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Background and objective: Hypertension (HTN) has been linked to an elevated risk of prostate cancer (PC) development and poorer prognosis in localized cases, and is a common side effect of hormonal PC treatments. However, its relationship with the prognosis of metastatic PC is still unclear. We assessed the prognostic role of treatment-related HTN in patients with de novo metastatic hormone-sensitive PC (mHSPC) undergoing androgen deprivation therapy (ADT) alone or in combination with docetaxel or androgen receptor pathway inhibitors (ARPIs). Methods: Our retrospective analysis included 100 patients with de novo mHSPC treated with ADT, ADT + docetaxel, or ADT + ARPI between 2014 and 2021. Data on clinical variables, antihypertensive drugs, and blood pressure were collected from treatment initiation to 7 mo from ADT start. HTN development within 7 mo from hormonal treatment initiation was graded according to the Common Toxicity Criteria for Adverse Events version 5.0, and Cox analyses were performed for time to castration resistance (TTCR) and overall survival (OS). Key findings and limitations: In the overall population, grade (G) 2–3 HTN development within 7 mo from hormonal treatment initiation was associated with improved TTCR and OS at both univariate (TTCR: 19.8 vs 7.9 mo, hazard ratio [HR]: 0.35, 95% confidence interval [CI]: 0.20–0.63, p

Abstract The EU project PROMETEO has the scope of testing a 25 kW solid oxide electrolysis system integrated with a concentrated solar power plant via thermal energy storage in a relevant environment. Given the plant layout and the hydrogen demand characteristics, this work aims to identify how to operate the system effectively when renewable electricity is unavailable and how to modulate the load during hydrogen generation, thus defining the system's operation modes and control strategy. A 5 kWe stack has been tested at the FBK facility. The hot standby tests show that feeding a reducing gas at the negative electrode and air at the positive electrode, without polarizing the stack, effectively keeps the stack hot at 750°C and prevents degradation. Conversely, the electric protection approach leads to significant stack degradation (15% voltage drop in 200 h for one cluster). Regarding modulation of hydrogen generation, with low steam flowrates, the stack current and the flow rate of produced hydrogen mainly depend on the steam flow rate, while it is not affected by the stack temperature; conversely, with high steam flowrates, the current depends only on the stack temperature (from 25 A at 670°C to 65 A at 760°C). Based on the results, two hot standby modes and two load control strategies to be implemented and tested in the PROMETEO prototype are proposed.

Advanced urothelial carcinoma (aUC) has a dismal prognosis, with a 5-year survival rate of approximately 10%. Platinum-based chemotherapy has been the backbone of the first-line treatment of aUC for over 40 years. Only in the last decade, the treatment of aUC has evolved and been enriched with new classes of drugs that demonstrated pivotal improvements in terms of oncological responses and, ultimately, survival. Thus, the approach to aUC is becoming more and more tailored to the single patient, particularly owing to targeted therapies, such as fibroblast growth factor receptor (FGFR) inhibitors, antibody-drug conjugates (ADCs) targeting TROP2 and Nectin-4, anti-Her-2 therapies and others. However, due to the rapidly evolving scenario, the optimal sequence of systemic treatment is unknown and several important research questions remain unanswered, including the identification of reliable biomarkers to guide treatment decisions. Through ongoing research and clinical trials, we can continue to refine personalized treatment strategies and ultimately enhance patient care in this challenging disease setting. In this review, we provide a comprehensive overview of the current and emerging landscape of targeted therapies for aUC. We delved into the opportunities and challenges presented by personalized treatment approaches and explored potential future directions in this rapidly evolving field.

Anthropogenic threats impacting ecological targets should be mitigated and solved using fast and schematic tools useful in conservation strategies. Herein, we suggest a mixed and quick approach implementing coarse-grained (and expert-based) threat analysis with the fine-grained (and analytical) DPSIR (driving forces, pressure, status, impact, and response) framework of indicators, all included in a single causal chain. Both approaches are largely used in conservation but never combined. A simulated example of the application of the set of indicators (status, pressure, impact, and response) on dune ecosystems (and nested targets represented by halo-psammophilous plants) has been included. Due to its schematic format, values as targets, pressures as threats, and responses as conservation strategies have been unified in a single conceptual framework. This synthetic framework can also be used to communicate to academic students the complexities of socio-ecological systems on the conservation front lines using a simplified cause–effect chain.

