Search

The Protein Ensemble Database (PED) (URL: https://proteinensemble.org) is the primary resource for depositing structural ensembles of intrinsically disordered proteins. This updated version of PED reflects advancements in the field, denoting a continual expansion with a total of 461 entries and 538 ensembles, including those generated without explicit experimental data through novel machine learning (ML) techniques. With this significant increment in the number of ensembles, a few yet-unprecedented new entries entered the database, including those also determined or refined by electron paramagnetic resonance or circular dichroism data. In addition, PED was enriched with several new features, including a novel deposition service, improved user interface, new database cross-referencing options and integration with the 3D-Beacons network-all representing efforts to improve the FAIRness of the database. Foreseeably, PED will keep growing in size and expanding with new types of ensembles generated by accurate and fast ML-based generative models and coarse-grained simulations. Therefore, among future efforts, priority will be given to further develop the database to be compatible with ensembles modeled at a coarse-grained level.

One of the challenges that Europe has undertaken is the transition from a linear economic system to a circular economy, where waste and resources are recovered and regenerated. The practice of upcycling in the agri-food sector represents one of the most promising solutions to the enormous problem of food waste. However, the information available to consumers about foods made with upcycled ingredients is still scarce, limiting their acceptance and creating a critical barrier to their success in the market. The objective of this study is to determine the factors that affect Italian consumers’ intention to purchase and willingness to pay for a specific upcycled food enriched with a high-value vegetable by-product by applying a logit model, an interval regression, and a contingent valuation. Results show that knowledge about upcycling and the circular economy is still limited. Innovative consumers who are already aware of upcycling, who are not food neophobic, and who have a positive opinion of recycling are more willing to purchase upcycled products. At the same time, women who are already aware that the food industry produces considerable quantities of waste and who have a positive image of recycling are more willing to pay for a specific upcycled food. Finally, our sample proved to be willing to pay a premium price for an upcycled frozen margherita pizza. An informed consumer, aware of the environmental and health benefits of upcycled products, may become more willing to purchase them and to pay more compared to the same conventional products.

Summary: Background: Mucositis is a common and highly impactful side effect of conventional and emerging cancer therapy and thus the subject of intense investigation. Although common practice, mucositis assessment is heterogeneously adopted and poorly guided, impacting evidence synthesis and translation. The Multinational Association of Supportive Care in Cancer (MASCC) Mucositis Study Group (MSG) therefore aimed to establish expert recommendations for how existing mucositis assessment tools should be used, in clinical care and trials contexts, to improve the consistency of mucositis assessment. Methods: This study was conducted over two stages (January 2022–July 2023). The first phase involved a survey to MASCC-MSG members (January 2022–May 2022), capturing current practices, challenges and preferences. These then informed the second phase, in which a set of initial recommendations were prepared and refined using the Delphi method (February 2023–May 2023). Consensus was defined as agreement on a parameter by >80% of respondents. Findings: Seventy-two MASCC-MSG members completed the first phase of the study (37 females, 34 males, mainly oral care specialists). High variability was noted in the use of mucositis assessment tools, with a high reliance on clinician assessment compared to patient reported outcome measures (PROMs, 47% vs 3%, 37% used a combination). The World Health Organization (WHO) and Common Terminology Criteria for Adverse Events (CTCAE) scales were most commonly used to assess mucositis across multiple settings. Initial recommendations were reviewed by experienced MSG members and following two rounds of Delphi survey consensus was achieved in 91 of 100 recommendations. For example, in patients receiving chemotherapy, the recommended tool for clinician assessment in clinical practice is WHO for oral mucositis (89.5% consensus), and WHO or CTCAE for gastrointestinal mucositis (85.7% consensus). The recommended PROM in clinical trials is OMD/WQ for oral mucositis (93.3% consensus), and PRO-CTCAE for gastrointestinal mucositis (83.3% consensus). Interpretation: These new recommendations provide much needed guidance on mucositis assessment and may be applied in both clinical practice and research to streamline comparison and synthesis of global data sets, thus accelerating translation of new knowledge into clinical practice. Funding: No funding was received.

