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Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is an essential protein involved in the maintenance of repressive epigenetic marks, ensuring epigenetic stability and fidelity. As an epigenetic regulator, UHRF1 comprises several functional domains (UBL, TTD, PHD, SRA, RING) that are collectively responsible for processes like DNA methylation, histone modification, and DNA repair. UHRF1 is a downstream effector of the RB/E2F pathway, which is nearly universally deregulated in cancer. Under physiological conditions, UHRF1 protein levels are cell cycle-dependent and are post-translationally regulated by proteasomal degradation. Conversely, UHRF1 is overexpressed and serves as an oncogenic driver in multiple cancers. This review focuses on the functional domains of UHRF1, highlighting its key interacting proteins and oncogenic roles in solid tumors including retinoblastoma, osteosarcoma, lung cancer, and breast cancer. Additionally, current therapeutic strategies targeting UHRF1 domains or its interactors are explored, providing an insight on potential clinical applications.

Small cell lung cancer (SCLC) is a deadly neuroendocrine malignancy, notorious for its rapid tumor growth, early metastasis, and relatively cold immune environment. Only standard chemotherapies and a few immune checkpoint inhibitors have been approved for SCLC treatment, revealing an urgent need for novel therapeutic approaches. Moreover, SCLC has been recently recognized as a malignancy with high intratumoral and intertumoral heterogeneity, which explains the modest response rate in some patients and the early relapse. Molecular subtypes defined by the expression of lineage-specific transcription factors (ASCL1, NEUROD1, POU2F3, and, in some studies, YAP1) or immune-related genes display different degrees of neuroendocrine differentiation, immune cell infiltration, and response to treatment. Despite the complexity of this malignancy, a few biomarkers and targets have been identified and many promising drugs are currently undergoing clinical trials. In this review, we integrate the current progress on the genomic landscape of this shapeshifting malignancy, the characteristics and treatment vulnerabilities of each subtype, and promising drugs in clinical phases.

Abstract: Glioblastoma multiforme (GBM) is the most aggressive primary malignant brain tumor in adults, with a poor prognosis that highlights a dire clinical need for innovative therapeutic interventions. Despite significant advances in diagnoses and multimodality therapies, the overall prognosis for patients with GBM remains poor, with a median survival time of 15-18 months. Therefore, there is an unmet medical need to develop alternative treatment strategies to improve clinical outcomes. Dysregulation of post-transcriptional control and translational machinery have been implicated in malignant tumor development. Cytoplasmic polyadenylation element binding proteins (CPEB1-CPEB4) are RNA-binding proteins that regulate poly(A) tail elongation of target mRNAs and subsequently contribute to phenotypic changes in cancer cells. Notably, a self-cleaving ribozyme was identified in the CPEB3 gene, but its role in cancer is wholly unexplored. Considering the role of CPEB3 as a tumor suppressor gene and the promotion of cancer progression through the downregulation of CPEB3, our hypothesis is that the CPEB3 ribozyme regulates CPEB3 expression, and its activity contributes to the progression of tumors. Using antisense oligonucleotides (ASOs) as an approach, we demonstrated that inhibition of CPEB3 ribozyme resulted in an increase of CPEB3 mRNA and protein expression. Blocking the CPEB3 ribozyme led to a significant reduction in cell proliferation, migration, and invasion in GBM cell lines. Gene set enrichment analysis (GSEA) revealed the downregulation of epithelial-mesenchymal transition (EMT), angiogenesis, and hypoxia gene sets in GBM cells treated with ASO compared to Ctrl-ASO. We further measured VEGFA mRNA and protein expression and found that ASO-treated GBM cells secreted significantly less VEGF in conditioned media. Inhibition of the CPEB3 ribozyme also mitigated the EMT process in GBM cells. Subsequently, ASO strategies were applied to patient-derived glioma stem cells (GSCs), representing a clinically relevant model for pre-clinical therapeutic intervention. We found that treatment of CPEB3 ribozyme ASO up-regulated CPEB3 mRNA and inhibited cell proliferation in GSCs. Furthermore, the combination of ASO and temozolomide chemotherapy exhibited a more pronounced decrease in GSCs proliferation compared to individual treatment alone. Collectively, this study highlights the significance of the CPEB3 ribozyme in GBM and explores therapeutic approaches focused on targeting CPEB3 in cancer. Citation Format: Claire Chen, Eric Wang, Lily Tong, Mehran Nikan, Daniela A. Bota, Claudia Benavente, Andrej Luptak. Suppression of the CPEB3 ribozyme modulates the progression of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3180.