This review article explores the potential of blockchain technology (BCT) as a key enabler for fostering transparency, trust, and citizen engagement in smart governance within smart cities. By examining the benefits of BCT in various aspects of smart city systems, such as data security and privacy, the paper highlights the advantages of implementing consortium blockchain architecture and the Proof of Authority (PoA) consensus algorithm and discusses the challenges of scalability and security concerns. Based on the literature showed in this article, we believe that the use of BCT in smart governance could significantly enhance citizen participation and help manage and deliver public services, paving the way for more effective decision-making processes and improved quality of life for citizens.

In this study, we focused on the computational analysis of a selected single-point mutation identified by a NGS screening panel in the TET2 enzyme classified as “variant of uncertain clinical significance.” The mutation, namely Q1084P, occurs at the interface between TET2, an important epigenetic regulator, and NANOG, a transcription factor fundamental for hematopoietic cells differentiation. Notably, the mutation occurs in a protein region distant from the active site; moreover, the experimental structures of the interacting region of both proteins are unknown, making it difficult to validate the impact of TET2 mutation on its binding with NANOG. To address these challenges, we employed an integrated computational approach combining molecular docking, molecular dynamics simulations and protein-protein interaction prediction. Our findings indicate that the single-point mutation might effectively reduce the TET2-NANOG interaction, which would consequently impair cells differentiation and hematopoiesis process, consistent with the clinical presentation of pure red cell aplastic anemia. These results, along with the proposed computational method, provide insights for establishing clinical correlations between variants of uncertain significance and anemias in general, comprising common hematological problems widespread in the world population and for which dedicated NGS panels are still not available.

Abstract Friedreich ataxia (FRDA) is a life-threatening hereditary ataxia; its incidence is 1:50,000 individuals in the Caucasian population. A unique therapeutic drug for FRDA, the antioxidant Omaveloxolone, has been recently approved by the US Food and Drug Administration (FDA). FRDA is a multi-systemic neurodegenerative disease; in addition to a progressive neurodegeneration, FRDA is characterized by hypertrophic cardiomyopathy, diabetes mellitus and musculoskeletal deformities. Cardiomyopathy is the predominant cause of premature death. The onset of FRDA typically occurs between the ages of 5 and 15. Given the complexity and heterogeneity of clinical features and the variability of their onset, the identification of biomarkers capable of assessing disease progression and monitoring the efficacy of treatments is essential to facilitate decision making in clinical practice. We conducted an RNA-seq analysis in peripheral blood mononuclear cells from FRDA patients and healthy donors, identifying a signature of small non-coding RNAs (sncRNAs) capable of distinguishing healthy individuals from the majority of FRDA patients. Among the differentially expressed sncRNAs, microRNAs are a class of small non-coding endogenous RNAs that regulate posttranscriptional silencing of target genes. In FRDA plasma samples, hsa-miR-148a-3p resulted significantly upregulated. The analysis of the Receiver Operating Characteristic (ROC) curve, combining the circulating expression levels of hsa-miR-148a-3p and hsa-miR-223-3p (previously identified by our group), revealed an Area Under the Curve (AUC) of 0.86 (95%, Confidence Interval 0.77–0.95; p-value

The significant share of energy-related emissions in the glass industry necessitates robust energy efficiency strategies. This paper evaluates the status and prospects of energy efficiency by integrating the measurement, assessment, and improvement of energy performance through energy data and modelling. Measurement and assessment are crucial for effective energy management in hard-to-abate industrial sectors, providing insight into the existence and extent of potential energy efficiency gains. The use of appropriate performance indicators allows for comparison across production contexts and the monitoring of improvements achieved through interventions. The benchmarking of a representative sample of container glass furnaces reveals a current potential for improvement of around 10% based on alignment with best practices. Energy modelling is used to map energy flows along the various systems involved in production, thereby identifying major energy losses. Energy efficiency options can then be categorised based on their contribution to improving energy performance, facilitating the identification of solutions that address current bottlenecks. The study discusses promising opportunities arising from improved batch compositions and outlines the role of renewable penetration on the viability of hydrogen use and furnace electrification. The proposed approach can be transferred to other hard-to-abate industrial sectors to drive progress in decarbonisation.

Pediatric Hodgkin lymphoma (HL) is a curable disease for more than 90% of children and adolescents in high income countries. However, similar results cannot be achieved, particularly for advanced disease, in low- and middle-income countries (LMICs), where challenging socioeconomic realities and the consequent scarcity of local resources heavily impact on the treatment and patients’ outcome. Information regarding the management and outcome of pediatric HL in LMICs is still limited. In this narrative review, we summarize the results reported in the literature so far and discuss the critical key points that have emerged from this overview.

