BRAF mutational status is associated with survival outcomes in locally advanced resectable and metastatic NSCLC.

BACKGROUND: Immunotherapy-based treatments have demonstrated high efficacy in patients with advanced and locally advanced non-small-cell lung cancer (NSCLC). BRAF mutations affect a small but significant fraction of NSCLC. The efficacy of these therapies in this subgroup of patients is unknown. MATERIALS AND METHODS: Plasma and tissue samples from 116 resectable stage IIIA/B NSCLC patients, included in NADIM and NADIM II clinical trials (NADIM cohort), and from a prospective academic cohort with 84 stage IV NSCLC patients (BLI-O cohort), were analyzed by next-generation sequencing. RESULTS: The p.G464E, p.G466R, p.G466V, p.G469V, p.L597Q, p.T599I, p.V600E (n = 2) BRAF mutations, were identified in four (3.45 %) samples from the NADIM cohort, all of which were cases treated with neoadjuvant chemoimmunotherapy (CH-IO), and four (4.76 %) samples from the BLI-O cohort, corresponding to cases treated with first-line immunotherapy (n = 2) or CH-IO (n = 2). All these patients were alive and had no evidence of disease at data cut-off. Conversely, patients with BRAF wild-type (wt) tumors in the BLI-O cohort had a median progression-free survival (PFS) of 5.49 months and a median overall survival (OS) of 12.00 months (P-LogRank = 0.013 and 0.046, respectively). Likewise, PFS and OS probabilities at 36 months were 60.5 % and 76.1 % for patients with BRAF-wt tumors in the NADIM cohort. The pathological complete response (pCR) rate after neoadjuvant CH-IO in patients with BRAF-positive tumors (n = 4) was 100 %, whereas the pCR rate in the BRAF-wt population was 44.3 % (RR: 2.26; 95 % CI: 1.78-2.85; P < 0.001). CONCLUSION: BRAF mutations may be a good prognostic factor for advanced and locally advanced NSCLC patients undergoing immunotherapy-based treatments.

Compounding one problem with another? A look at biodegradable microplastics.

Environmental concerns about microplastics (MPs) have motivated research of their sources, occurrence, and fate in aquatic and soil ecosystems. To mitigate the environmental impact of MPs, biodegradable plastics are designed to naturally decompose, thus reducing the amount of environmental plastic contamination. However, the environmental fate of biodegradable plastics and the products of their incomplete biodegradation, especially micro-biodegradable plastics (MBPs), remains largely unexplored. This comprehensive review aims to assess the risks of unintended consequences associated with the introduction of biodegradable plastics into the environment, namely, whether the incomplete mineralization of biodegradable plastics could enhance the risk of MBPs formation and thus, exacerbate the problem of their environmental dispersion, representing a potentially additional environmental hazard due to their presumed ecotoxicity. Initial evidence points towards the potential for incomplete mineralization of biodegradable plastics under both controlled and uncontrolled conditions. Rapid degradation of PLA in thermophilic industrial composting contrasts with the degradation below 50 % of other biodegradables, suggesting MBPs released into the environment through compost. Moreover, degradation rates of <60 % in anaerobic digestion for polymers other than PLA and PHAs suggest a heightened risk of MBPs in digestate, risking their spread into soil and water. This could increase MBPs and adsorbed pollutants' mobilization. The exact behavior and impacts of additive leachates from faster-degrading plastics remain largely unknown. Thus, assessing the environmental fate and impacts of MBPs-laden by-products like compost or digestate is crucial. Moreover, the ecotoxicological consequences of shifting from conventional plastics to biodegradable ones are highly uncertain, as there is insufficient evidence to claim that MBPs have a milder effect on ecosystem health. Indeed, literature shows that the impact may be worse depending on the exposed species, polymer type, and the ecosystem complexity.

Hyperkinetic Movement Disorder Caused by the Recurrent c.892C>T NACC1 Variant.

