Search

This paper explores the dualistic nature of experiential learning (EL) definitions in higher education, advocating for a balanced integration of broad and narrow constructs. Through case study and collaborative inquiry, diverse disciplinary perspectives--from engineering to performing arts and urban education--are examined to understand EL's application and impact. The paper highlights the importance of accommodating both overarching frameworks for universal applicability and specific definitions for disciplinary depth. It proposes that broad definitions enhance inclusivity and adaptability, while narrow constructs ensure targeted learning experiences and skill development. The findings suggest that EL is a versatile pedagogical tool. It is adaptable to varied academic landscapes and yet maintains its essence of active, reflective engagement with the world. Finally, the paper argues that both broad and narrow definitions of EL are necessary to ensure EL remains a transformative educational pedagogy, and proposes a framework for describing, rather than defining, EL.

Cystic fibrosis (CF) is an autosomal recessive disorder characterized by respiratory failure due to a vicious cycle of defective Cystic Fibrosis Transmembrane conductance Regulator (CFTR) function, chronic inflammation and recurrent bacterial and fungal infections. Although the recent introduction of CFTR correctors/potentiators has revolutionized the clinical management of CF patients, resurgence of inflammation and persistence of pathogens still posit a major concern and should be targeted contextually. On the background of a network-based selectivity that allows to target the same enzyme in the host and microbes with different outcomes, we focused on sphingosine-1-phosphate (S1P) lyase (SPL) of the sphingolipid metabolism as a potential candidate to uniquely induce anti-inflammatory and antifungal activities in CF. As a feasibility study, herein we show that interfering with S1P metabolism improved the immune response in a murine model of CF with aspergillosis while preventing germination of Aspergillus fumigatus conidia. In addition, in an early drug discovery process, we purified human and A. fumigatus SPL, characterized their biochemical and structural properties, and performed an in silico screening to identify potential dual species SPL inhibitors. We identified two hits behaving as competitive inhibitors of pathogen and host SPL, thus paving the way for hit-to-lead and translational studies for the development of drug candidates capable of restraining fungal growth and increasing antifungal resistance.

The aromatic amino acid L-tryptophan (Trp) is essentially metabolized along the host and microbial pathways. While much is known about the role played by downstream metabolites of each pathways in intestinal homeostasis, their role in lung immune homeostasis is underappreciated. Here we have examined the role played by the Trp hydroxylase/5-hydroxytryptamine (5-HT) pathway in calibrating host and microbial Trp metabolism during Aspergillus fumigatus pneumonia. We found that 5-HT produced by mast cells essentially contributed to pathogen clearance and immune homeostasis in infection by promoting the host protective indoleamine-2,3-dioxygenase 1/kynurenine pathway and limiting the microbial activation of the indole/aryl hydrocarbon receptor pathway. This occurred via regulation of lung and intestinal microbiota and signaling pathways. 5-HT was deficient in the sputa of patients with Cystic fibrosis, while 5-HT supplementation restored the dysregulated Trp partitioning in murine disease. These findings suggest that 5-HT, by bridging host-microbiota Trp partitioning, may have clinical effects beyond its mood regulatory function in respiratory pathologies with an inflammatory component.

ObjectiveImmunotherapeutic inhibition of PD-1 by systemically administered monoclonal antibodies is widely used in cancer treatment, but it may cause severe immune-related adverse events (irSAEs). Neoadjuvant PD-1 inhibition before surgery has shown promise in reducing recurrence by stimulating durable antitumor immunity. Local intratumoral (IT) immunotherapy is a potential strategy to minimize irSAEs, but antibodies have limited tumor penetration, making them less suitable for this approach. Therapeutic self-delivering RNAi (INTASYL) is an emerging modality well-suited for neoadjuvant immunotherapy. This study presents preclinical proof-of-concept for PH-762, an INTASYL designed to silence PD-1, currently in clinical development for advanced cutaneous malignancies (ClinicalTrials.gov#NCT06014086).Methods and analysisPH-762 pharmacology was characterized in vitro, and in vivo antitumor efficacy was evaluated using a murine analogue (mPH-762) in syngeneic tumor models with varying PD-1 responsiveness. Bilateral Hepa1-6 models assessed abscopal effects of local treatment. Ex vivo analyses explored mechanisms of direct and abscopal efficacy.ResultsPH-762 was rapidly internalized by human T cells, silencing PD-1 mRNA and decreasing PD-1 surface protein, enhancing TCR-stimulated IFN-γ and CXCL10 secretion. In vivo, IT mPH-762 provided robust antitumor efficacy, local and lymphatic biodistribution, and was well tolerated. Ex vivo analyses revealed that IT mPH-762 depleted PD-1 protein, promoted leukocyte and T cell infiltration, and correlated with tumor control. IT mPH-762 also demonstrated efficacy against untreated distal tumors (abscopal effect) by priming systemic antitumor immunity.ConclusionThese data support PH-762 as a promising candidate for neoadjuvant immunotherapy in clinical studies.