Abstract Background Plant pathogens secrete effector proteins into host cells to suppress immune responses and manipulate fundamental cellular processes. One of these processes is autophagy, an essential recycling mechanism in eukaryotic cells that coordinates the turnover of cellular components and contributes to the decision on cell death or survival. Results We report the characterization of AVH195, an effector from the broad-spectrum oomycete plant pathogen, Phytophthora parasitica. We show that P. parasitica expresses AVH195 during the biotrophic phase of plant infection, i.e., the initial phase in which host cells are maintained alive. In tobacco, the effector prevents the initiation of cell death, which is caused by two pathogen-derived effectors and the proapoptotic BAX protein. AVH195 associates with the plant vacuolar membrane system and interacts with Autophagy-related protein 8 (ATG8) isoforms/paralogs. When expressed in cells from the green alga, Chlamydomonas reinhardtii, the effector delays vacuolar fusion and cargo turnover upon stimulation of autophagy, but does not affect algal viability. In Arabidopsis thaliana, AVH195 delays the turnover of ATG8 from endomembranes and promotes plant susceptibility to P. parasitica and the obligate biotrophic oomycete pathogen Hyaloperonospora arabidopsidis. Conclusions Taken together, our observations suggest that AVH195 targets ATG8 to attenuate autophagy and prevent associated host cell death, thereby favoring biotrophy during the early stages of the infection process.

Francesco Malfona, Anna Maria Testi, Sabina Chiaretti, Maria Luisa Moleti Department of Translational and Precision Medicine, ‘Sapienza’ University, Rome, ItalyCorrespondence: Maria Luisa Moleti, Hematology Institute, Via Benevento 6, Rome, 00161, Italy, Tel +39 3384714201, Fax +39 0644641984, Email moleti@bce.uniroma1.itAbstract: Despite excellent results in frontline therapy, particularly in pediatric age, refractory Burkitt lymphoma still remains a therapeutic challenge, with dismal outcome. The prognosis is very poor, ranging from less than 10% to 30– 40%, with longer survival only in transplanted patients. On account of the paucity of data, mostly reporting on small series of patients, with heterogeneous characteristics and salvage treatments, at present it is impossible to draw definitive conclusions on the treatment of choice for this difficult to treat subset of patients. New insights into Burkitt lymphoma/leukemia cell biology have led to the development of new drugs, currently being tested, directed at different specific targets. Herein, we describe the results so far reported in refractory Burkitt lymphoma/leukemia, with standard treatments and hematopoietic stem cell transplant, and we review the new targeted drugs currently under evaluation.Keywords: Burkitt lymphoma, target therapy, relapse, refractory, outcome

The objective of this article is to analyze the Art of war of the native societies of the Canary archipelago, which were wiped out in the 15th century during the invasion called «Norman-Castillian». Despite the technological backwardness that distinguished them, their resistance lasted for almost a century, which was also due to the way in which they knew how to exploit their advantages and leverage on the opponent’s weaknesses. Aboriginal people left no written record of their cultures, and accounts of their characteristic features are therefore due to the victors who write history. The study of the salient war episodes of the conquest of the islands is therefore a tool to highlight the fighting techniques, the geopolitical organization and other aspects of great importance, such as the fragile demographic stability. The sources used are medieval and modern ones of European production, with the support of the current academic bibliography.

Background. Childhood Hodgkin lymphoma (HL) is an eminently curable disease. Good outcomes can be achieved even in resource-limited settings and increasingly, the focus is on limiting long-term toxicity. Contemporary treatment incorporates a risk-stratified, response-adapted approach using multiagent chemotherapy with/without low-dose radiotherapy. Many developing countries continue to use ABVD-based regimens due to limited acute toxicity, cost, and ease of delivery. Objective. We herein report the outcomes of childhood HL diagnosed and treated in an Iraqi single-center over a 16 years period. Methods. Children ≤14 years with biopsy-proven HL were enrolled. Most patients received ABVD chemotherapy or COPP/ABV when Dacarbazine was unavailable. Radiotherapy was not available. Results. Three hundred-three children were consecutively newly diagnosed with HL; 284 were considered eligible for the retrospective analysis (treatment refusals 9; deaths before therapy 5; initially diagnosed of non-Hodgkin lymphoma 5). ABVD scheme was administered to 184 children (65%), COPP/ABV to 83 (29%), other schemes to the remaining 17 patients. Complete response (CR) was achieved in 277 (98%); 4 (1.4%) showed disease progression and 1 stable disease. Four patients in CR abandoned therapy and were in CR at the time of analysis, 2 died from infection. Relapse occurred in 42 patients (15%). The 15-year OS and EFS are 89.7% and 70.3%, respectively. Conclusion. In this single-center, over a 16-year period, almost 90% of children suffering from HL survive, despite the numerous limitations in diagnostic procedures, shortage of chemotherapy, no radiotherapy facilities, absence of effective second-line treatments and finally therapy abandonment for social and financial reasons.