BACKGROUND: Genetic syndromes of hyperkinetic movement disorders associated with epileptic encephalopathy and intellectual disability are becoming increasingly recognized. Recently, a de novo heterozygous NACC1 (nucleus accumbens-associated 1) missense variant was described in a patient cohort including one patient with a combined mitochondrial oxidative phosphorylation (OXPHOS) deficiency. OBJECTIVES: The objective is to characterize the movement disorder in affected patients with the recurrent c.892C>T NACC1 variant and study the NACC1 protein and mitochondrial function at the cellular level. METHODS: The movement disorder was analyzed on four patients with the NACC1 c.892C>T (p.Arg298Trp) variant. Studies on NACC1 protein and mitochondrial function were performed on patient-derived fibroblasts. RESULTS: All patients had a generalized hyperkinetic movement disorder with chorea and dystonia, which occurred cyclically and during sleep. Complex I was found altered, whereas the other OXPHOS enzymes and the mitochondria network seemed intact in one patient. CONCLUSIONS: The movement disorder is a prominent feature of NACC1-related disease.

Evaluating hunting and capture methods for urban wild boar population management.

Wild ungulates are expanding in range and number worldwide leading to an urgent need to manage their populations to minimize conflicts and promote coexistence with humans. In the metropolitan area of Barcelona (MAB), wild boar is the main wildlife species causing a nuisance, from traffic accidents to health risks. Selective harvesting of specific sex and age classes and reducing anthropogenic food resources would be the most efficient approach to dealing with overpopulation. Nonetheless, there is a gap in knowledge regarding the age and sex selectivity of the capture methods currently applied in the MAB for wild boar population control. Thus, this study aimed to evaluate the performance and age and sex bias of different hunting and capture methods and the seasonal patterns in their performance (number of captured individuals per event). From February 2014 to August 2022, 1454 wild boars were captured in the MAB using drop net, teleanaesthesia, cage traps, night stalks, and drive hunting. We applied generalized linear models (GLM) to compare the performance of these methods for the total number of wild boars, the wild boars belonging to each age category (i.e., adult, yearling, and juvenile), and for each season. The studied capture methods showed age-class bias and sex bias in adults (>2 years). Drive hunting and drop net removed mainly adult females and yearlings (1-2 years), with drive hunting having the highest performance for adult males. Instead, cage traps and drop net were the best methods to capture juveniles (<1 year). Overall, global performance was higher in summer, decreasingly followed by autumn and spring, winter being the worst performing season. Wildlife managers and researchers should consider the different performance and sex and age bias of each hunting and capture method, as well as the associated public cost, to improve efficiency and achieve the best results in wild boar population management.

Magnetic anisotropy engineering in onion-structured metal oxide nanoparticles combining dual exchange coupling and proximity effects.

A series of exchange-coupled magnetic nanoparticles combining several magnetic phases in an onion-type structure were synthesized by performing a three-step seed-mediated growth process. Iron and cobalt precursors were alternatively decomposed in high-boiling-temperature solvents (288-310 °C) to successively grow CoO and Fe3-δO4 shells (the latter in three stages) on the surface of Fe3-δO4 seeds. The structure and chemical composition of these nanoparticles were investigated in depth by combining a wide panel of advanced techniques, such as scanning transmission electron microscopy (STEM), electron energy-loss spectroscopy-spectrum imaging (EELS-SI), 57Fe Mössbauer spectrometry, and X-ray circular magnetic dichroism (XMCD) techniques. The size of the nanoparticles increased progressively after each thermal decomposition step, but the crystal structure of core-shell nanoparticles was significantly modified during the growth of the second shell. Indeed, the antiferromagnetic CoO phase was progressively replaced by the CoFe2O4 ferrimagnet due to the concomitant processes of partial solubilization/crystallization and the interfacial cationic diffusion of iron. A much more complex chemical structure than that suggested by a simple size variation of the nanoparticles is thus proposed, namely Fe3-δO4@CoO-CoFe2O4@Fe3-δO4, where an intermediate Co-based layer was shown to progressively become a single, hybrid magnetic phase (attributed to proximity effects) with a reduction in the CoO amount. In turn, the dual exchange-coupling of this hybrid Co-based intermediate layer (with high anisotropy and ordering temperature) with the surrounding ferrite (core and outer shells) stabilized the particle moment well above room temperature. These effects allow for the production of Fe oxide-based magnetic nanoparticles with high effective anisotropy, thus revealing the potential of this strategy to design rare-earth-free permanent nanomagnets at room temperature.

