conditions of oscillating versus sustained exposure dynamics (a) Relative Mean Normalized Expression (MNE) levels of AR measured in the liver of fish exposed to increasing plasma concentrations of BDP over 21 days (n = 12–20) and (b) fatpad height (n = 36) in the same fish Fatpad is an androgen-dependent secondary sexual characteristic typical of fathead minnow males and asterisks a significant difference versus the control group (p < 0.05) (c,d) These data were used to generate the best-fit regression curves for AR gene expression (solid black curve) and the fatpad height (solid red curve) expressed as effect magnitude at increasing plasma concentrations of BDP (expressed as AUC) in conditions of oscillating and sustained exposure to BDP Full lines indicate known cause-effect linkages whereas dashed lines indicate hypothesised linkages or linkages for which the direction of the response is difficult to predict or generalise (i.e The asterisk indicates that the EC50 value for the modulation of AR refers to BOH Note that the immune response is highly dynamic and dependent on the dynamic of exposure using synthetic glucocorticoids as model chemicals internal exposure and chemical-specific PK/PD properties have profound influences not only on the application of a given AOP but also on AOP development and its potential transferability across chemicals in a decision-making context determining the pathway-specific sensitivity to this factor can increase the predictive power of the qAOP Anchoring these responses to adverse phenotypes arising after chronic exposure is still a critical factor for data interpretation whereas plasma concentrations of BDP in fish that exhibited adverse effects were 1 to 50-fold higher than the blood concentrations measured in humans after BDP administration via inhalation.The example of BDP and DEX clearly indicate that chemical-specific properties should be carefully considered in the studies performed with the aim to develop qAOPs and in the selection of reference chemicals similarly potent compounds with different uptake and PK profiles may exhibit different in vivo risks This discrepancy can be predicted by uptake and PK/PD considerations but its success is critically dependent on the accurate extrapolation of dosimetry The development of more accurate physiologically-based PK/PD models able to tackle chronic exposure scenarios for different model species will empower cross-species extrapolation and allow us to maximise the informative and predictive power of data generated using different models All the experimental in vivo protocols and procedures involving fish were performed in accordance with the United Kingdom Animals (Scientific Procedures) Act The in vivo studies were carried out at Brunel University London (United Kingdom) under Project License and Personal Licences granted and approved by the United Kingdom Home Office All in vivo experimental protocols were also approved by the Research Ethics Committee of Brunel University London Experiment 1 included three treatment groups exposed to nominal concentrations of 10 100 and 1000 ng BDP/L and one control group receiving only clean water Each treatment group included three replicate tanks each hosting 12 adult male fathead minnows (36 fish per treatment) Experiment 2 included two treatment groups exposed to 10 and 1000 ng BDP/L and one solvent control group Water in all fish tanks contained DMF at 0.0095% which is within the limit recommended by OECD guidelines The observed range of therapeutic Cmax of 17-BMP was between 0.8 and 1.4 ng/mL It is important to note that these concentrations reflect the systemic level of 17-BMP after inhalation It is likely that concentrations of 17-BMP in the upper respiratory tract are higher than the systemic concentrations in the blood blood concentrations are highly relevant for the prediction of adverse effects at systemic level the first exposure concentration (10 ng/L) was selected as it was the NOEC of Experiment 1 The aim was to evaluate if the NOEC was constant under different exposure dynamics The second concentration (1000 ng/L) induced statistically observable effects in the majority of measured endpoints The aim was to evaluate if different exposure dynamics are able to affect the magnitude of the effects the question was whether the response of each endpoint was driven by the Cmax or by the AUC which takes into account the amplification efficiency of both the target genes and the reference gene to calculate the mean normalized expression (MNE) of each target gene The Log KOW and the Log D7.4 used in the model were predicted by ALOGPS and were The predictions of the FPM were based on water concentrations measured on Day 21 Water concentrations measured at different time points during the studies were used to predict drug plasma concentrations over 21 days The latter was calculated using the GraphPad Prism Software (GraphPad Software Statistical significance was set at a level of p < 0.05 No data were available for the in vitro modulation of AR by 17-BMP thus the EC50 for BOH was used (EC50 = 12 nM = 5 ng/mL; AR beta-lactamase assay in agonist mode; Pubchem ID 20469) How to cite this article: Margiotta-Casaluci Internal exposure dynamics drive the Adverse Outcome Pathways of synthetic glucocorticoids in fish A correction has been published and is appended to both the HTML and PDF