This review article explores the potential of blockchain technology (BCT) as a key enabler for fostering transparency, trust, and citizen engagement in smart governance within smart cities. By examining the benefits of BCT in various aspects of smart city systems, such as data security and privacy, the paper highlights the advantages of implementing consortium blockchain architecture and the Proof of Authority (PoA) consensus algorithm and discusses the challenges of scalability and security concerns. Based on the literature showed in this article, we believe that the use of BCT in smart governance could significantly enhance citizen participation and help manage and deliver public services, paving the way for more effective decision-making processes and improved quality of life for citizens.

Abstract Bladder mechanical properties are critical for organ function and tissue homeostasis. Therefore, alterations of tissue mechanics are linked to disease onset and progression. This study aims to characterize the tissue elasticity of the murine bladder wall considering its different anatomical components, both in healthy conditions and in actinic cystitis, a state characterized by tissue fibrosis. Here, we exploit Brillouin microscopy, an emerging technique in the mechanobiology field that allows mapping tissue mechanics at the microscale, in non-contact mode and free of labeling. We show that Brillouin imaging of bladder tissues is able to recognize the different anatomical components of the bladder wall, confirmed by histopathological analysis, showing different tissue mechanical properties of the physiological bladder, as well as a significant alteration in the presence of tissue fibrosis. Our results point out the potential use of Brillouin imaging on clinically relevant samples as a complementary technique to histopathological analysis, deciphering complex mechanical alteration of each tissue layer of an organ that strongly relies on mechanical properties to perform its function.

Cell-free massive MIMO (CF-mMIMO) networks leverage seamless cooperation among numerous access points to serve a large number of users over the same time/frequency resources. This paper addresses the challenges of pilot and data power control, as well as pilot assignment, in the uplink of a cell-free massive MIMO (CF-mMIMO) network, where the number of users significantly exceeds that of the available orthogonal pilots. We first derive the closed-form expression of the achievable uplink rate of a user. Subsequently, harnessing the universal function approximation capability of artificial neural networks, we introduce a novel multi-task deep learning-based approach for joint power control and pilot assignment, aiming to maximize the minimum user rate. Our proposed method entails the design and unsupervised training of a deep neural network (DNN), employing a custom loss function specifically tailored to perform joint power control and pilot assignment, while simultaneously limiting the total network power usage. Extensive simulations demonstrate that our method outperforms the existing power control and pilot assignment strategies in terms of achievable network throughput, minimum user rate, and per-user energy consumption. The model versatility and adaptability are assessed by simulating two different scenarios, namely a urban macro (UMa) and an industrial one.

The field of non-residential buildings is very heterogeneous. This results in a compartmentalized approach that prevents desired energy efficiency improvements from being achieved at a large scale. This paper proposes a transversal approach to energy efficiency based on the aggregation of building typologies and the integration of the scales of analysis.Upon energy and occupancy analogies we define shared buildings as buildings characterized by a low energy intensity, the predominance of HVAC systems on energy uses, and a large and variable occupancy. This concept gathers in itself a considerable energy efficiency potential, as shared buildings are found to account for 35% of non-residential energy consumption. We overview energy efficiency hotspots and operational criticalities in shared buildings and outline the development of a framework that is fit-for-purpose for the quantification of the energy efficiency potential at multiple scales.Improvement in ventilation energy management in a university stock is used to exemplify the approach: first, we apply dynamic simulation to a single building obtaining 65% HVAC energy savings; then, we generalize the results to the property stock obtaining reductions from 190 to 130 kWh/(m2y) in energy intensity, simultaneously fulfilling the desired energetic and economic targets.