Outcomes and clinical characteristics of the compassionate use of plitidepsin in COVID-19 patients with solid tumours, haematological malignancies or anti-CD20 antibody treatment.

OBJECTIVE: To study the effect of plitidepsin antiviral treatment in immunocompromised COVID-19 patients with underlying haematological malignancies or solid tumours, particularly those who have undergone anti-CD20 therapies. DESIGN: We conducted a retrospective observational study, involving 54 adults treated with plitidepsin on compassionate use as an antiviral drug. Our analysis compared outcomes between patients with solid tumours and those with haematological malignancies, and a cohort of cases treated or not with anti-CD20 monoclonal antibodies. RESULTS: Patients with a history of anti-CD20 therapies showed a prolonged time-to-negative RT-PCR for SARS-CoV-2 infection compared to non-treated patients (33 d (28;75) vs 15 (11;25); p = .002). Similar results were observed in patients with solid tumours in comparison to those with haematological malignancies (13 (10;16) vs 26 (17;50); p < .001). No serious adverse events were documented. CONCLUSIONS: Patients with haematological malignancies appear to be at a heightened risk for delayed SARS-CoV-2 clearance and subsequent clinical complications. These findings support plitidepsin as a well-tolerated treatment in this high-risk group. A phase II clinical trial (NCT05705167) is ongoing to evaluate plitidepsin as an antiviral drug in this population.KEY POINTSHaematological patients face an increased risk for severe COVID-19.Anti-CD20 therapies could increase fatal outcomes in COVID-19 patients.Persistent viral replication is increased in immunocompromised patients.Plitidepsin does not lead to new serious adverse events in immunocompromised patients.

Genética del TDAH en la práctica clínica / Genetics of ADHD in clinical practice

Resumen El trastorno por déficit de atención/hiperactividad (TDAH) es un trastorno del neurodesarrollo complejo y heterogéneo desde una perspectiva causal, clínica y pro nóstica. La investigación refleja su carácter multifactorial con un papel destacado de los factores genéticos. Los estudios poblacionales han señalado históricamente la implicación de numerosas variantes genéticas de escaso tamaño de efecto, las cuales por sí mismas apenas incre mentan el riesgo de TDAH y difícilmente justifican su ele vada heredabilidad. Muchas de ellas están presentes en más del 60% de la población general, lo que sugiere su pa pel modulador más que causal. No obstante, gracias a la irrupción de nuevas técnicas genéticas en los últimos 15 años, se están identificando un mayor número de casos con trastornos genéticos (muchos de ellos monogénicos), cuyas variantes genéticas explican por sí mismas la presencia del TDAH. El estudio detallado de los antecedentes personales y familiares, así como una exploración física completa, puede ayudar a identificar algunos de ellos. La identificación de la causa en este conjunto de casos tiene un valor crucial en el asesoramiento clínico, el consejo genético-familiar y la anticipación pronóstica, así como en la realización o evitación de estudios complementarios y en el diseño del plan terapéutico.

Abstract Attention-deficit/hyperactivity disorder (ADHD) is a complex and heterogeneous neurodevelopmental disor der from a causal, clinical and prognostic perspective. Research reflects its multifactorial nature with a promi nent role of genetic factors. Population studies have historically pointed to the involvement of numerous genetic variants of small effect size, which hardly by themselves increase the risk of presenting the disorder and hardly justify its high heritability. Many of them are present in more than 60% of the general population, suggesting their modulatory rather than causal role. However, after the irruption of new genetic techniques in the last 15 years, a greater number of cases are be ing identified with genetic disorders (many of them monogenic), whose genetic variants alone explain the presence of ADHD. A detailed study of the personal and family history, as well as a complete physical examination, can help to identify some of them. The identification of the cause in this group of cases has a crucial value in clinical counseling, genetic-familial counseling and prognostic anticipation, as well as in the performance or avoidance of complementary stud ies and in the design of the intervention plan.

"I heard it before or not": time-course of ERP response and behavioural correlates associated with false recognition memory.