Background & aims: This phase Ib/II trial evaluated the safety and efficacy of capmatinib in combination with spartalizumab or spartalizumab alone in patients with advanced hepatocellular carcinoma (HCC). Methods: Eligible patients who had progressed or were intolerant to sorafenib received escalating doses of capmatinib 200 mg, 300 mg, and 400 mg twice a day (bid) plus spartalizumab 300 mg every 3 weeks (q3w) in the phase Ib study. Once the recommended phase II dose (RP2D) was determined, the phase II study commenced with randomised 1:1 treatment with either capmatinib + spartalizumab (n = 32) or spartalizumab alone (n = 30). Primary endpoints were safety and tolerability (phase Ib) and investigator-assessed overall response rate per RECIST v1.1 for combination vs. single-agent arms using a Bayesian logistic regression model (phase II). Results: In phase Ib, the RP2D for capmatinib in combination with spartalizumab was determined to be 400 mg bid. Dose-limiting toxicity consisting of grade 3 diarrhoea was reported in one patient at the capmatinib 400 mg bid + spartalizumab 300 mg q3w dose level. The primary endpoint in the phase II study was not met. The observed overall response rate in the capmatinib + spartalizumab arm was 9.4% vs. 10% in the spartalizumab arm. The most common any-grade treatment-related adverse events (TRAEs, ≥20%) were nausea (37.5%), asthenia and vomiting (28.1% each), diarrhoea, pyrexia, and decreased appetite (25.0% each) in the combination arm; TRAEs ≥10% were pruritus (23.3%), and rash (10.0%) in the spartalizumab-alone arm. Conclusion: Capmatinib at 400 mg bid plus spartalizumab 300 mg q3w was established as the RP2D, with manageable toxicities and no significant safety signals, but the combination did not show superior clinical activity compared with spartalizumab single-agent treatment in patients with advanced HCC who had previously been treated with sorafenib. Impact and implications: Simultaneous targeting of MET and programmed cell death protein 1 may provide synergistic clinical benefit in patients with advanced HCC. This is the first trial to report a combination of capmatinib (MET inhibitor) and spartalizumab (programmed cell death protein 1 inhibitor) as second-line treatment after sorafenib for advanced HCC. The combination did not show superior clinical activity compared with spartalizumab single-agent treatment in patients with advanced HCC who had previously been treated with sorafenib. The results indicate that there is a clear need to identify a reliable predictive marker of response for HCC and to identify patients with HCC that would benefit from the combination of checkpoint inhibitor +/- targeted therapy. Clinical trial number: NCT02795429.

Over the past decade, molecular characterization has led to change the management of advanced non-small cell lung cancer (NSCLC) harboring driver mutations. Rearranged during transfection (RET) gene fusions, occurring in 1% to 2% of NSCLC, have emerged as an oncogenic druggable target. Systemic targeted therapies with highly selective RET inhibitors (RETi), selpercatinib and pralsetinib, represent a recent clinical breakthrough. While the development of RETi has improved survival, with their increasing use, it is crucial to be aware of the risks of rare but serious adverse events (AEs). A particular challenge for clinicians in applying targeted therapies is not only diagnosing but also interpreting rare mutations. Herein, we report a case of a 43-year-old Caucasian advanced NSCLC patient diagnosed with a rare RET gene fusion, ANK3::RET, identified with Next Generation Sequencing (NGS). Selpercatinib has been initiated at the recommended initial dose after one incomplete chemotherapy cycle due to a severe infusion reaction, but it subsequently required a dose adjustment following grade 3 (G3) AEs. During treatment, we used a particular selpercatinib dosage (160 mg in the morning and 80 mg in the evening) with good tolerance and without compromising effectiveness. Our finding broadens the range of RET fusion types in not-Asian NSCLC. To the best of our knowledge, our case demonstrates, for the first time, a clinical and radiological response to frontline highly selective RETi selpercatinib, expanding the spectrum of potential oncogenic RET fusion partners in newly diagnosed NSCLC patients. Furthermore, to our knowledge, this is the first case describing a RET fusion-positive (RET+) NSCLC patient treated with a modified selpercatinib dosage outside the drug data sheet and demonstrating a safe and effective use.

