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Abstract Soft tissue sarcomas represent an heterogeneous group of rare mesenchymal tumors comprising 1% of all solid malignancies. Among them, liposarcoma is one of the most common histotypes with atypical lipomatous tumor/well differentiated liposarcoma and dedifferentiated liposarcoma (ALT/WDLPS and DDLPS) as the major sub-entities. The unavailability of predictive, prognostic and druggable biomarkers makes the management of these lesions challenging. In recent years CDK4 and its inhibitors have emerged as potential agents for these lesions especially for ALT/WDLPS and DDLPS but the results are not conclusive and need to be elucidated. This study involved 21 ALT/WDLPS and DDLPS patients. Histological analyses of MDM2 and CDK4 were carried out. Moreover, a DDLPS patient-derived cancer model was established in vitro and in vivo assessing the efficacy of palbociclib in combination and sequential treatment. Finally, in silico analyses on CDK4 expression were carried out. The results showed a higher expression of CDK4 and MDM2 in DDLPS compared to ALT/WDLPS. Moreover, no correlation between MDM2 expression and CDK4 was observed. Next, in vitro analysis of CDK4 inhibitor palbociclib showed an antagonistic effect when combined to other chemotherapeutics, while it exhibited a significant synergy when administered in sequential schedule with lenvatinib. Next, in vivo analysis on DDLPS xenotransplanted embryos assessing the efficacy and safety profile of the in vitro tested schedules confirmed the observed data. This proof-of-concept study sheds light on the natural history of ALT/WDLPS and DDLPS and provides the rationale for the clinical applicability of sequential treatment with palbociclib in the management of DDLPS.

Abstract Background Assisted Reproductive Technologies (ARTs) have been validated in human and animal to solve reproductive problems such as infertility, aging, genetic selection/amplification and diseases. The persistent gap in ART biomedical applications lies in recapitulating the early stage of ovarian folliculogenesis, thus providing protocols to drive the large reserve of immature follicles towards the gonadotropin-dependent phase. Tissue engineering is becoming a concrete solution to potentially recapitulate ovarian structure, mostly relying on the use of autologous early follicles on natural or synthetic scaffolds. Based on these premises, the present study has been designed to validate the use of the ovarian bioinspired patterned electrospun fibrous scaffolds fabricated with poly(ε-caprolactone) (PCL) for multiple preantral (PA) follicle development. Methods PA follicles isolated from lamb ovaries were cultured on PCL scaffold adopting a validated single-follicle protocol (Ctrl) or simulating a multiple-follicle condition by reproducing an artificial ovary engrafted with 5 or 10 PA (AO5PA and AO10PA). The incubations were protracted for 14 and 18 days before assessing scaffold-based microenvironment suitability to assist in vitro folliculogenesis (ivF) and oogenesis at morphological and functional level. Results The ivF outcomes demonstrated that PCL-scaffolds generate an appropriate biomimetic ovarian microenvironment supporting the transition of multiple PA follicles towards early antral (EA) stage by supporting follicle growth and steroidogenic activation. PCL-multiple bioengineering ivF (AO10PA) performed in long term generated, in addition, the greatest percentage of highly specialized gametes by enhancing meiotic competence, large chromatin remodeling and parthenogenetic developmental competence. Conclusions The study showcased the proof of concept for a next-generation ART use of PCL-patterned scaffold aimed to generate transplantable artificial ovary engrafted with autologous early-stage follicles or to advance ivF technologies holding a 3D bioinspired matrix promoting a physiological long-term multiple PA follicle protocol.

The objective of this research is the investigation on the relationship between the Italian and Portuguese architectural culture in a time span between the end of the second World War and the Carnation Revolution, that sees the fall of the Salazar regime in Portugal in 1974, paying particular attention on the figure of Portuguese architect Fernando Távora (1923-2005), one of the greatest exponents of the Protuguese architectural scene of that period. The debate that took place in those years in Italy around the design, paying attention to the relationship with the context and the right “language” to use, combined with the liveliness of the architectural landscape, pushed some Portuguese architects to have an interest in the Italian architectural sphere with which they come into contact through travels, publications and meetings. This research does not want to be an historiographical analysis of the development of projects but rather a process of synthesis of the compositional thought of the architect and the influences deriving from the Italian culture context, whether explicit or documented, but also stemmed from personal experiences and architectures visited by Tavora during his travels to Italy. The research delves into the compositional aspects of some of Tavora’s projects, developed and produced at this stage of his professional career, through a parallel with several Italian buildings of the same period or belonging to classical architecture, which Tavora knows and has had the chance to visit in person. By redesigning the architectures of Tàvora, as well as the Italian ones examined in the analysis, it was possible to fully understand the links between the various projects and therefore developing a schematic graphic clarifying the examined aspects and support the written text. This article is excerpted from the writer’s doctoral thesis: G. Liverani, Contesto e progetto. Influenze italiane sull’architettura di Fernando Távora, Università di Bologna: Bologna 2017 (Tutor Antonio Esposito).