Electrophysiological and behavioural correlates of true and false memories were examined in the Deese/Roediger-McDermont (DRM) paradigm. A mass univariate approach for analysing event-related potentials (ERP) in the temporal domain was used to examine the electrophysiological effects associated with this paradigm precisely (point-by-point) and without bias (data-driven). Behaviourally, true and false recognition did not differ, and the predicted DRM effect was observed, as false recognition of critical lures (i.e., new words semantically related to studied words) was higher than false alarms of new (unrelated) words. Neurally, an expected old/new effect was observed during the time-range of the late positive component (LPC) over left centro-parietal scalp electrodes. Furthermore, true recognition also evoked larger LPC amplitudes than false recognition over both left centro-parietal and fronto-central scalp electrodes. However, we did not observe LPC-related differences between critical lures and new words, nor between correct rejections of critical lures and new words. In contrast, correct rejections of critical lures were accompanied by higher activation of a sustained positive slow wave (SPSW) in right fronto-central electrodes beyond 1200 ms. This result reveals a key role of post-retrieval processes in recognition. Results are discussed in light of theoretical approaches to false memory in the DRM paradigm.

Nerve Injury Triggers Time-dependent Activation of the Locus Coeruleus, Influencing Spontaneous Pain-like Behavior in Rats.

BACKGROUND: Dynamic changes in neuronal activity and in noradrenergic locus coeruleus (LC) projections have been proposed during the transition from acute to chronic pain. Thus, the authors explored the cellular cFos activity of the LC and its projections in conjunction with spontaneous pain-like behavior in neuropathic rats. METHODS: Tyrosine hydroxylase:Cre and wild-type Long-Evans rats, males and females, were subjected to chronic constriction injury (CCI) for 2 (short-term, CCI-ST) or 30 days (long-term, CCI-LT), evaluating cFos and Fluoro-Gold expression in the LC, and its projections to the spinal cord (SC) and rostral anterior cingulate cortex (rACC). These tests were carried out under basal conditions (unstimulated) and after noxious mechanical stimulation. LC activity was evaluated through chemogenetic and pharmacologic approaches, as were its projections, in association with spontaneous pain-like behaviors. RESULTS: CCI-ST enhanced basal cFos expression in the LC and in its projection to the SC, which increased further after noxious stimulation. Similar basal activation was found in the neurons projecting to the rACC, although this was not modified by stimulation. Strong basal cFos expression was found in CCI-LT, specifically in the projection to the rACC, which was again not modified by stimulation. No cFos expression was found in the CCI-LT LCipsilateral (ipsi)/contralateral (contra)→SC. Chemogenetics showed that CCI-ST is associated with greater spontaneous pain-like behavior when the LCipsi is blocked, or by selectively blocking the LCipsi→SC projection. Activation of the LCipsi or LCipsi/contra→SC dampened pain-like behavior. Moreover, Designer Receptor Exclusively Activated by Designer Drugs (DREADDs)-mediated inactivation of the CCI-ST LCipsi→rACC or CCI-LT LCipsi/contra→rACC pathway, or intra-rACC antagonism of α-adrenoreceptors, also dampens pain-like behavior. CONCLUSIONS: In the short term, activation of the LC after CCI attenuates spontaneous pain-like behaviors via projections to the SC while increasing nociception via projections to the rACC. In the long term, only the projections from the LC to the rACC contribute to modulate pain-like behaviors in this model.

Breast cancer survivors suffering from lymphedema: What really do affect to corporeality/body image? A qualitative study.

Breast cancer-related lymphedema is currently one of the most serious complications that most affect the quality of life of women undergoing breast cancer. The aim of this study was to explore in-depth the experience of women who suffer from lymphoedema after breast cancer and how does this condition affect corporeality, with no judgements. For this purpose, a qualitative methodology was followed. In-depth interviews, interviewer's field notes and participants' letters were used for data collection. The participants were twenty Spanish women with lymphoedema after overcome a breast cancer in the past. Healthcare specialists with experience in the topic were also included. Results showed 2 main categories: "From cancer to lymphedema, another disease another disease" and "Potential for transition and transformation towards a new way of life". As a conclusion, the difficulty in accessing adequate treatment, the need for greater awareness of lymphedema and the importance of the emotional and psychological dimension of this chronic disease. Highlighting the attitudes that these women develop for self-care and the concept of new corporeality. After breast cancer, women with lymphedema experience a drastic change that affects all areas of their lives. The adaptation process, and the search for resources and aid, play a fundamental role in overcoming this process.