Osteosarcoma (OS) is a primary malignant bone tumor with high metastasis. Poor prognosis highlights a clinical need for novel therapeutic strategies. Exosomes, also known as extracellular vesicles, have been identified as essential players in the modulation of cancer. Recent studies have suggested that OS-derived exosomes can drive pro-tumorigenic or anti-tumorigenic phenotypes by transferring specific cargos, including proteins, nucleic acids, and metabolites, to neighboring cells, significantly impacting the regulation of cellular processes. This review discusses the advancement of exosomes and their cargos in OS. We examine how these exosomes contribute to the modulation of cellular phenotypes associated with tumor progression and metastasis. Furthermore, we explore the potential of exosomes as valuable biomarkers for diagnostics and prognostic purposes and their role in shaping innovative therapeutic strategies in OS treatment development.

Abstract Background Stability during early postnatal life in preterm infants is related to better outcomes. Although vital signs are monitored continuously in Neonatal Intensive Care Unites, this monitoring does not include all physiological parameters nor data such as movement patterns. Although there are scattered sources of data, there is no centralized data hub for neonates information. Results We have created the first neonate data hub for easy and interactive access to upload or download postural, physiological, and medical data of neonates: NeoVault. NeoVault is a platform that provides access to information through two interfaces: 1) via a Web interface (designed for medical personnel, data scientists, researchers); and 2) via a RESTful API (Application Programming Interfaces) -designed for developers-, aiming to integrate access to information into third-party applications. The web access allows searching and filtering according to specific parameters, visualization of data through graphs and images, and generation of datasets in CSV format. Access through the RESTful API is described in OpenAPI, enabling access to information from any device, facilitating it in an interoperable format. Currently, it contains nearly 800,000 postural records and 3.000 physiological data entries. The physiological and postural data stored for each neonate in NeoVault are collected through the NRP (Neonates Recording Platform) tool, which allows for the automatic and reliable collection of data. Conclusion NeoVault is an open platform for simple access to postural, physiological, and medical data of neonates that can be utilized by researchers, data scientists, medical personnel, and programmers. It enables integration into third-party applications and the generation of customized datasets.

Abstract The lake‐basin‐type model classified the stratigraphic record of ancient lake systems according to rates of potential accommodation relative to sediment + water supply. The model convolved all modes and paths of water supply (direct fall, surficial, subsurface) with amounts and types of sediment supply (clastic, biogenic, chemical) into a single basin‐filling volume term (sediment + water); its major strength was its widespread applicability. This was supported by subsequent investigations confirming the utility of this approach, but it also revealed some important limitations due to simplifications in the original model. The model has been expanded here to address all inland waters (lakes, ponds, wetlands, playas) as well as adding two major subdivisions of the sediment + water term: (1) water supply paths and (2) the volume of water supply relative to sediment supply. Water supply flow paths in the subsurface are subdivided into ‘throughflow’, ‘recharge’ and ‘discharge’. Each of these groundwater hydrology states can be defined quite precisely by the ratio of net outflow to inflow, from persistently open to consistently closed. These paths can be deciphered using stable carbonate and oxygen isotope composition of primary lacustrine limestones, detailed sedimentology, stratigraphy, palaeontology and mineralogy. Distinguishing water supply paths provides additional insights into playa systems and the occurrence and character of evaporites and carbonates. The volume ratio of water to sediment supply most directly influences the water depths of lakes, ponds and wetlands, which affect water body hydrodynamics and ecosystem behaviour as well as the details of stratal stacking and depositional sequences. It helps fine‐tune estimates of the distribution of sediment texture, bedding, composition and organic matter content. The aim of this contribution is to address questions about the fundamental types of inland water bodies and to explain the new lake‐basin subtypes and provide examples that illustrate their potential to enable higher‐resolution, robust analysis of inland water systems and their stratigraphic records.

Abstract Background Identifying children and adolescents with cardiometabolic risk at an early stage is crucial for effective treatment and prevention. From a practical perspective, this could be accomplished by assessing the presence of abdominal obesity, which serves as a surrogate indicator of increased cardiometabolic risk and is easy to measure. However, the assessment of abdominal obesity via waist circumference has not yet become a standard procedure in pediatric healthcare. The present study aimed to analyze the secular trends in increased cardiometabolic risk, as indicated by waist circumference among Spanish children and adolescents. Methods This study included 4861 children and adolescents aged 8 to 16 years from two nationwide representative cross-sectional surveys, the EnKid study and the PASOS study, conducted in 1998–2000 and 2019–2020, respectively. Anthropometric variables were measured in both surveys by trained personnel. Three different waist-to-height (WHtR) cutoffs were used to define abdominal obesity as criteria for cardiometabolic risk. BMI categories were defined according to the IOTF and WHO growth charts. Results Abdominal obesity [waist to height ratio (cm/cm) > 0.49] significantly increased from 40.7 to 56.1% and 93.8 to 97.2% in participants with overweight and obesity, respectively, between 1998–2000 and 2019–2020 (p

