Search

Abstract Identifying master epigenetic factors controlling proliferation and survival of cancer cells allows to discover new molecular targets exploitable to overcome resistance to current pharmacological regimens. In breast cancer (BC), resistance to endocrine therapy (ET) arises from aberrant Estrogen Receptor alpha (ERα) signaling caused by genetic and epigenetic events still mainly unknown. Targeting key upstream components of the ERα pathway provides a way to interfere with estrogen signaling in cancer cells independently from any other downstream event. By combining computational analysis of genome-wide ‘drop-out’ screenings with siRNA-mediated gene knock-down (kd), we identified a set of essential genes in luminal-like, ERα + BC that includes BRPF1, encoding a bromodomain-containing protein belonging to a family of epigenetic readers that act as chromatin remodelers to control gene transcription. To gather mechanistic insights into the role of BRPF1 in BC and ERα signaling, we applied chromatin and transcriptome profiling, gene ablation and targeted pharmacological inhibition coupled to cellular and functional assays. Results indicate that BRPF1 associates with ERα onto BC cell chromatin and its blockade inhibits cell cycle progression, reduces cell proliferation and mediates transcriptome changes through the modulation of chromatin accessibility. This effect is elicited by a widespread inhibition of estrogen signaling, consequent to ERα gene silencing, in antiestrogen (AE) -sensitive and -resistant BC cells and pre-clinical patient-derived models (PDOs). Characterization of the functional interplay of BRPF1 with ERα reveals a new regulator of estrogen-responsive BC cell survival and suggests that this epigenetic factor is a potential new target for treatment of these tumors.

Purpose: The purpose of this research was to provide a model for dynamic knowledge management in Iranian government organizations.Method: This research is applied in terms of purpose, survey-exploratory in terms of approach, and qualitative in terms of type. The statistical population of this research was a group of experts, including university professors, and senior managers of the Zanjan Province Industry, Mining and Trade Organization, and based on theoretical sampling, 11 of them were selected as a statistical sample and were interviewed. The approach adopted in this research to analyze the interviews was theme analysis.Findings: The results of the research led to the presentation of a new model in the field of dynamic knowledge management in Iranian government organizations, including five main variables (including: promotional levers of dynamic knowledge management, intra-organizational factors of dynamic knowledge management, extra-organizational factors of dynamic knowledge management, executive levers of dynamic knowledge management, and expected consequences of dynamic knowledge management).Conclusion: The results of this research showed that if dynamic knowledge management is implemented well in Iran's government organizations, it can be expected that organizational productivity and agility and the satisfaction of stakeholders will improve.

Abstract We present unprecedented datasets of current and future projected weather files for building simulations in 15 major cities distributed across 10 climate zones worldwide. The datasets include ambient air temperature, relative humidity, atmospheric pressure, direct and diffuse solar irradiance, and wind speed at hourly resolution, which are essential climate elements needed to undertake building simulations. The datasets contain typical and extreme weather years in the EnergyPlus weather file (EPW) format and multiyear projections in comma-separated value (CSV) format for three periods: historical (2001–2020), future mid-term (2041–2060), and future long-term (2081–2100). The datasets were generated from projections of one regional climate model, which were bias-corrected using multiyear observational data for each city. The methodology used makes the datasets among the first to incorporate complex changes in the future climate for the frequency, duration, and magnitude of extreme temperatures. These datasets, created within the IEA EBC Annex 80 “Resilient Cooling for Buildings”, are ready to be used for different types of building adaptation and resilience studies to climate change and heatwaves.