Objectives: Gastrointestinal stromal tumors, the most prevalent mesenchymal tumors (80 %) of the gastrointestinal tract, comprise less than 1 % of all gastrointestinal neoplasms and about 5 % of all sarcomas. Despite their rarity, Gastrointestinal stromal tumors present diverse clinical manifestations, anatomic locations, histological subtypes, and prognostic outcomes. Methods: This scoping review comprehensively explores the epidemiology, clinical characteristics, diagnostic and prognostic modalities, as well as new therapeutic options for Gastrointestinal stromal tumors. Results: A particular focus is placed on the promising role of bio-nanomaterials as multifunctional agents for drug delivery and 3D tumor microenvironment modeling. Bio-nanomaterials offer promising opportunities for targeted drug delivery, overcoming treatment resistance, and improving therapeutic efficacy. Conclusion: Despite significant advancements, Gastrointestinal stromal tumors remain a complex clinical entity with ongoing challenges. The integration of nanotechnology into Gastrointestinal stromal tumors management offers the potential to enhance patient outcomes. Future studies should prioritize the development and evaluation of nanomaterial-based therapies in clinical trials to facilitate the translation of laboratory discoveries into real-world clinical applications.

Extrusion-based 3D printing is widely used in various industries, enabling the rapid creation of prototypes and functional parts at a lower cost compared to traditional technologies. However, one limitation of this technology is the surface finish of the components, where the roughness is not optimal. This paper presents a solution to improve the surface finish of components by leveraging the principles of ironing and ball burnishing. The tool, appropriately heated and passed over the component, smooths out imperfections by uniforming the surface profile. Unlike the traditional ironing method, the use of this tool reduces processing times and enhances surface roughness with a simpler construction and control mechanism compared to a conventional hot-end. The average surface roughness obtained is Ra = 0.796 μm; these values are comparable to those obtained by grinding. The geometry of the tool tips can vary significantly based on specific applications.

Introduction Acute febrile illness (AFI), traditionally attributed to malaria, is a common reason for seeking primary healthcare in rural South and Southeast Asia. However, malaria transmission has declined while health workers are often poorly equipped to manage non-malarial AFIs. This results in indiscriminate antibiotic prescribing and care escalation, which promotes antibiotic resistance and may increase healthcare costs. To address this problem, an electronic clinical decision support algorithm (eCDSA) called ‘Electronic clinical Decision support for Acute fever Management (EDAM)’ has been developed for primary health workers which integrates clinical, epidemiological and vital sign data with simple point-of-care tests to produce a diagnosis and management plan.Methods and analysis This is a pragmatic cluster-randomised trial aiming to assess the effect of EDAM and related training on antibiotic prescribing rates in rural Cambodian primary health centres (PHCs) as the primary outcome, along with a range of secondary outcomes including safety. Patients with AFI are eligible for recruitment if they are aged ≥1 year. A cluster is defined as a PHC and PHCs will be randomised to control (standard of care) and intervention (EDAM and associated training) arms, with 15 PHCs per arm. Patients will be followed up after 7 days to ascertain the safety profile of EDAM. Each PHC will recruit 152 patients (total 4560), based on a baseline antibiotic prescription rate of 25% and expected reduction to 17.5% with EDAM.Ethics and dissemination Results will be published in international peer-reviewed journals to inform the design of future versions of EDAM and of future trials of similar eCDSAs and other digital health interventions targeted towards rural populations. This study was approved by the Oxford University Tropical Research Ethics Committee (550-23) and the Cambodian National Ethics Committee for Health Research (395-NECHR).Trial registration number International Standard Randomized Controlled Trial Number Registry (ISRCTN15157105).