Background: Hymenoptera venom allergy is a public health issue and has an undeniable impact on quality of life. Allergen immunotherapy (AIT) has shown long-term efficacy in this severe and potentially lethal allergy. However, no biomarker can predict the effectiveness of this treatment. Objectives: We evaluated the contribution of IgE blocking activity, a functional biomarker carried out in our center using flow cytometry, to predict the efficacy of AIT. Methods: This retrospective study from 1985 to 2022 describes in detail the demographic, clinical, and biological characteristics of patients who benefited from AIT with Hymenoptera venom at the University Hospital of Limoges. The outcome measure used was the presence of anaphylactic reaction (grade I to IV according to Ring and Messmer) in case of a new sting after discontinuation of AIT. Results: Our study, mainly composed of patients allergic to Vespula wasp venom, did not emphasize the interest of IgE blocking activity in the prediction of a relapse after a new sting. However, this inhibition showed a significant correlation with the amount of IgG4 antibodies. Conclusion: There is no biomarker that can help make the decision of stopping AIT. However, low levels of IgE blocking activity may suggest a likelihood of relapse. Serum IgG4, in correlation with IgE blocking activity, could be useful for monitoring treatment response. Additional studies are necessary to gain a thorough understanding of the composition of inhibitory antibodies.

Moving from the earlier periods in which the lungs were believed to represent sterile environments, our knowledge on the lung microbiota has dramatically increased, from the first descriptions of the microbial communities inhabiting the healthy lungs and the definition of the ecological rules that regulate its composition, to the identification of the changes that occur in pathological conditions. Despite the limitations of lung as a microbiome reservoir due to the low microbial biomass and abundance, defining its microbial composition and function in the upper and lower airways may help understanding the impact on local homeostasis and its disruption in lung diseases. In particular, the understanding of the metabolic and immune significance of microbes, their presence or lack thereof, in health and disease states could be valuable in development of novel druggable targets in disease treatments. Next-generation sequencing has identified intricate inter-microbe association networks that comprise true mutualistic or antagonistic direct or indirect relationships in the respiratory tract. In this review, the tripartite interaction of bacteria, fungi and the mammalian host is addressed to provide an integrated view of the microbial-host cross-talk in lung health and diseases from an immune and metabolic perspective.

The environmental light/dark cycle has left its mark on the body's physiological functions to condition not only our inner biology, but also the interaction with external cues. In this scenario, the circadian regulation of the immune response has emerged as a critical factor in defining the host-pathogen interaction and the identification of the underlying circuitry represents a prerequisite for the development of circadian-based therapeutic strategies. The possibility to track down the circadian regulation of the immune response to a metabolic pathway would represent a unique opportunity in this direction. Herein, we show that the metabolism of the essential amino acid tryptophan, involved in the regulation of fundamental processes in mammals, is regulated in a circadian manner in both murine and human cells and in mouse tissues. By resorting to a murine model of pulmonary infection with the opportunistic fungus Aspergillus fumigatus, we showed that the circadian oscillation in the lung of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO)1, generating the immunoregulatory kynurenine, resulted in diurnal changes in the immune response and the outcome of fungal infection. In addition, the circadian regulation of IDO1 drives such diurnal changes in a pre-clinical model of cystic fibrosis (CF), an autosomal recessive disease characterized by progressive lung function decline and recurrent infections, thus acquiring considerable clinical relevance. Our results demonstrate that the circadian rhythm at the intersection between metabolism and immune response underlies the diurnal changes in host-fungal interaction, thus paving the way for a circadian-based antimicrobial therapy.