Abstract Recruitment of fibroblasts to tumors and their activation into cancer-associated fibroblasts (CAFs) is a strategy used by tumor cells to direct extracellular matrix (ECM) remodeling, invasion, and metastasis, highlighting the need to investigate the molecular mechanisms driving CAF function. Endothelin-1 (ET-1) regulates the communication between cancer and stroma and facilitates the progression of serous ovarian cancer (SOC). By binding to Endothelin A (ETA) and B (ETB) receptors, ET-1 enables the recruitment of β-arrestin1 (β-arr1) and the formation of signaling complexes that coordinate tumor progression. However, how ET-1 receptors might “educate” human ovarian fibroblasts (HOFs) to produce altered ECM and promote metastasis remains to be elucidated. This study identifies ET-1 as a pivotal factor in the activation of CAFs capable of proteolytic ECM remodeling and the generation of heterotypic spheroids containing cancer cells with a propensity to metastasize. An autocrine/paracrine ET-1/ETA/BR/β-arr1 loop enhances HOF proliferation, upregulates CAF marker expression, secretes pro-inflammatory cytokines, and increases collagen contractility, and cell motility. Furthermore, ET-1 facilitates ECM remodeling by promoting the lytic activity of invadosome and activation of integrin β1. In addition, ET-1 signaling supports the formation of heterotypic HOF/SOC spheroids with enhanced ability to migrate through the mesothelial monolayer, and invade, representing metastatic units. The blockade of ETA/BR or β-arr1 silencing prevents CAF activation, invadosome function, mesothelial clearance, and the invasive ability of heterotypic spheroids. In vivo, therapeutic inhibition of ETA/BR using bosentan (BOS) significantly reduces the metastatic potential of combined HOFs/SOC cells, associated with enhanced apoptotic effects on tumor cells and stromal components. These findings support a model in which ET-1/β-arr1 reinforces tumor/stroma interaction through CAF activation and fosters the survival and metastatic properties of SOC cells, which could be counteracted by ETA/BR antagonists.

Abstract Background Metabolic dysfunction-associated Steatotic Liver Disease (MASLD) displays a worse prognosis in subjects with type 2 diabetes (T2D); effective treatments are, so far, scanty. Semaglutide showed efficacy in improving steatohepatitis. We longitudinally observed a MASLD cohort of T2D subjects starting semaglutide, to detect an improvement of non-invasive surrogates of steatosis and fibro-inflammatory liver involvement, evaluating the role of mild alcohol consumption. Patients and methods In 62 overweight/obese T2D subjects with MASLD (36 non-drinker and 26 mild alcohol consumers), anthropometric, bio-humoral and transient elastography (TE) data were collected before (T0) and after an average time of 6.4 month (T1) from injective semaglutide prescription. Circulating levels of hormones (GIP, GLP-1, glucagon, insulin) and inflammatory markers (TNFα, MCP-1, IL-18, IL-10) were measured. Steatotic and necro-inflammatory liver involvement was evaluated with FibroScan controlled attenuation parameter (CAP) and liver stiffness (LS), respectively. Results Significant (p

Abstract Scientific literature supports the evidence that cancer stem cells (CSCs) retain inside low reactive oxygen species (ROS) levels and are, therefore, less susceptible to cell death, including ferroptosis, a type of cell death dependent on iron-driven lipid peroxidation. A collection of lung adenocarcinoma (LUAD) primary cell lines derived from malignant pleural effusions (MPEs) of patients was used to obtain 3D spheroids enriched for stem‐like properties. We observed that the ferroptosis inducer RSL3 triggered lipid peroxidation and cell death in LUAD cells when grown in 2D conditions; however, when grown in 3D conditions, all cell lines underwent a phenotypic switch, exhibiting substantial resistance to RSL3 and, therefore, protection against ferroptotic cell death. Interestingly, this phenomenon was reversed by disrupting 3D cells and growing them back in adherence, supporting the idea of CSCs plasticity, which holds that cancer cells have the dynamic ability to transition between a CSC state and a non-CSC state. Molecular analyses showed that ferroptosis resistance in 3D spheroids correlated with an increased expression of antioxidant genes and high levels of proteins involved in iron storage and export, indicating protection against oxidative stress and low availability of iron for the initiation of ferroptosis. Moreover, transcriptomic analyses highlighted a novel subset of genes commonly modulated in 3D spheroids and potentially capable of driving ferroptosis protection in LUAD-CSCs, thus allowing to better understand the mechanisms of CSC-mediated drug resistance in tumors.