Introduction Non-prescription antibiotic dispensing is prevalent among community pharmacies in several low- and middle-income countries. We evaluated the impact of a multi-faceted intervention to address this challenge in urban community pharmacies in Indonesia.Methods A pre-post quasi-experimental study was carried out in Semarang city from January to August 2022 to evaluate a 7-month long intervention comprising: (1) online educational sessions for pharmacists; (2) awareness campaign targeting customers; (3) peer visits; and (4) pharmacy branding and pharmacist certification. All community pharmacies were invited to take part with consenting pharmacies assigned to the participating group and all remaining pharmacies to the non-participating group. The primary outcome (rate of non-prescription antibiotic dispensing) was measured by standardised patients displaying symptoms of upper respiratory tract infection, urinary tract infection (UTI) and seeking care for diarrhoea in a child. χ2 tests and multivariate random-effects logistic regression models were conducted. Thirty in-depth interviews were conducted with pharmacists, staff and owners as well as other relevant stakeholders to understand any persistent barriers to prescription-based dispensing of antibiotics.Findings Eighty pharmacies participated in the study. Postintervention, non-prescription antibiotics were dispensed in 133/240 (55.4%) consultations in the participating group compared with 469/570 (82.3%) in the non-participating group (p value

Abstract The overexpression of the ecotropic viral integration site-1 gene (EVI1/MECOM) marks the most lethal acute myeloid leukemia (AML) subgroup carrying chromosome 3q26 abnormalities. By taking advantage of the intersectionality of high-throughput cell-based and gene expression screens selective and pan-histone deacetylase inhibitors (HDACis) emerge as potent repressors of EVI1. To understand the mechanism driving on-target anti-leukemia activity of this compound class, here we dissect the expression dynamics of the bone marrow leukemia cells of patients treated with HDACi and reconstitute the EVI1 chromatin-associated co-transcriptional complex merging on the role of proliferation-associated 2G4 (PA2G4) protein. PA2G4 overexpression rescues AML cells from the inhibitory effects of HDACis, while genetic and small molecule inhibition of PA2G4 abrogates EVI1 in 3q26 AML cells, including in patient-derived leukemia xenografts. This study positions PA2G4 at the crosstalk of the EVI1 leukemogenic signal for developing new therapeutics and urges the use of HDACis-based combination therapies in patients with 3q26 AML.

Abstract In order to better understand the mechanisms generating genetic diversity in the recent allotetraploid species Coffea arabica, here we present a chromosome-level assembly obtained with long read technology. Two genomic compartments with different structural and functional properties are identified in the two homoeologous genomes. The resequencing data from a large set of accessions reveals low intraspecific diversity in the center of origin of the species. Across a limited number of genomic regions, diversity increases in some cultivated genotypes to levels similar to those observed within one of the progenitor species, Coffea canephora, presumably as a consequence of introgressions deriving from the so-called Timor hybrid. It also reveals that, in addition to few, early-occurring exchanges between homoeologous chromosomes, there are numerous recent chromosomal aberrations including aneuploidies, deletions, duplications and exchanges. These events are still polymorphic in the germplasm and could represent a fundamental source of genetic variation in such a lowly variable species.

Abstract Background Community-based health programmes have been a cornerstone of primary care in Laos for decades. The study presented here aimed to document prospects for the development of current programmes, considering perceptions about health and health care priorities in the communities, implementation challenges, the policy landscape and opportunities associated with the availability of new technologies. Methods The research design primarily involved qualitative in-depth interviews with stakeholders (n = 35) responsible for the planning, management, or implementation of community-based care in Laos at different levels of the health system. These included health managers at central departments or institutes of the Ministry of Health, provincial health departments, district health offices, heads of health centres, village health volunteers, community representatives, and international stakeholders. Results There was consensus that service delivery is still a challenge in many areas, due to geographic inaccessibility of health facilities, communication barriers, health-seeking behaviour, trust, and gender discrimination, particularly among ethnic minorities. In these settings, community health workers have the potential to extend the reach of the formal health system, acting as cultural brokers across sectors of society, ethnicities, and worldviews. To maximise impact, planners need to carefully consider the implementation model, financing arrangements, health system integration, and changing health priorities in the communities. Conclusions This study examined challenges to, and opportunities for, the expansion and health system integration of community-based care in Laos. Further development and horizontal integration of community-based care remains a complex financing and governance challenge, although the renewed emphasis on primary care and the ongoing process of decentralisation provide a favourable policy environment in the country to sustain and potentially expand existing programmes.