Background: A drug repositioning effort supported the possible use of the anti-HIV drug etravirine as a disease-modifying drug for Friedreich ataxia (FRDA). Etravirine increases frataxin protein and corrects the biochemical defects in cells derived from FRDA patients. Because of these findings, and since etravirine displays a favorable safety profile, we conducted a pilot open-label phase 2 clinical trial assessing the safety and potential efficacy of etravirine in FRDA patients. Methods: Thirty-five patients were stratified into three severity groups and randomized to etravirine 200 mg/day or 400 mg/day. They were treated for 4 months. Safety endpoints were the number and type of adverse events and number of dropouts. Efficacy endpoints were represented by changes in peak oxygen uptake and workload as measured by incremental exercise test, SARA score, cardiac measures, measures of QoL and disability. Data were collected 4 months before the start of the treatment (T − 4), at the start (T0), at the end (T4) and 4 months after the termination of the treatment (T + 4). Results: Etravirine was reasonably tolerated, and adverse events were generally mild. Four months of etravirine treatment did not significantly increase the peak oxygen uptake but was associated with a change in the progression of the SARA score (p value < 0.001), compared to the 4 months pre- and post-treatment. It also significantly increased peak workload (p value = 0.021). No changes in the cardiac measures were observed. Health and QoL measures showed a worsening at the suspension of the drug. Conclusions: In this open trial etravirine treatment was safe, reasonably well tolerated and appreciably improved neurological function and exercise performance. Even though a placebo effect cannot be ruled out, these results suggest that etravirine may represent a potential therapeutic agent in FRDA deserving testing in a randomized placebo-controlled clinical trial.

Abstract Prion disease is a fatal neurodegenerative disorder characterized by accumulation of an abnormal prion protein (PrPSc) in the central nervous system. To identify PrPSc aggregates for diagnostic purposes, pathologists use immunohistochemical staining of prion protein antibodies on tissue samples. With digital pathology, artificial intelligence can now analyze stained slides. In this study, we developed an automated pipeline for the identification of PrPSc aggregates in tissue samples from the cerebellar and occipital cortex. To the best of our knowledge, this is the first framework to evaluate PrPSc deposition in digital images. We used two strategies: a deep learning segmentation approach using a vision transformer, and a machine learning classification approach with traditional classifiers. Our method was developed and tested on 64 whole slide images from 41 patients definitively diagnosed with prion disease. The results of our study demonstrated that our proposed framework can accurately classify WSIs from a blind test set. Moreover, it can quantify PrPSc distribution and localization throughout the brain. This could potentially be extended to evaluate protein expression in other neurodegenerative diseases like Alzheimer's and Parkinson's. Overall, our pipeline highlights the potential of AI-assisted pathology to provide valuable insights, leading to improved diagnostic accuracy and efficiency.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of Non-Hodgkin Lymphoma (NHL). It often involves the gastrointestinal tract, head and neck, and skin, but virtually any tissue or organ can be affected. The primary NHL of the nasal cavity and paranasal sinuses are extremely rare, causing diagnostic and therapeutic difficulties. We present the case of a 49-year-old woman with a 4-week history of diplopia and right superior eyelid swelling. Clinical, radiological, and histological examination led to the diagnosis of DLBCL of the right frontal sinus with anterior invasion of subcutaneous soft tissues and posterior intracranial involvement of the frontal region. She underwent three cycles of MATRIX chemotherapy, three cycles of R-DA-EPOCH, and CAR-T therapy. Unfortunately, treatments were unsuccessful and the patient died 11 months after diagnosis. In conclusion, an early diagnosis of DLBCL of the frontal sinus is difficult as it is often confused with other nasal pathologies. This causes a delay in treatment.

Abstract Purpose To describe unusual clinical features and therapeutic management of a case of cytomegalovirus (CMV) ocular disease in a patient on immunomodulatory therapy. Setting/venue Moorfields Eye Hospital NHS Foundation Trust, London, UK. Methods Medical history, clinical findings, investigation results, and multimodal imaging were retrospectively collected. Results A 61-year-old, South-East Asian man, developed CMV-related endotheliitis and occlusive retinal vasculitis, diagnosed by wide-angle fluorescein angiography. No retinitis was present on the fundus examination. Suspicion of CMV etiology was based on anterior segment findings, especially the presence of coin-shaped endothelial lesions. The diagnosis was confirmed by aqueous polymerase chain reaction (PCR) analysis which was positive for CMV DNA. The combined use of topical and systemic valganciclovir resulted in significant improvement of the picture. Conclusions CMV can manifest in the eye as occlusive retinal vasculitis without the presence of typical retinitis.