BackgroundIncreased global access to safe, effective and quality-assured medical products remains a primary goal for the full realization of the World Health Assembly Resolution WHA 67.20 on regulatory systems strengthening for medical products as well as target 3.8 of the Sustainable Development Goals (SDG). To promote the development of efficient regulatory systems, the WHO introduced the Global Benchmarking Tool (GBT) in 2016, upon which the WHO–Listed Authority (WLA) framework was later established. This study aimed to appraise the development of the WLA framework across various phases while highlighting its achievements, challenges, and areas for improvement.MethodsAn exploratory study design using a qualitative approach was used to gather information from relevant documents as well as views and experiences from purposefully selected participants from diverse backgrounds. Data was collected using a combination of desk reviews and In-depth one-to-one or small group interviews employing semi-structured interview guides with open-ended questions. Data was analysed using an inductive thematic analysis approach.ResultsThe leading role of the WHO was noted in developing and implementing essential documents and mediating consultative processes among stakeholders. The framework was revealed to bring an evidence-based, inclusive, and transparent approach to recognizing regulatory authorities (RAs) operating at the highest standards of performance. The framework was anticipated to promote regulatory reliance among all RAs, the WHO’s prequalification programme, and procurement agencies. Furthermore, remarkable progress towards WLA listing was noted among transitional WLAs including the Stringent Regulatory Authorities (SRAs). Challenges related to the availability of resources, resistance to change, and complexity were associated with the framework.ConclusionThe study provides a well-rounded view with regard to the roles of the WHO, Member States and other stakeholders in establishing and operationalizing the WLA framework. Furthermore, evaluating the performance and possible WLA designation of RAs operating at international regulatory standards underscores its high relevance in contributing to public health globally. Maintenance along with timely addressing of highlighted next steps to improve the framework particularly in creating better understanding, more communication, and coordination are highly encouraged.

A finite element (FE) modelling approach is developed to reproduce the cyclic elastoplastic response and to assess the low cycle fatigue (LCF) life of two cellular materials (strut-based, gyroid) investigated in a previous experimental campaign. The cyclic response of different FE models (unit cell, one layer structure) is compared in terms of computational cost and modelling accuracy. The most satisfactory model is further updated based on the actual relative density of fabricated cellular materials. The LCF assessment exploits a volume-based strain energy density (SED) criterion, calibrated after comparing static properties of strut-based and bulk materials. The cyclic elastoplastic response is well reproduced for both cellular materials, whereas the estimated fatigue lives are in closer agreement for the gyroid structure than the strut-based one.

IMPORTANCE:. The opioid crisis is impacting people across the country and deserves attention to be able to curb the rise in opioid-related deaths. OBJECTIVES:. To evaluate practice patterns in opioid infusion administration and dosing for patients with acute respiratory failure receiving invasive mechanical ventilation. DESIGN:. Retrospective cohort study. SETTING AND PARTICIPANTS:. Patients from 21 hospitals in Kaiser Permanente Northern California and 96 hospitals in Philips electronic ICU Research Institute. MAIN OUTCOMES AND MEASURES:. We assessed whether patients received opioid infusion and the dose of said opioid infusion. RESULTS:. We identified patients with a diagnosis of acute respiratory failure who were initiated on invasive mechanical ventilation. From each patient, we determined if opioid infusions were administered and, among those who received an opioid infusion, the median daily dose of fentanyl infusion. We used hierarchical regression models to quantify variation in opioid infusion use and the median daily dose of fentanyl equivalents across hospitals. We included 13,140 patients in the KPNC cohort and 52,033 patients in the eRI cohort. A total of 7,023 (53.4%) and 16,311 (31.1%) patients received an opioid infusion in the first 21 days of mechanical ventilation in the KPNC and eRI cohorts, respectively. After accounting for patient- and hospital-level fixed effects, the hospital that a patient was admitted to explained 7% (95% CI, 3–11%) and 39% (95% CI, 28–49%) of the variation in opioid infusion use in the KPNC and eRI cohorts, respectively. Among patients who received an opioid infusion, the median daily fentanyl equivalent dose was 692 µg (interquartile range [IQR], 129–1341 µg) in the KPNC cohort and 200 µg (IQR, 0–1050 µg) in the eRI cohort. Hospital explained 4% (95% CI, 1–7%) and 20% (95% CI, 15–26%) of the variation in median daily fentanyl equivalent dose in the KPNC and eRI cohorts, respectively. CONCLUSIONS AND RELEVANCE:. In the context of efforts to limit healthcare-associated opioid exposure, our findings highlight the considerable opioid exposure that accompanies mechanical ventilation and suggest potential under and over-treatment with analgesia. Our results facilitate benchmarking of hospitals’ analgesia practices against risk-adjusted averages and can be used to inform usual care control arms of analgesia and sedation clinical trials.