versions of this paper The vision of toxicity testing in the 21st century: moving from discussion to action National Research Council Toxicity Testing in the 21st Century: A Vision and a Strategy Adverse Outcome Pathways: a Conceptual Framework to Support Ecotoxicology Research and Risk Assessment An integrated approach for prioritizing pharmaceuticals found in the environment for risk assessment Development and application of the adverse outcome pathway framework for understanding and predicting chronic toxicity: I Challenges and research needs in ecotoxicology Adverse outcome pathway (AOP) development I: strategies and principles EPA National Center for Computational Toxicology Quantitative in vitro to in vivo extrapolation (QIVIVE): An essential element for in vitro-based risk assessment Glucocorticoid receptor signaling in health and disease A theoretical model for utilizing mammalian pharmacology and safety data to prioritize potential impacts of human pharmaceuticals to fish Beclomethasone dipropionate: absolute bioavailability pharmacokinetics and metabolism following intravenous intranasal and inhaled administration in man Metabolic and Reproductive Effects of Relatively Low Concentrations of Beclomethasone Dipropionate Mode of action of human pharmaceuticals in fish: The effects of the 5-alpha-reductase inhibitor Reproductive and endocrine effects of mixtures of steroidal pharmaceuticals with diverse mechanisms of action in a fish reproduction assay Effects of a glucocorticoid receptor agonist Prioritization of pharmaceuticals for potential environmental hazard through leveraging a large-scale mammalian pharmacological dataset Pharmacokinetics and Pharmacodynamics of Dexamethasone Sodium-m-Sulfobenzoate (DS) after Intravenous and Intramuscular Administration: A Comparison with Dexamethasone Phosphate (DP) A computational model of the hypothalamic: pituitary: gonadal axis in female fathead minnows (Pimephales promelas) exposed to 17alpha-ethynylestradiol and 17beta-trenbolone Reverse engineering adverse outcome pathways Defining and modeling known adverse outcome pathways: Domoic acid and neuronal signaling as a case study Crucial role of mechanisms and modes of toxic action for understanding tissue residue toxicity and internal effect concentrations of organic chemicals Advancing environmental toxicology through chemical dosimetry: External exposures versus tissue residues Intermittent Exposure of Fish to Estradiol Effects analysis of time-varying or repeated exposures in aquatic ecological risk assessment of agrochemicals Validating therapeutic targets through human genetics Systems pharmacology: network analysis to identify multiscale mechanisms of drug action Challenges and Limitations of Gene Expression Profiling in Mechanistic and Predictive Toxicology Genomic Signatures and Dose-Dependent Transitions in Nasal Epithelial Responses to Inhaled Formaldehyde in the Rat Progesterone Alters Global Transcription Profiles at Environmental Concentrations in Brain and Ovary of Female Zebrafish (Danio rerio) Progress and promises in toxicogenomics in aquatic toxicology: is technical innovation driving scientific innovation The potential of AOP networks for reproductive and developmental toxicity assay development Dose-dependent pharmacokinetics of dexamethasone oral 2-mg doses of dexamethasone liquid and tablet formulations: a randomized crossover study in healthy adult volunteers The read-across hypothesis and environmental risk assessment of pharmaceuticals Quantitative Cross-Species Extrapolation between Humans and Fish: The Case of the Anti-Depressant Fluoxetine An evolutionarily conserved program of B-cell development and activation in zebrafish Processing of gene expression data generated by quantitative real-time RT-PCR Waterborne beclomethasone dipropionate affects the physiology of fish while its metabolite beclomethasone is not taken up Differences in the glucocorticoid to progesterone receptor selectivity of inhaled glucocorticoids Download references This work was funded by a Biotechnology and Biological Sciences Research Council (BBSRC) Research Grant (BB/100646X/1) co-funded by the AstraZeneca Global Safety Catalan Institute for Water Research (ICRA) Scientific and Technological Park of the University of Girona the quantification of secondary sexual characteristics the gene expression and flow cytometry analyses the analytical quantification of drug concentrations in water and plasma prepared the figures and wrote the manuscript with additional inputs from S.F.O. This work was co-funded by the AstraZeneca Global Safety a biopharmaceutical company specialized in the discovery manufacturing and marketing of prescription medicines AstraZeneca provided support in the form of salaries for author S.F.O. but did not have any additional role in the study design Download citation Anyone you share the following link with will be able to read this content: a shareable link is not currently available for this article Sign up for the Nature Briefing newsletter — what matters in science is ending his tenure on the Board of Directors Bruno “expressed the intention to conclude his mandate as a member of the Board of Directors to pursue his own entrepreneurial activities.” As a consequence he is “not available to be indicated” as chief executive officer of Pirelli “I wish to thank Mr Giorgio Bruno for his