Introducción: Los desórdenes gastrointestinales funcionales son entidades comunes en niños y adolescentes a nivel mundial e intervienen en la calidad de vida del paciente y su familia. Objetivo: Determinar la frecuencia de los desórdenes gastrointestinales funcionales en adolescentes preuniversitarios. Métodos: Estudio observacional, descriptivo de corte transversal, en 259 adolescentes, perteneciente al preuniversitario José Martí. Las variables utilizadas fueron edad, sexo, rasgo fenotípico de la piel, antecedentes personales de dengue, primogénito, padres separados, hijo único, prematuridad y nacimiento por cesárea. Se utilizó el Cuestionario para síntomas digestivos pediátricos, basado en los criterios de Roma IV. Para el análisis estadístico se utilizaron porcentajes, promedio, el estadígrafo ji cuadrado de Pearson y se calculó el odds ratio. Se tuvo en cuenta un intervalo de confianza del 95 % y p< 0,05. Resultados: Un total de 78 (30,1 %) adolescentes cumplieron los criterios diagnósticos de Roma IV para algún desorden gastrointestinal funcional. Se encontró predominio de los adolescentes de 17 años (38,5 %) y del sexo femenino (40,3 %). El estreñimiento funcional se diagnosticó en el 14,3 % de los adolescentes, seguido de la dispepsia funcional (12 %). Conclusiones: Los desórdenes con mayor frecuencia encontrados, fueron los trastornos de dolor abdominal funcional y de la defecación, entre los que se encuentra el estreñimiento funcional y la dispepsia funcional como los más diagnosticados, con predominio en los adolescentes del sexo femenino, de color de la piel negra y padres separados.

Background: The capsule formulation of CDK4/6 inhibitor palbociclib has reduced solubility at gastric pH > 4.5 and may have decreased activity when used with proton-pump inhibitors (PPI). Herein, we report the effect of PPI on palbociclib capsule activity and safety in the PARSIFAL study. Methods: First-line endocrine-sensitive, hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) patients received palbociclib capsules plus fulvestrant or letrozole. The primary endpoint was progression-free survival (PFS). This post-hoc analysis compared PPI use. Patients were PPI-naïve (N-PPI) if not on PPI during the study, and either early (E-PPI) or long-term PPI (LT-PPI) if on PPI at study entry or for at least ≥⅔ of treatment, respectively. PPI groups were not mutually exclusive. Results: Among 486 patients, 66.9 % were N-PPI, 13.2 % E-PPI, 18.7 % LT-PPI, and 11.5 % of the PPI users were defined as neither. Median PFS (mPFS) was 29.6 months in the study population, 28.7 months in N-PPI, 23.0 months in E-PPI (Hazard Ratio [HR] 1.5; 95%Confidence Interval [CI] 1.1–2.2; p = 0.024), and 23.0 months in LT-PPI (HR 1.4; 95%CI 1.0–1.9; p = 0.035). By landmark analysis, PPI use was associated with poorer mPFS at 3 and 12 months. Grade ≥3 hematological adverse events occurred in 71.7 % of N-PPI, 57.8 % of E-PPI (p = 0.021), and 54.9 % of LT-PPI (p = 0.003). Dose reductions and dosing delays due to hematological toxicity occurred in 70.8 % of N-PPI, 56.3 % of E-PPI (p = 0.018), and 52.7 % of LT-PPI (p = 0.002). Conclusions: PPI use may reduce palbociclib capsule toxicity, dose modifications, and clinical activity in HR+/HER2- ABC.

In this article, we propose a method exploiting irregular and unaligned Sentinel-2 satellite image time series (SITS) for large-scale land cover pixel-based classification. We perform end-to-end learning by combining a time and space informed kernel interpolator with a sparse variational Gaussian processes (SVGP) classifier. The interpolator embeds irregular and unaligned SITS onto a fixed and reduced size latent representation. The spatial information is taken into account by using a spatial positional encoding. The obtained latent representation is given to the SVGP classifier and all the parameters are jointly optimized w.r.t. the classification task. We run experiments with irregular and unaligned Sentinel-2 SITS of the full year 2018 over an area of 200 000 $\text{km}^{2}$ (about two billion pixels) in the south of France (27 MGRS tiles). Such experimental condition exacerbates the irregular and unaligned issues of SITS. In terms of overall accuracy, with the learned latent representation instead of linearly interpolated SITS, the results of the SVGP classifier are improved by about 10 points. Moreover, with the learned latent representation, the SVGP classifier outperforms the main state-of-the-art methods from the literature at large scale (e.g., seven points for the multilayer perceptron) and is robust to the available timestamps used for training and testing.

Thermomechanical modeling of additively manufactured parts made by laser powder bed fusion aims to control stresses and distortions built during processing. This is, by nature, a multiscale metallurgical and mechanical problem, notably due to the strong texture of the grain structure that results from the process and may locally dictate the thermomechanical behavior law. Similarly, stresses and distortions are directly influenced by the heat transfer process at the system scale, including the consequences of the link between the part and the substrate and the weaker interactions with the powder bed and the gas environment. To achieve relevant modeling, we first demonstrate capabilities to assess at part scale, both i- the prediction of the grain structure and ii- the thermomechanical analyses. A discussion follows that summarizes the foreseen directions to achieve coupling and/or chaining between grain structure simulations and mechanical analyses at part scale.