Abstract Background Pisum sativum (PS) is a universal legume plant utilized for both human and animal consumption, particularly its seeds, known as green peas. The processing of PS in food industries and households produces a significant amount of waste that needs to be valorized. Methods In this study, the metabolite profiles of the 70% ethanolic extracts of PS wastes, namely peels (PSP) and a combination of leaves and stems (PSLS), were investigated by liquid chromatography-electrospray ionization-quadrupole time-of-flight tandem mass spectrometry (LC-ESI-QTOF-MS/MS) followed by molecular networking. Results Different classes of metabolites were identified, being flavonoids and their derivatives, along with phenolic acids, the most abundant categories. Additionally, a comprehensive network pharmacology strategy was applied to elucidate potentially active metabolites, key targets, and the pathways involved in cytotoxic activity against breast cancer. This cytotoxic activity was investigated in MCF-7 and MCF-10a cell lines. Results revealed that PSLS extract exhibited a potent cytotoxic activity with a good selectivity index (IC50 = 17.67 and selectivity index of 3.51), compared to the reference drug doxorubicin (IC50 = 2.69 µg/mL and selectivity index of 5.28). Whereas PSP extract appeared to be less potent and selective (IC50 = 32.92 µg/mL and selectivity index of 1.62). A similar performance was also observed for several polyphenolics isolated from the PSLS extract, including methyl cis p-coumarate, trans p-coumaric acid, and liquiritigenin/ 7-methyl liquiritigenin mixture. Methyl cis p-coumarate showed the most potent cytotoxic activity against MCF-7 cell line and the highest selectivity (IC50 = 1.18 µg/mL (6.91 µM) and selectivity index of 27.42). The network pharmacology study revealed that the isolated compounds could interact with several breast cancer-associated protein targets including carbonic anhydrases 1, 2, 4, 9, and 12, as well as aldo-keto reductase family 1 member B1, adenosine A3 receptor, protein tyrosine phosphatase non-receptor type 1, and estrogen receptor 2. Conclusion The uncovered therapeutic potential of PSLS and its metabolite constituents pave the way for an efficient and mindful PS waste valorization, calling for further in-vitro and in-vivo research. Graphical Abstract

Este estudio se centra en la gestión de sistemas de drenaje urbano capaces de reducir la contaminación de las aguas pluviales. Se enfoca en la eliminación de níquel (Ni), presente en las aguas de escorrentía urbana, debido a su toxicidad y posible acumulación en los organismos vivos. Se plantean ensayos en columnas de laboratorio utilizando Filtralite como material filtrante. Se emplea el módulo HP1 para calibrar un modelo que analiza el transporte y eliminación de este metal pesado. Se observa que la interacción entre el material y la disolución contaminada aumenta el pH, lo que provoca la precipitación de hidróxido de Ni en los primeros nodos de la columna. Los resultados indican que la concentración del contaminante en la disolución depende directamente del pH. En condiciones ácidas, el Ni permanece en la disolución, pero a partir de un pH de 7.5, comienza su eliminación, hasta desaparecer para valores superiores a 11.

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.

Lane management strategies are vital for solving traffic congestion and improving transportation efficiency in metropolitan corridors. These corridors, which facilitate economic and social interactions by connecting major urban areas, face significant challenges such as congestion, environmental concerns, and the need for sustainable growth. Effective lane management involves techniques such as HOV lanes, HOT lanes, reversible lanes, and dynamic toll pricing, which have been implemented worldwide. This study addresses the questions ‘What are the benefits and limitations of lane management strategies in metropolitan corridors?’ and ‘When should decision-makers consider implementing lane management strategies in a metropolitan corridor?’ This paper aims to evaluate lane management strategies to increase the multimodal efficiency of metropolitan corridors. A systematic literature review of case studies reveals that while these strategies significantly reduce congestion and emissions, they also face road safety, compliance, and public resistance issues. In addition, gaps in existing research on metropolitan corridors and lane management will be identified, and areas for future research are proposed. The impacts of new societal trends and evolving urban planning concepts are examined. The study highlights the need for adaptive planning and innovative solutions.