contribution over many years to the management of the Pirelli Group and for the fundamental support assured over time to the company’s top management In light of his firm decision to embark on a new entrepreneurial course Bruno my most deeply felt good wishes for the challenges before him which will also still see our collaboration,” said Marco Tronchetti Provera.” “After collaborating for many years on the guidance of the development of the Pirelli Group I have decided to embark on my own entrepreneurial course which will absorb my professional energies in future,” shares Giorgio Bruno “I thank Pirelli and Mr Tronchetti for this long journey together for the many shared experiences to date and for those that we will certainly share in future as entrepreneurs I offer my very best wishes for a future of great satisfaction.” Andrea Casaluci, aged 50, has worked for Pirelli since 2002 and served as the company’s general manager operations since 2018 A little while back we published our list of the top 5 most well-known actors born in Mississauga and talked about some of the most noteworthy roles they’ve taken on in their careers our city has produced a lot of female talent as well so it’s time to recognize their achievements with a run-through of Mississauga’s top 5 actresses (based again on IMDb’s “STARmeter” popularity rating) How familiar are with you with these five ladies Most notable role: Young Lara Croft from Lara Croft: Tomb Raider  Mississauga pop singer and former member of the music group All Saints she attended The Royal School in Hamstead and later expressed an interest in going into show business She appeared in the hit 2001 film Lara Croft: Tomb Raider (based on the popular video game series Tomb Raider) where she portrayed a young version of the titular character Lara Croft.  another one of Rachel’s hobbies is playing guitar.  Most notable role: One of the Junior Plastics from Mean Girls  She attended Dublin Heights middle school in Toronto and later studied drama at Cawthra Park secondary school in Mississauga She makes a brief appearance in the 2004 classic comedy Mean Girls as a member of the “Junior Plastics,” a trio of snobby popular girls.  Shelley has also made appearances in Canadian sitcom Life with Derek and the Roxy Hunter film series Most notable role: Mary from Haunted Case Files  Julie Krol is both an actress and a writer She attended McMaster University where she studied Theatre & Film as well as English Some of her more noteworthy roles include the character Mary from the 2016 television series Haunted Case Files and minor character Elsa from the 2009 disaster film 2012.  Most notable role: Deedee Doodle from The Doodlebops  1981 and has been performing since the incredibly young age of three Her passion for song and dance led her to study at the Etobioke School of the Arts in lieu of a traditional high school Her most notable role is the character Deedee Doodle from the Canadian children’s show The Doodlebops She has also performed at the Gemini Awards an award show recognizing achievements in Canada’s television industry.  Some of Lennox’s other roles include Sharpay Evans in the stage musical version of High School Musical and the character of Veronica in the holiday TV movie Gotta Catch Santa Claus.  Most notable role: Alex Nuñez from Degrassi: The Next Generation  1986 and later completed her post-secondary education at the University of Guelph She has starred in quite a number of roles throughout her career including Alex Nuñez from Canadian TV series Degrassi: The Next Generation She also played Emily Ashby in the 2008 series Hooking Up and Georgia in the TV film Devil’s Diary.  Casaluce has compared herself to her Degrassi character Alex saying that they are both very strong and independent people.  Do you know of any other Mississauga actresses that you think are worth mentioning Subscribe to INsauga – Ontario Headline News’ daily email newsletter for a chance to win a $100 gift card to Toronto Eaton Centre OR Sherway Gardens Standard-tires focus and low plant utilisation rates in country now accounting for less than 3% of group sales Italy – Pirelli’s tire plants in Russia are running at a capacity-utilisation rate of around 65% with output fully dedicated to the local market the Russian operations are focused on the production of standard tires explained on a recent first quarter results call Pirelli’s performance in the standard tires segment “reflects greater selectivity in this channel and the halting of car production [by major OEs] in Russia due to the Ukraine conflict.” the ‘saturation’ level of Pirelli plants was around 90% – over 95% in the high-value tire production – further underlining the lower utilisation rates in Russia While Russia still represents 8% of Pirelli’s production the country now “accounts for less than 3% of our total sales So it is [becoming] less & less meaningful,” said Casaluci Pirelli exported around 3.5 million tires from Russia adding: “Today the export is finished those exports are delivered from local production in Romania and partially from Turkey through an off-take agreement Pirelli’s first-quarter report also noted a ‘normalisation’ of energy and raw materials costs from the market disruptions that followed the onset of Russia’s war on Ukraine These adjustments included declines of 16% and 47% respectively for Brent crude and European