Summary: When exposed to sensory sequences, do macaque monkeys spontaneously form abstract internal models that generalize to novel experiences? Here, we show that neuronal populations in macaque ventrolateral prefrontal cortex jointly encode visual sequences by separate codes for the specific pictures presented and for their abstract sequential structure. We recorded prefrontal neurons while macaque monkeys passively viewed visual sequences and sequence mismatches in the local-global paradigm. Even without any overt task or response requirements, prefrontal populations spontaneously form representations of sequence structure, serial order, and image identity within distinct but superimposed neuronal subspaces. Representations of sequence structure rapidly update following single exposure to a mismatch sequence, while distinct populations represent mismatches for sequences of different complexity. Finally, those representations generalize across sequences following the same repetition structure but comprising different images. These results suggest that prefrontal populations spontaneously encode rich internal models of visual sequences reflecting both content-specific and abstract information.

Abstract Cystic fibrosis (CF) is an autosomal recessive disorder characterized by respiratory failure due to a vicious cycle of defective Cystic Fibrosis Transmembrane conductance Regulator (CFTR) function, chronic inflammation and recurrent bacterial and fungal infections. Although the recent introduction of CFTR correctors/potentiators has revolutionized the clinical management of CF patients, resurgence of inflammation and persistence of pathogens still posit a major concern and should be targeted contextually. On the background of a network-based selectivity that allows to target the same enzyme in the host and microbes with different outcomes, we focused on sphingosine-1-phosphate (S1P) lyase (SPL) of the sphingolipid metabolism as a potential candidate to uniquely induce anti-inflammatory and antifungal activities in CF. As a feasibility study, herein we show that interfering with S1P metabolism improved the immune response in a murine model of CF with aspergillosis while preventing germination of Aspergillus fumigatus conidia. In addition, in an early drug discovery process, we purified human and A. fumigatus SPL, characterized their biochemical and structural properties, and performed an in silico screening to identify potential dual species SPL inhibitors. We identified two hits behaving as competitive inhibitors of pathogen and host SPL, thus paving the way for hit-to-lead and translational studies for the development of drug candidates capable of restraining fungal growth and increasing antifungal resistance.

PURPOSE: Palbociclib is a cyclin-dependent kinase 4 and 6 inhibitor approved for advanced breast cancer. In the adjuvant setting, the potential value of adding palbociclib to endocrine therapy for hormone receptor-positive breast cancer has not been confirmed. PATIENTS AND METHODS: In the prospective, randomized, phase III PALLAS trial, patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer were randomly assigned to receive 2 years of palbociclib (125 mg orally once daily, days 1-21 of a 28-day cycle) with adjuvant endocrine therapy or adjuvant endocrine therapy alone (for at least 5 years). The primary end point of the study was invasive disease-free survival (iDFS); secondary end points were invasive breast cancer-free survival, distant recurrence-free survival, locoregional cancer-free survival, and overall survival. RESULTS: Among 5,796 patients enrolled at 406 centers in 21 countries worldwide over 3 years, 5,761 were included in the intention-to-treat population. At the final protocol-defined analysis, at a median follow-up of 31 months, iDFS events occurred in 253 of 2,884 (8.8%) patients who received palbociclib plus endocrine therapy and in 263 of 2,877 (9.1%) patients who received endocrine therapy alone, with similar results between the two treatment groups (iDFS at 4 years: 84.2% v 84.5%; hazard ratio, 0.96; CI, 0.81 to 1.14; P = .65). No significant differences were observed for secondary time-to-event end points, and subgroup analyses did not show any differences by subgroup. There were no new safety signals for palbociclib in this trial. CONCLUSION: At this final analysis of the PALLAS trial, the addition of adjuvant palbociclib to standard endocrine therapy did not improve outcomes over endocrine therapy alone in patients with early hormone receptor-positive breast cancer.