Resumen: Introducción: La rizartrosis es una enfermedad que afecta a parte de la población activa, mermando su capacidad laboral y su calidad de vida. La trapecectomía y suspensión mediante el sistema Mini TightRope® un periodo de incapacidad laboral temporal (ILT). Objetivo: Evaluar los tiempos medios de ILT en los pacientes intervenidos en nuestro centro y estudiar si existen factores que puedan retrasar la reincorporación al trabajo tras esta cirugía. Material y métodos: Estudio retrospectivo de los pacientes a los que se realizó una trapecectomía y artroplastia de suspensión mediante el sistema Mini TightRope® entre los años 2015 y 2016, con un seguimiento mínimo de un año. Se realizó una entrevista telefónica y una revisión de la historia clínica y de la radiología, recogiendo datos epidemiológicos y laborales. Se compararon los grupos por edad, sexo, mano dominante y requerimientos profesionales biomecánicos de los pacientes, así como haber estado en ILT previo a la cirugía. Resultados: Se incluyeron un total de 36 pacientes (29 mujeres y 7 varones) con una edad media de 55,7 años. La mediana para la vuelta al trabajo fue de 126 días. Los trabajadores autónomos se reincorporaron 72 días antes (p = 0,004); los trabajadores que estaban en ILT previa a la cirugía tuvieron una ILT total mayor, y tardaron en volver al trabajo 91 días más que aquellos que no lo estaban (p

Abstract Fracture-related infections (FRIs), particularly those caused by methicillin-resistant Staphylococcus aureus (MRSA), are challenging to treat. This study designed and evaluated a hydrogel loaded with a cocktail of bacteriophages and vancomycin (1.2 mg/mL). The co-delivery hydrogel showed 99.72% reduction in MRSA biofilm in vitro. The hydrogel released 54% of phages and 82% of vancomycin within 72 h and maintained activity for eight days, in vivo the co-delivery hydrogel with systemic antibiotic significantly reduced bacterial load by 0.99 log10 CFU compared to controls, with active phages detected in tissues at euthanasia (2 × 103 PFU/mL). No phage resistance was detected in the phage treatment groups, and serum neutralization resulted in only a 20% reduction in phage count. In this work, we show that a phage-antibiotic co-delivery system via CMC hydrogel is a promising adjunct to systemic antibiotic therapy for MRSA-induced FRI, highlighting its potential for localized, sustained delivery and improved treatment outcomes.

Preterm infants are prone to NeuroDevelopmental Impairment (NDI). Some previous works have identified clinical variables that can be potential predictors of NDI. However, machine learning (ML)-based models still present low predictive capabilities when addressing this problem. This work attempts to evaluate the application of ML techniques to predict NDI using clinical data from a cohort of very preterm infants recruited at birth and assessed at 2 years of age. Six different classification models were assessed, using all features, clinician-selected features, and mutual information feature selection. The best results were obtained by ML models trained using mutual information-selected features and employing oversampling, for cognitive and motor impairment prediction, while for language impairment prediction the best setting was clinician-selected features. Although the performance indicators in this local cohort are consistent with similar previous works and still rather poor. This is a clear indication that, in order to obtain better performance rates, further analysis and methods should be considered, and other types of data should be taken into account together with the clinical variables.

Photocatalysis based on titanium dioxide (TiO2) has become a promising method to remediate industrial and municipal effluents in an environmentally friendly manner. However, the efficiency of TiO2 is hampered by problems such as rapid electron–hole recombination and limited solar spectrum absorption. Furthermore, the sensitization of TiO2 through heterojunctions with other materials has gained attention. Vanadium, specifically in the form of ammonium vanadate ((NH4)2V3O8), has shown promise as a photocatalyst due to its ability to effectively absorb visible light. However, its use in photocatalysis remains limited. Herein, we present a novel synthesis method to produce lamellar (NH4)2V3O8 as a sensitizer in a supramolecular hybrid photocatalyst of TiO2–stearic acid (SA), contributing to a deeper understanding of its structural and magnetic characteristics, expanding the range of visible light absorption, and improving the efficiency of photogenerated electron–hole separation. Materials, such as TiO2–SA and (NH4)2V3O8, were synthesized and characterized. EPR studies of (NH4)2V3O8 demonstrated their orientation-dependent magnetic properties and, from measurements of the angular variation of g-values, suggest that the VO2+ complexes are in axially distorted octahedral sites. The photocatalytic results indicate that the 2D/2D heterojunction layered TiO2/vanadate at a ratio (1:0.050) removed 100% of the methylene blue, used as a model contaminant in this study. The study of the degradation mechanism of methylene blue emphasizes the role of reactive species such as hydroxyl radicals (•OH) and superoxide ions (O2•−). These species are crucial for breaking down contaminant molecules, leading to their degradation. The band alignment between ammonium vanadate ((NH4)2V3O8) and TiO2–SA, shows effective separation and charge transfer processes at their interface. Furthermore, the study confirms the chemical stability and recyclability of the TiO2–SA/(NH4)2V3O8 photocatalyst, demonstrated that it could be used for multiple photocatalytic cycles without a significant loss of activity. This stability, combined with its ability to degrade organic pollutants under solar irradiation, means that the TiO2–SA/(NH4)2V3O8 photocatalyst is a promising candidate for practical environmental remediation applications.