Mesothelioma (MM) is an aggressive and lethal disease with few therapeutic opportunities. Platinum-pemetrexed chemotherapy is the backbone of first-line treatment for MM. The introduction of immunotherapy (IO) has been the only novelty of the last decades, allowing an increase in survival compared to standard chemotherapy (CT). However, IO is not approved for epithelioid histology in many countries. Therefore, therapy for relapsed MM remains an unmet clinical need, and the prognosis of MM remains poor, with an average survival of only 18 months. Increasing evidence reveals MM complexity and heterogeneity, of which histological classification fails to explain. Thus, scientific focus on possibly new molecular markers or cellular targets is increasing, together with the search for target therapies directed towards them. The molecular landscape of MM is characterized by inactivating tumor suppressor alterations, the most common of which is found in CDKN2A, BAP1, MTAP, and NF2. In addition, cellular targets such as mesothelin or metabolic enzymes such as ASS1 could be potentially amenable to specific therapies. This review examines the major targets and relative attempts of therapeutic approaches to provide an overview of the potential prospects for treating this rare neoplasm.

Este relato de experiência reporta as atividades de um projeto de extensão universitária realizadas online durante a pandemia de COVID-19. As atividades foram realizadas de forma lúdica com crianças e adolescentes de 9 a 13 anos em situação de vulnerabilidade econômica e social, e consistiram na elaboração e acompanhamento de atividades com temas de matemática, nutrição e linguagem de programação. Para isso foi elaborado um material didático original no formato de gibi, divididos em dois volumes e distribuídos de maneira impressa para as crianças. No volume 1, os assuntos foram: operações básicas de matemática, frações e gráficos enquadrados no contexto de informações nutricionais, precificação de produtos dos supermercados e receitas culinárias. No volume 2, foram abordados os conceitos de unidades de medidas, medidas de tendência centrais, cálculo de volumes e porcentagem, relacionados ao contexto de Índice de Massa Corporal (IMC), forma das embalagens de alimentos e reciclagem. O principal desafio encontrado foi manter o grupo coeso até o final do projeto, visto a dificuldade das crianças e dos pais na realização das atividades e no acesso à internet; de um total de 23 participantes, apenas 9 completaram todas as atividades propostas nos gibis. Por outro lado, os alunos e professores do Instituto de Biociências de Botucatu da Universidade Estadual Paulista (IBB-UNESP) envolvidos no projeto experimentaram a interdisciplinaridade e o eixo extensionista de forma ampla. Como resultado, um novo projeto foi elaborado com a comunidade do Instituto Semeando o Futuro com uma participação mais ampla da universidade, crianças e pais. Palavras-chave: Matemática; Nutrição; Crianças e Adolescentes; COVID-19 A playful approach to education: A report on activities during the pandemic Abstract: This experience report describes the activities of a university extension project carried out online during the COVID-19 pandemic. The activities were carried out playfully with children and adolescents aged 9 to 13 who are economically and socially vulnerable and consisted of preparing and monitoring activities on the themes of mathematics, nutrition, and programming language. To this end, original didactic material was produced in comic book format, divided into two volumes, and distributed in print to the children. In Volume 1, the subjects were basic mathematical operations, fractions, and graphs in the context of nutritional information, supermarket product pricing, and cooking recipes. Volume 2 covered the concepts of measurement units, measures of central tendency, calculating volumes and percentages related to the context of Body Mass Index (BMI), the shape of food packaging, and recycling. The main challenge encountered was keeping the group together until the end of the project, given the difficulty of the children and their parents in carrying out the activities and accessing the internet; out of a total of 23 participants, only 9 completed all the activities proposed in the comic books. On the other hand, the students and teachers from the Botucatu Biosciences Institute at São Paulo State University (IBB-UNESP) involved in the project experienced interdisciplinarity and the extensionist axis of the project extensively. As a result, a new project was drawn up with the community of the Instituto Semeando o Futuro, with broader participation from the university, children, and parents. Keywords: Mathematics; Nutrition; Child and Adolescents; COVID-19