Background: Neutralizing antibodies targeting the SARS-CoV-2 Spike protein reduce COVID-19-related risk of hospitalization, particularly in high-risk individuals. The COCOPREV-R study aimed to evaluate and compare clinical outcomes in high-risk SARS-CoV-2 patients treated with dual monoclonal antibody therapies and to identify associated virological factors. Methods: The COCOPREV-R study retrospectively collected real-world data from high-risk patients receiving Bamlanivimab/Etesevimab or Casirivimab/Imdevimab dual monoclonal antibody therapies (22 February 2021 to 15 June 2021). Results: The study included 1004 patients with COVID-19, of whom 691 received Bamlanivimab/Etesevimab and 313 received Casirivimab/Imdevimab. The alpha variant represented 90.1% of those for whom data were available. The risk of hospitalization within 30 days was lower with Bamlanivimab/Etesevimab (12.7%, CI 95% [9.9–16.3%]) compared to Casirivimab/Imdevimab (28.4%, CI 95% [22.7–35.1%) (p < 0.001). The 30-day mortality rates were comparable between both groups (p = 0.982). Analysis of SARS-CoV-2 PCR negativity showed no difference between the two treatment groups (95.2% [93.0–96.9%] and 93.5% [89.1–96.6%] until day 30, p = 0.851 for Bamlanivimab/Etesevimab and Casirivimab/Imdevimab, respectively). Among persistently positive samples with available sequencing results (n = 43), Spike protein changes occurred only in Bamlanivimab/Etesevimab (42.9%) vs. Casirivimab/Imdevimab (0.0%) groups. Q493R (25.0%) and E484K (12.5%) were the most common mutations selected by Bamlanivimab/Etesevimab in follow-up samples. Other factors (immunodepression, comorbidities, and age) did not appear to be associated with the occurrence of Spike protein mutations. Conclusions: A higher rate of hospitalization was seen with Casirivimab/Imdevimab (RONAPREVE®) in comparison with Bamlanivimab/Etesevimab treatment, but with the emergence of Spike mutations only in the Bamlanivimab/Etesevimab group.

Aspergillus fumigatus is an environmental fungus recently included in the fungal high-priority pathogens by the World Health Organization. While immunodeficiency and/or pre-existing lung damage represent a well-recognized fertile ground for fungal growth, it is increasingly being recognized that severe viral infections may similarly favor A. fumigatus colonization and infection, as recently experienced in the Coronavirus disease 2019 (COVID-19) pandemic. Herein, in a murine model of COVID-19-associated pulmonary aspergillosis (CAPA), obtained by the concomitant exposure to the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike protein and A. fumigatus conidia, we found that the microbial compound indole-3-aldehyde (3-IAld) was able to ameliorate CAPA by working at multiple levels during viral infection and fungal superinfection, including epithelial barrier protection, promotion of antiviral responses, and limiting viral replication. As a consequence, 3-IAld limited the pathogenic sequelae of fungal superinfection as revealed by the controlled fungal burden and restrained inflammatory pathology. These results point to indole compounds as potential agents to prevent CAPA.

Abstract The aromatic amino acid L-tryptophan (Trp) is essentially metabolized along the host and microbial pathways. While much is known about the role played by downstream metabolites of each pathways in intestinal homeostasis, their role in lung immune homeostasis is underappreciated. Here we have examined the role played by the Trp hydroxylase/5-hydroxytryptamine (5-HT) pathway in calibrating host and microbial Trp metabolism during Aspergillus fumigatus pneumonia. We found that 5-HT produced by mast cells essentially contributed to pathogen clearance and immune homeostasis in infection by promoting the host protective indoleamine-2,3-dioxygenase 1/kynurenine pathway and limiting the microbial activation of the indole/aryl hydrocarbon receptor pathway. This occurred via regulation of lung and intestinal microbiota and signaling pathways. 5-HT was deficient in the sputa of patients with Cystic fibrosis, while 5-HT supplementation restored the dysregulated Trp partitioning in murine disease. These findings suggest that 5-HT, by bridging host-microbiota Trp partitioning, may have clinical effects beyond its mood regulatory function in respiratory pathologies with an inflammatory component.

Introducción: La epigenética juega un papel fundamental en la prevención del sobrepeso/obesidad en los primeros 1000 días de la vida. Objetivo: Identificar la asociación entre factores epigenéticos prenatales, perinatales, postnatales y el desarrollo de sobrepeso/obesidad en los primeros 1000 días de vida. Métodos: Estudio de casos y controles en pacientes ingresados entre septiembre de 2022 y agosto de 2023. Las variables fueron: Sobrepeso/obesidad y eventos epigenéticos relacionados con los periodos prenatal, perinatal y postnatal. Para el análisis estadístico de los factores de riesgo se midió la fuerza de la asociación con el odds ratio (OR) y sus intervalos de confianza (IC 95 %). Resultados: Los menores de 2 años con antecedentes prenatales de aumento exagerado de peso de la madre durante la gestación tuvieron un riesgo 6 veces mayor de padecer la enfermedad (OR: 6,46). El consumo suplementos nutricionales prenatales (OR: 6,05), el bajo peso al nacer (OR: 5,39), la rápida ganancia de peso en la etapa de lactante (OR: 4,5) y la desnutrición o bajo peso al inicio de la gestación (OR: 3,54) fueron también factores de riesgo. Conclusiones: Existe una fuerte asociación entre la presencia de sobrepeso/obesidad durante los primeros 1000 días de la vida y el antecedente de ganancia exagerada de peso de la madre durante la gestación, no consumir suplementos nutricionales prenatales, el bajo peso al nacer, la rápida ganancia de peso en la etapa de lactante y la desnutrición materna al inicio de la gestación.