Durante la Edad Moderna, en el Mediterráneo occidental, se afianzó el consumo de un producto cuyo uso ha desaparecido por completo en la actualidad: la nieve. Su utilización resultaba fundamental en la conservación de alimentos, la medicina y, especialmente, como ingrediente base en la gastronomía. A priori podríamos pensar que el empleo de la nieve, un producto que nos resulta tan extraño en la actualidad, estaba reservado para grupos sociales muy reducidos y que se trataba de un bien de lujo. No obstante, esta observación no podría estar más alejada de la realidad, especialmente si hablamos de la ciudad de Valencia. Las condiciones climáticas, sociales y económicas favorecieron el desarrollo del comercio de un producto cuya popularización se enmarcó en la revolución del consumo y la democratización del lujo. Para poder conocer con mayor profundidad los detalles, causas y consecuencias de la evolución en el uso de este producto, en este artículo se realizará una aproximación a los factores que explicaron la enorme popularidad que gozó la nieve en la sociedad valenciana del siglo XVIII. Entre ellos se abordará la evolución de los factores coyunturales, como los cambios fiscales, las guerras o las epidemias, y otros de carácter coyuntural como el desarrollo económico que experimentó la Valencia dieciochesca, los cambios en la forma de consumir y la relación entre el comercio del frío y las condiciones climatológicas. Por último, se hará un breve estudio comparativo para situar el consumo de nieve de Valencia en el contexto peninsular.

En un paciente con parálisis cerebral hay un desbalance muscular progresivo que en la cadera lleva primero a aducción, posteriormente a flexión y rotación interna; y si el desbalance es grave y persisten las posturas viciosas, se producirán cambios adaptativos en partes blandas y óseas aumentando la anteversión y el valgo del fémur pudiendo evolucionar a subluxación o luxación. En pacientes con parálisis cerebral se realizó 302 procedimientos quirúrgicos en cadera; y en el presente trabajo evaluamos 92 caderas en 46 pacientes en los que se ha realizado tenotomía de aductores, recto interno y/o neurectomía de ramas anteriores de obturadores, complementando luego con ejercicios activos y pasivos de caderas y rodillas. En los pacientes no ambulatorios se logró mejorar los cuidados de enfermería en el 9S % de operados; y en los ambulatorios además se mejoró la marcha en el 92 % ; y el índice de migración en el 70 %.

Background: Coronary artery disease (CAD) is one of the leading causes of death worldwide. The buildup of atherosclerotic plaque, including lipids and cellular waste, characterizes this disease. Smooth muscle cells (SMCs) can migrate and proliferate to form a fibrous cap that stabilizes the atherosclerotic plaque in response to plaque buildup. However, in some severe cases, the fibrous cap is unable to prevent plaque rupture, which can lead to a thrombotic event causing a stroke or myocardial infarction. Studies have been conducted to identify genes associated with this disease. However, the influence of sex on CAD risk is poorly understood due to the complexity of the disease and the lack of women in clinical studies. Methods: This study is investigated with a unique collection of human aortic smooth muscle cells (huASMCs) derived from 118 male and 33 female individuals who either underwent a heart transplant or were victims of motor vehicle accidents. In this investigation, we explore differentially expressed genes between males and females related to atherosclerosis using a unique RNAseq dataset of human aortic SMCs. Results: Our study identified 8 genes ( CHST1, DKK2, DLL4, EIF1AXP1, GALNT13, NOTCH4, SELL, SPARCL1 ) that exhibit sex-biased effects in SMCs. Of these, 6 genes were found in the Athero-Express dataset and 5 of them were associated with atherosclerosis-relevant phenotypes. We discovered a novel NOTCH4/DLL4 pathway that plays a role in the differential expression of these genes between males and females. This pathway is linked to coronary artery physiology and may play a role in the pathophysiology of coronary artery disease that differs between the sexes. Conclusions: Overall, this investigation shows that differentially expressed genes between males and females in human aortic SMCs exist.