Background: High-Grade Gliomas are the most common primary brain malignancies and despite the multimodal treatment, and the increasing amount of adjuvant treatment options the overall prognosis remains dismal. The present investigation aims to analyze the safety profile of the use of intraoperative ultrasounds (Io-US) in a homogeneous and matched cohort of patients suffering from High-grade gliomas (HGG) operated on with or without the aid of Io-US and Fluorescein in specific relation to the incidence of neurological and functional status sequelae. Methods and materials: A retrospective analysis was performed on 74 patients affected by HGG. 22 patients were treated with Io-US matched with neuronavigational system (Group A); 15 patients were treated both with the use of Io-US and Fluorescein matched with neuronavigational system (Group B); 37 patients were treated with the use of the neuronavigational system only (Group C). Primary endpoints were the extent of resection and functional outcome (measured with Karnofski Performance Status) Results: Significative differences were observed in terms of a higher extent of resection in Group B. In a multivariate analysis, this data appears to be independent of the location (eloquent/non-eloquent) of the lesion and from its histology. Regarding functional outcomes, no differences were detected between the two groups. Conclusions: The present study is the first that analyzes the simultaneous use of Io-US and Fluorescein, and the results demonstrate that these two instruments together could improve the extent of resection in HGG while ensuring good outcomes in terms of functional status.

Abstract Tuberculosis (TB) is one of the deadliest infectious disorders in the world. To effectively TB manage, an essential step is to gain insight into the lineage of Mycobacterium tuberculosis (MTB) and the distribution of drug resistance. Although the Campania region is declared a cluster area for the infection, to contribute to the effort to understand TB evolution and transmission, still poorly known, we have generated a dataset of 159 genomes of MTB strains, from Campania region collected during 2018–2021, obtained from the analysis of whole genome sequence. The results show that the most frequent MTB lineage is the 4 according for 129 strains (81.11%). Regarding drug resistance, 139 strains (87.4%) were classified as multi susceptible, while the remaining 20 (12.58%) showed drug resistance. Among the drug-resistance strains, 8 were isoniazid-resistant MTB, 4 multidrug-resistant MTB, while only one was classified as pre-extensively drug-resistant MTB. This dataset expands the existing available knowledge on drug resistance and evolution of MTB, contributing to further TB-related genomics studies to improve the management of this disease.

Abstract Verifying the intrinsic stability of demographic processes over time and space is a pivotal task from both science and policy perspectives. Compared with other regions of the old continent, a latent peculiarity of demographic systems in Southern Europe is their persistent heterogeneity over space, especially observed across metropolitan regions. ‘Centers’ and ‘peripheries’ are thus becoming representative of, respectively, territories undergoing demographic growth and decline. The former corresponds to urban areas, being attractive for different population segments. The present study illustrates the results of a statistical analysis of total population data over time (2011–2020) and its decomposition in natural increase and net migration rates in 14 metropolitan cities of Italy. Assuming that central and peripheral (e.g., suburbs) locations show differential trends of natural increase and net migration, our analysis verifies whether (i) central locations behave homogeneously in terms of population dynamics, and whether (ii) a North–South gradient holds. Results indicate how (metropolitan) demographic patterns no longer reflect a traditional gap between Northern and Southern regions, while outlining a subtler divide in growing and declining contexts. The few still-growing metropolitan areas were all located in North-Central Italy, and reflect more polarized socioeconomic contexts than in the past. Internal migration was likely the most powerful factor that discriminates growing from declining cities. Such evidence indicates that strengthening the self-restraining capacity of Southern Italian territories contributes to increase their attractiveness of international migration flows, counteracting demographic shrinkage.

In this paper, we present a 6.78 MHz Pulsed Wireless Power Transfer (PWPT) system specifically designed for powering the electronics placed on a suction roll of a paper mill machinery, thus enabling rotating equipment monitoring. The system utilizes a pair of different resonant coils to maintain a stable coupling coefficient for a fraction of the roll rotation period while guaranteeing compactness and ease of installation. Designed using both Commercial-off-the-Shelf (COTS) and custom components, the developed WPT system achieves a DC-DC efficiency of 62% in the specific working conditions. The transferred power is used to supply an Internet-of-Things (IoT) node that continuously measures and transmits data about the operation status. A fully operational system for battery and angular position monitoring has been developed and tested in a laboratory environment. This research presents a comprehensive analysis of the system and explores the interaction of different coils to maintain a stable coupling coefficient in dynamic applications. The same approach can be employed for rotating machinery with similar geometrical constraints or more general dynamic applications characterized by periodic movements and limited space for the coupling system.