Conclusion: Not surprisingly, the treadmill CPX results is the greatest physiological response in our group. Despite being of short duration, the TUGT results in an increased physiological response.

Se propone una metodología para la delimitación de las áreas urbanas articuladas por ciudades medias en España. Con la referencia temporal 2000-2020, se trabaja sobre un conjunto de treinta y cuatro ciudades medias interiores. El criterio de partida es el de accesibilidad, tomando la referencia de la isócrona de veinte minutos. Sobre el análisis de seis indicadores –tasa de variación de suelo urbanizado, de vivienda, y de población, índice de juventud, de población activa agraria y de población de servicios– se genera el Índice de Transformación Urbana (ITU), apoyado en el uso de técnicas multicriterio y de cartografía analítica. Se establecen tipologías de áreas urbanas según la dinámica de transformación observada (alta, media y baja) y, en cada área, se identifica el alcance, intensidad y gradación de los procesos de dispersión urbana.

ABSTRACTBacterial colonization in the gut plays a pivotal role in neonatal necrotizing enterocolitis (NEC) development, but the relationship between bacteria and NEC remains unclear. In this study, we aimed to elucidate whether bacterial butyrate end-fermentation metabolites participate in the development of NEC lesions and confirm the enteropathogenicity of Clostridium butyricum and Clostridium neonatale in NEC. First, we produced C.butyricum and C.neonatale strains impaired in butyrate production by genetically inactivating the hbd gene encoding β-hydroxybutyryl-CoA dehydrogenase that produces end-fermentation metabolites. Second, we evaluated the enteropathogenicty of the hbd-knockout strains in a gnotobiotic quail model of NEC. The analyses showed that animals harboring these strains had significantly fewer and less intense intestinal lesions than those harboring the respective wild-type strains. In the absence of specific biological markers of NEC, the data provide original and new mechanistic insights into the disease pathophysiology, a necessary step for developing potential novel therapies.

Plasma ctDNA is a promising method to determine patient outcome in multiple cancer types. Here, the authors use shallow WGS to create machine learning signatures to identify tumor phenotypes and predict therapy response in patients with metastatic breast cancer.

Background: Breast cancer is the most common malignancy and the second leading cause of cancer-related mortality in Spanish women. Ribociclib in combination with endocrine therapy (ET) has shown superiority in prolonging survival in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC) vs. ET alone. Methods: CompLEEment-1 is a single-arm, open-label phase 3b trial evaluating ribociclib plus letrozole in a broad population of patients with HR+, HER2– ABC. The primary endpoints were safety and tolerability. Here we report data for Spanish patients enrolled in CompLEEment-1. Results: A total of 526 patients were evaluated (median follow-up: 26.97 months). Baseline characteristics showed a diverse population with a median age of 54 years. At study entry, 56.5% of patients had visceral metastases and 8.7% had received prior chemotherapy for advanced disease. Rates of all-grade and Grade ≥3 adverse events (AEs) were 99.0% and 76.2%, respectively; 21.3% of patients experienced a serious AE, and 15.8% of AEs led to treatment discontinuation. AEs of special interest of neutropenia, increased alanine aminotransferase, increased aspartate aminotransferase and QTcF prolongation occurred in 77.8%, 14.8%, 11.4% and 4.0% of patients, respectively. Patients aged >70 years experienced increased rates of all-grade and Grade ≥3 neutropenia and anemia. Efficacy results were consistent with the global study. Conclusions: Results from Spanish patients enrolled in CompLEEment-1 are consistent with global data showing efficacy and a manageable safety profile for ribociclib plus letrozole treatment in patients with HR+, HER2− ABC, including populations of interest (NCT02941926). Trial registration: ClinicalTrials.gov NCT02941926