BackgroundIndocyanine green fluorescence technology (ICG) in pediatric minimally invasive surgery has undergone an important improvement in the last 5 years. However, its use in open surgery is still limited. In this paper, we aim to report our preliminary experience with Rubina® lens ICG fluorescence technology in combination with the IMAGE1 S™ system from KARL STORZ in open excision of masses in children.MethodsThe records of 18 patients undergoing open surgery for head, neck and thorax masses between September and November 2022 were retrospectively reviewed. Rubina® lens ICG fluorescence technology system was used in all the cases. In 10 cases we adopted the holding arm system and in 8 cases the hand-held technique. Data about patients' demographics, surgery and outcomes were collected and analyzed through the following criteria: mass localization, intraoperative time (min), ICG administration (ml), intraoperative complications, postoperative complications.ResultsA total of 18 patients were operated: 4 thyroglossal duct cysts, 3 supraorbital cysts, 2 neck masses, 2 pre-auricular and 2 scalp cysts, 2 gynecomastias, 2 lymphangiomas, 1 nose mass. In all the cases, intralesional injection of 0.5–1 ml of ICG solution was performed peri-operatively. Mean operative time was 58.4 min (35–134 min). Postoperative complications included seroma formation in 2 cases. Surgical pathology reports confirmed complete mass excision in all the cases.ConclusionBased on our preliminary experience, ICG fluorescence guided surgery using Rubina® lens system was very helpful also in open surgery procedures. Rubina® lens system permits to have a very low complication rate, a time-saving surgery, a real time reliability of anatomic structures and an excellent clinical safety. In our experience, holding arm system seems more comfortable than hand-held system. However, further cases need to be performed to evaluate the exact role and to identify new indications of this technique in open pediatric surgical procedures.

Postoperative pain presents several challenges in pediatric Minimally Invasive Surgery. The Faces, Legs, Activity, Cry, and Consolability (FLACC) scale is a valid scale for pediatric postoperative pain. The aim of our study was to assess postoperative pain using FLACC scale and to analyze the correlation between FLACC scale score and analgesic requirement in children underwent Minimally Invasive Surgery. We retrospectively analyzed data of 153 children aged 2 months-3 years who underwent Minimally Invasive Surgery in our unit from January 2019 and December 2019. Postoperative pain assessment was established using FLACC scale. In each patient were analyzed the correlation between FLACC score and analgesic requirement. Pain evaluation was assigned immediately after surgery and at 15 and 60 minutes. 36.6% of patients (56 children) were asleep so considered pain free; 21.6% of patients (33 children) had a FLACC score more than 7 so they required analgesics and the pain assessment 15 and 60 minutes after was significantly lower. 41.8% of patients (64 children) had a postoperative FLACC score less than 3, so they didn’t require any analgesic treatment. On the basis of our results, we recommend FLACC scale for postoperative pain assessment in children underwent MIS aged 2 months-3 years. FLACC scale is an effective and precise scale in detection of postoperative analgesic requirement in children and it could be extended in different age groups with further research.