natural gas prices compared to the first three months of last year natural rubber (TSR20) traded 23% lower year-on-year while butadiene at €970/tonne averaged 9% lower than in the first quarter of 2022 Pirelli’s plants at Kirov and Voronezh have annual capacities to produce 6 million units and 2.3 million units respectively of passenger car and light truck tires The Father John Redmond Catholic Secondary School Cheerleading team won its first cheer competition of the season on Dec Team members include captain Alex Marcinkowski Coaches are Christine Sinclair and Rita McParland and the information within may be out of date The Father John Redmond Catholic Secondary School cheerleading team started the season on a high note The team won their first cheer competition of the season at the Hershey Centre Sports Zone More than 35 school and club teams were competing at the fourth annual Breath of Life Cheer Competition “It was a very exciting day as many of the girls have never been to competition before and they did amazing,” said coach Christine Sinclair adding the team had to change their routine the morning of the competition since two girls were injured “The girls really pulled together as a team focused on what they needed to do and pulled out a first place win,” she said The Remond Redhawks will be attempting to defend their title when they compete at the Ontario Cheerleading Federation Central Regional Competition in February at the Hershey Centre They are also hosting the Redhawk Cheer-a-thon on Friday 19 to raise money for new cheer mats and registration fees to the Cheer Alliance National Competition in May 2009 at the Hershey Centre They have also invited the York University cheerleaders to work with them The girls will perform their routine for at the school’s Christmas assembly Your browser is out of date and potentially vulnerable to security risks.We recommend switching to one of the following browsers: Cawthra Park Secondary School has produced a long list of alumni who have gone on to careers in theatre Cawthra Park Secondary School, located in southeast Mississauga, is one of two schools to offer a Regional Arts Program in Peel region The program provides a comprehensive education in the arts while students complete the regular Ontario curriculum The school was built in 1972 and now has more than 1,000 students enrolled. the school puts on a fall musical and a spring play No doubt those productions inspired a few students to go on to careers in the arts Here are five notable alumni from Cawthra Park Secondary School: Wali Shah is a poet and public speaker who was Mississauga’s poet laureate from 2017 to 2019 Born in Pakistan, Shah’s family moved to Toronto when he was three years old and Mississauga when he was nine, according to U of T Mississauga. He face racism growing up after 9/11 and got into a bad crowd After being arrested for an assault as a teen loaned him a book of poetry by Tupac Shakur according to a profile in the Toronto Star Shah has delivered TED talks spoken at hundreds of schools and colleges across North America and closed out President Barack Obama’s 2020 visit to Toronto Daria Werbowy is a supermodel who has been featured in ads for many well-known brands such as Prada she has appeared on the cover of many magazines including Harper’s Bazaar Werbowy was born in Poland and holds dual Canadian and Ukrainian citizenship Her family moved to Mississauga when she was three years old Sofia Elementary and Cawthra Park Secondary schools Now retired from modelling, she is now reportedly living in Ireland Andre Dae Kim is one of several Cawthra Park alumni who appeared in the Canadian teen drama series Degrassi and Amanda Stepto are also Degrassi stars who reportedly went to Cawthra Park Born in Edmonton, Kim landed a role on  Degrassi: Next Generation while he was in Grade 11 at Cawthra Park, according to a University of Toronto Mississauga profile. Since then Kim has gone on to appear in many TV shows including Star Trek: Strange New Worlds and most recently Vampire Academy, according to IMDb. A post shared by Andre Dae Kim (@andredaekim) Boman Martinez-Reid (Bomanizer) rose to TikTok stardom during the height of the pandemic His videos parody reality television with overly dramatized fights featuring his family and friends He now has two million followers on TikTok and more opportunities on the horizon He was signed to the Creative Artists Agency based in Hollywood which also represents Tom Hanks He has also been invited to several red carpet events including the Oscars He told the Toronto Star that he felt fortunate to be a part of the theatre program at Cawthra Park So I’m being cancelled.. pic.twitter.com/QIPanKoqzk — Bo Crave (@Bomanizer) March 4, 2023 Isaiah Peck began dancing at the age of nine and in 2015 he booked his first lead role as Henry in the show The Next Step a Canadian teen drama series on the Family Channel.  He joined the cast on their international Wild Rhythm & Live On Stage tours across Canada CBC calls him a “vibrant entertainer” with a love for music He has had appearances in shows and movies such as American Girl – Isabelle Dances into the Spotlight and TVO Kids – The Power of Play and Backstage He has also starred in the drama short Transitions the Netflix series Ginny and Georgia A post shared by Zay (@isaiahpeck) Get news delivered straight to your inbox.