In this work, the effect of thermal annealing on silver nanoparticles@polymer (AgNPs@polymer) nanocomposite coatings was investigated. These photo-generated metallized coatings have a spatial distribution of metal nanoparticles, with a depth-wise decrease in their concentration. During annealing, both structural and morphological variations, as well as a spatial reorganization of AgNPs, were observed, both at the surface and in the core of the AgNPs@polymer coating. Owing to their increased mobility, the polymer chains reorganize spontaneously, and, at the same time, a hopping diffusion process, caused by the minimization of the surface energy, promotes the migration and coalescence of the silver nanoparticles towards the surface. The layer of discrete nanoparticles gradually transforms from a weakly percolative assembly to a denser and more networked structure. Consequently, the surface of the coatings becomes significantly more electrically conductive, hydrophobic, and reflective. The general trend is that the thinner the nanohybrid coating, the more pronounced the effect of thermal annealing on its spatial reorganization and properties. These results open up interesting prospects in the field of metallized coating technology and pave the way for integration into a wide variety of devices, e.g., efficient and inexpensive reflectors for energy-saving applications, electrically conductive microdevices, and printed electronic microcircuits.

CDK4/6 inhibitor resistance is common in breast cancer. Here, the authors show that p16 overexpression may be linked to reduced efficacy of CDK4/6 inhibition, and show that the combination with PI3K inhibitors may increase anti-tumour effects.

Cu2O offers a lot of potential for several optoelectronic applications. Here, the authors present a low temperature, fast and scalable approach to deposit Cu2O films with low resistivity, which is correlated to the defect landscape in the material.

Abstract The design and baseline data of the PRECISION study, which evaluates the effect of the dual endothelin receptor antagonist aprocitentan on blood pressure (BP) in patients with resistant hypertension (RHT) are presented. The study is a blinded, randomized, parallel‐group Phase 3 study and its three‐part design assesses the short‐term and sustained long‐term effects of aprocitentan on BP. Results are expected in 2022. Patients with uncontrolled BP (measured as unattended automated office BP) despite the use of three or more antihypertensive medications for at least 1 year were screened. They were switched to a single‐tablet triple fixed combination antihypertensive therapy for at least 4 weeks before entering a single‐blind placebo run‐in period. The 4‐week placebo run‐in period further excluded placebo responders. The randomization period consisted of three sequential parts: (1) a 4‐week double‐blind part with aprocitentan 12.5 mg, 25 mg, or placebo (1:1:1 ratio); (2) a 32‐week single‐blind part with aprocitentan 25 mg; and (3) a 12‐week randomized withdrawal part with aprocitentan 25 mg or placebo (1:1 ratio). The purpose was to demonstrate the BP lowering effect of aprocitentan in RHT (Part 1) and the persistence of this effect (Parts 2 and 3). Out of 1965 screened patients, 730 were randomized resulting in an overall inclusion failure rate of 62.8%. The most common reason for exclusion (44.4% of all screened patients) was failure to meet the BP inclusion criteria. These results underline the high proportion of pseudoresistant hypertension among patients referred for RHT.

ABSTRACT Metagenome analyses of the human microbiome suggest that horizontal gene transfer (HGT) is frequent in these rich and complex microbial communities. However, so far, only a few HGT studies have been conducted in vivo. In this work, three different systems mimicking the physiological conditions encountered in the human digestive tract were tested, including (i) the TNO gastro-Intestinal tract Model 1 (TIM-1) system (for the upper part of the intestine), (ii) the ARtificial COLon (ARCOL) system (to mimic the colon), and (iii) a mouse model. To increase the likelihood of transfer by conjugation of the integrative and conjugative element studied in the artificial digestive systems, bacteria were entrapped in alginate, agar, and chitosan beads before being placed in the different gut compartments. The number of transconjugants detected decreased, while the complexity of the ecosystem increased (many clones in TIM-1 but only one clone in ARCOL). No clone was obtained in a natural digestive environment (germfree mouse model). In the human gut, the richness and diversity of the bacterial community would offer more opportunities for HGT events to occur. In addition, several factors (SOS-inducing agents, microbiota-derived factors) that potentially increase in vivo HGT efficiency were not tested here. Even if HGT events are rare, expansion of the transconjugant clones can happen if ecological success is fostered by selecting conditions or by events that destabilize the microbial community. IMPORTANCE The human gut microbiota plays a key role in maintaining normal host physiology and health, but its homeostasis is fragile. During their transit in the gastrointestinal tract, bacteria conveyed by food can exchange genes with resident bacteria. New traits acquired by HGT (e.g., new catabolic properties, bacteriocins, antibiotic resistance) can impact the gut microbial composition and metabolic potential. We showed here that TIM-1, a system mimicking the upper digestive tract, is a useful tool to evaluate HGT events in conditions closer to the physiological ones. Another important fact pointed out in this work is that Enterococcus faecalis is a good candidate for foreign gene acquisition. Due to its high ability to colonize the gut and acquire mobile genetic elements, this commensal bacterium could serve as an intermediate for HGT in the human gut.