Metabolism regulates neuronal activity and modulates the occurrence of epileptic seizures. Here, using two rodent models of absence epilepsy, we show that hypoglycaemia increases the occurrence of spike-wave seizures. We then show that selectively disrupting glycolysis in the thalamus, a structure implicated in absence epilepsy, is sufficient to increase spike-wave seizures. We propose that activation of thalamic AMP-activated protein kinase, a sensor of cellular energetic stress and potentiator of metabotropic GABAB-receptor function, is a significant driver of hypoglycaemia-induced spike-wave seizures. We show that AMP-activated protein kinase augments postsynaptic GABAB-receptor-mediated currents in thalamocortical neurons and strengthens epileptiform network activity evoked in thalamic brain slices. Selective thalamic AMP-activated protein kinase activation also increases spike-wave seizures. Finally, systemic administration of metformin, an AMP-activated protein kinase agonist and common diabetes treatment, profoundly increased spike-wave seizures. These results advance the decades-old observation that glucose metabolism regulates thalamocortical circuit excitability by demonstrating that AMP-activated protein kinase and GABAB-receptor cooperativity is sufficient to provoke spike-wave seizures.

The association between MPO-ANCA-associated vasculitis (AAV) and interstitial lung disease (ILD) has been well established. Pulmonary fibrosis may coexist with, follow, or even precede the diagnosis of AAV, and its presence adversely affects the prognosis. The optimal approach to investigating ANCA in patients with ILD remains a subject of ongoing debate. Here we aim to describe presentation and progression of MPO-ANCA ILD. We conducted a retrospective evaluation of a cohort of individuals diagnosed with MPO-ANCA ILD, with or without accompanying renal impairment, at the Immunology and Cell Therapy Unit, Careggi University Hospital, Florence, Italy, between June 2016 and June 2022. Clinical records, imaging studies, pathologic examinations, and laboratory test results were collected. Among the 14 patients identified with MPO-ANCA ILD, we observed a significant association between MPO-ANCA titers assessed at the time of ILD diagnosis and renal involvement. Renal impairment in these cases often manifested as subclinical or slowly progressive kidney damage. Interestingly, complement C3 deposits were consistently found in all renal biopsy specimens, thereby suggesting the potential for novel therapeutic targets in managing renal complications associated with MPO-ANCA ILD. The presentation of MPO-ANCA vasculitis as ILD can be the first and only clinical manifestation. MPO-ANCA levels at ILD diagnosis could warn on the progression to renal involvement in patients with MPO-ANCA ILD, hence caution is needed because renal disease can be subclinical or smoldering.

We show the improvement to cosmological constraints from galaxy cluster surveys with the addition of cosmic microwave background (CMB)-cluster lensing data. We explore the cosmological implications of adding mass information from the 3.1σ detection of gravitational lensing of the CMB by galaxy clusters to the Sunyaev-Zel'dovich (SZ) selected galaxy cluster sample from the 2500 deg2 SPT-SZ survey and targeted optical and X-ray follow-up data. In the ΛCDM model, the combination of the cluster sample with the Planck power spectrum measurements prefers σ8ωm/0.30.5=0.831±0.020 . Adding the cluster data reduces the uncertainty on this quantity by a factor of 1.4, which is unchanged whether the 3.1σ CMB-cluster lensing measurement is included or not. We then forecast the impact of CMB-cluster lensing measurements with future cluster catalogs. Adding CMB-cluster lensing measurements to the SZ cluster catalog of the ongoing SPT-3G survey is expected to improve the expected constraint on the dark energy equation of state w by a factor of 1.3 to σ(w) = 0.19. We find the largest improvements from CMB-cluster lensing measurements to be for σ 8, where adding CMB-cluster lensing data to the cluster number counts reduces the expected uncertainty on σ 8 by respective factors of 2.4 and 3.6 for SPT-3G and CMB-S4.