Introduction: There are scarce papers about the use of fluorescence-guided surgery (FGS) in the open surgical field. This study aimed to assess the usefulness of FGS in an open setting in the pediatric population and to report our preliminary experience using the Rubina® Lens system. Methods: All patients undergoing ICG fluorescence-assisted open surgery over the period September 2022–September 2023 were enrolled. Each surgical procedure was performed using the Rubina® Lens for ICG fluorescence visualization. Results: A total of 25 patients, 14 boys and 11 girls with a median age at surgery of 5.8 years-old (range 0–15), were enrolled. Surgical indications were dermoid/epidermoid cysts of the head (n = 7), lymphangiomas of the head/neck (n = 2), thyroglossal duct cysts (n = 7), gynecomastia (n = 3), preauricular fistula (n = 2), second branchial cleft fistula (n = 1), fibrolipoma of the shoulder (n = 1) and myofibroma of the gluteal/perineal region (n = 2). In all procedures, an intralesional injection of 2.5 mg/mL ICG solution using a 30-gauge needle was administered. No adverse reactions to ICG occurred. Median operative time was 68.6 min (range 35–189). The visualization of ICG-NIRF with the Rubina® Lens was achieved in all cases. No intraoperative complications were reported. Postoperative complications occurred in 3/25 patients (12%), with gynecomastia (n = 1), thyroglossal duct cyst (n = 1) and neck lymphangioma (n = 1), who developed a fluid collection in the surgical site, requiring needle aspiration in outpatient care (Clavien–Dindo 2). Complete mass excision was confirmed with pathology reports. Conclusions: Based on this initial experience, FGS using the Rubina® Lens was very helpful in open surgery, providing enhanced visualization of anatomy and identification of margins, real-time reliability and low complication rate. It was easy to use, time saving, feasible and clinically safe. Previous experience in MIS is necessary to adopt this technology. The accuracy of the injection phase is important to avoid diffusion of the ICG into the perilesional tissue.

ROS proto-oncogene 1 (ROS1) rearrangements occur in 0.9–2.6% of patients with non small cell lung cancer (NSCLC), conferring sensitivity to treatment with specific tyrosine-kinase inhibitors (TKI). Crizotinib, a first-generation TKI, was the first target-therapy approved for the first-line treatment of ROS1-positive NSCLC. Recently, entrectinib, a multitarget inhibitor with an anti-ROS1 activity 40 times more potent than crizotinib and better activity on the central nervous system (CNS), received approval for treatment-naive patients. After a median time-to-progression of 5.5–20 months, resistance mechanisms can occur, leading to tumor progression. Therefore, newer generation TKI with greater potency and brain penetration have been developed and are currently under investigation. This review summarizes the current knowledge on clinicopathological characteristics of ROS1-positive NSCLC and its therapeutic options.

BackgroundThis phase I, four-arm, open-label study (NCT01347866) evaluated the PI3K/mTOR inhibitors PF-04691502 (arms A, B) and gedatolisib (PF-05212384; arms C, D) in combination with the MEK inhibitor PD-0325901 (arm A, D) or irinotecan (arm B, C) in patients with advanced solid tumors.ObjectivesPrimary endpoint was dose-limiting toxicity with each combination. Secondary endpoints included safety, pharmacokinetics and preliminary antitumor activity.Patients and methodsDose escalation followed a 3 + 3 design in arm C and a zone-based design in arm D.ResultsThe PF-04691502 combination arms were closed prematurely due to low tolerability, and the maximum tolerated doses (MTDs) were not determined for either arm. The MTD for the combination of gedatolisib with irinotecan 180 mg/m2 was estimated to be 110 mg weekly and for the combination with PD-0325901 was not reached at the highest dose evaluated (gedatolisib 154 mg weekly). Plasma concentrations of gedatolisib were generally similar across dose groups in arm C (with irinotecan) and arm D (with PD-0325901). Frequent dose delays or dose reductions were required for both combinations, potentially preventing sustained therapeutic drug concentrations. Gedatolisib plus irinotecan produced a response rate of ~5% and clinical benefit in 16% of patients with advanced colorectal cancer (progression-free survival, 2.8 months). Preliminary evidence of clinical activity was observed with gedatolisib plus PD-0325901 in patients with ovarian cancer (three partial responses, n = 5) or endometrial cancer (one partial response, n = 1) and KRAS mutations.ConclusionsFurther evaluations of gedatolisib are warranted in patients with advanced solid malignancies.