Compositionally graded Fe–Pt thin films were prepared on stationary 100 mm Si substrates by magnetron sputtering a base target of Fe on which a piece of Pt is asymmetrically positioned. Energy dispersive X-ray analysis was used to map the variation in film composition across the substrate, as a function of the size of the Pt piece. A scanning polar Magneto-Optical-Kerr-Effect system was used to probe the influence of composition and post-deposition annealing conditions (temperature and time) on coercivity. In this way, the maximum coercivity achievable for the sputtering system used could be established in a high throughput fashion. The evolution in coercivity with composition was correlated with the formation of L10 FePt and changes in its lattice parameters, as determined by scanning X-ray diffraction. High throughput coercivity mapping was then carried out on homogeneous Fe–Pt thin films of different compositions treated to different annealing conditions. This study serves as a step towards the integration of coercive FePt films into collectively fabricated devices.

Neuronal PAS domain protein 2 (NPAS2) is a hemeprotein comprising a basic helix–loop–helix domain (bHLH) and two heme-binding sites, the PAS-A and PAS-B domains. This protein acts as a pyridine nucleotide-dependent and gas-responsive CO-dependent transcription factor and is encoded by a gene whose expression fluctuates with circadian rhythmicity. NPAS2 is a core cog of the molecular clockwork and plays a regulatory role on metabolic pathways, is important for the function of the central nervous system in mammals, and is involved in carcinogenesis as well as in normal biological functions and processes, such as cardiovascular function and wound healing. We reviewed the scientific literature addressing the various facets of NPAS2 and framing this gene/protein in several and very different research and clinical fields.

Abstract In this work, a deep insight is given into the dielectric properties and the humidity response of flexible polymer matrices, composed of polyvinyl alcohol (PVA) and glycerol (Gly), using silver nanowire networks as transparent electrodes (AgNW TE). These electrodes, known for their high electrical conductivity, optical transparency, and excellent flexibility, are deposited here by open‐air, scalable spray coating technique. Analysis of the dielectric constant ε′ and loss tangent tanδ according to the density of the AgNWs shows that the latter do not cover the entire surface with PVA and induces an interfacial polarization effect. Wide frequency range of impedance spectroscopy (1 Hz to 1 MHz) on both, PVA‐Gly samples with AgNW TE (4 Ω sq−1) networks electrodes and sputtered silver electrodes (Ag bulk el), reveal no significant change in ε′ and tanδ. Finally, the humidity sensing properties of PVA‐Gly exhibit good response between 20% to 90% humidity range and low hysteresis. This is related to the non‐continuous structure of AgNW TE. At 100 Hz, the PVA‐10 wt% Gly presents high sensitivity of 0.08 nF/% RH with an hysteresis value of about 1.5% at 70% RH. These results indicate that AgNW networks show great potential for integration in transparent and flexible humidity sensors.

PurposeTo describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.MethodsGuided by phenotypic information, three children with negative WES underwent targeted single-gene testing.ResultsIndividual 1 had a clinical diagnosis consistent with infantile systemic hyalinosis, although WES and a next-generation sequencing (NGS)-based ANTXR2 test were negative. Sanger sequencing of ANTXR2 revealed a homozygous single base pair insertion, previously missed by the WES variant caller software. Individual 2 had neurodevelopmental regression and cerebellar atrophy, with no diagnosis on WES. New clinical findings prompted Sanger sequencing and copy number testing of PLA2G6. A novel homozygous deletion of the noncoding exon 1 (not included in the WES capture kit) was detected, with extension into the promoter, confirming the clinical suspicion of infantile neuroaxonal dystrophy. Individual 3 had progressive ataxia, spasticity, and magnetic resonance image changes of vanishing white matter leukoencephalopathy. An NGS leukodystrophy gene panel and WES showed a heterozygous pathogenic variant in EIF2B5; no deletions/duplications were detected. Sanger sequencing of EIF2B5 showed a frameshift indel, probably missed owing to failure of alignment.ConclusionThese cases illustrate potential pitfalls of WES/NGS testing and the importance of phenotype-guided molecular testing in yielding diagnoses.