Fast quasi-null-filling of radiation patterns for multiple solutions generation.

Here we present an improved, rapid method for filling quasi-nulls in symmetrical radiation patterns synthesized by equispaced linear arrays, leading to the generation of multiple solutions. Considering the polynomial representation of the pattern, this null-filling is achieved by displacing the roots radially off the unit circle, keeping a constant displacement. This allows analyzing how the potential solutions vary with the quasi-uniform filling and the associated directivity loss. This method is based on the Cardano-Vieta relations, which link the coefficients of a complex Schelkunoff polynomial with its roots. As examples of application, we have considered a 20/100 element Dolph-Chebyshev pattern, with a spacing between the elements [Formula: see text], side lobe level of - 20/- 28 dB and three inner sidelobes at - 40/- 50 dB.

Strategies for livestock wastewater treatment and optimised nutrient recovery using microalgal-based technologies.

Global sustainable development faces several challenges in addressing the needs of a growing population. Regarding food industries, the heightening pressure to meet these needs has resulted in increased waste generation. Thus, recognising these wastes as valuable resources is crucial to integrating sustainable models into current production systems. For instance, the current 24 billion tons of nutrient-rich livestock wastewater (LW) generated yearly could be recovered and valorised via biological uptake through microalgal biomass. Microalgae-based livestock wastewater treatment (MbLWT) has emerged as an effective technology for nutrient recovery, specifically targeting carbon, nitrogen, and phosphorus. However, the viability and efficacy of these systems rely on the characteristics of LW, including organic matter and ammonium concentration, content of suspended solids, and microbial load. Thus, this systematic literature review aims to provide guidance towards implementing an integral MbLWT system for nutrient control and recovery, discussing several pre-treatments used in literature to overcome the challenges regarding LW as a suitable media for microalgae cultivation.

[Genetics of ADHD in clinical practice]. / Genética del TDAH en la práctica clínica.

Attention-deficit/hyperactivity disorder (ADHD) is a complex and heterogeneous neurodevelopmental disorder from a causal, clinical and prognostic perspective. Research reflects its multifactorial nature with a prominent role of genetic factors. Population studies have historically pointed to the involvement of numerous genetic variants of small effect size, which hardly by themselves increase the risk of presenting the disorder and hardly justify its high heritability. Many of them are present in more than 60% of the general population, suggesting their modulatory rather than causal role. However, after the irruption of new genetic techniques in the last 15 years, a greater number of cases are being identified with genetic disorders (many of them monogenic), whose genetic variants alone explain the presence of ADHD. A detailed study of the personal and family history, as well as a complete physical examination, can help to identify some of them. The identification of the cause in this group of cases has a crucial value in clinical counseling, genetic-familial counseling and prognostic anticipation, as well as in the performance or avoidance of complementary studies and in the design of the intervention plan.

El trastorno por déficit de atención/hiperactividad (TDAH) es un trastorno del neurodesarrollo complejo y heterogéneo desde una perspectiva causal, clínica y pronóstica. La investigación refleja su carácter multifactorial con un papel destacado de los factores genéticos. Los estudios poblacionales han señalado históricamente la implicación de numerosas variantes genéticas de escaso tamaño de efecto, las cuales por sí mismas apenas incrementan el riesgo de TDAH y difícilmente justifican su elevada heredabilidad. Muchas de ellas están presentes en más del 60% de la población general, lo que sugiere su papel modulador más que causal. No obstante, gracias a la irrupción de nuevas técnicas genéticas en los últimos 15 años, se están identificando un mayor número de casos con trastornos genéticos (muchos de ellos monogénicos), cuyas variantes genéticas explican por sí mismas la presencia del TDAH. El estudio detallado de los antecedentes personales y familiares, así como una exploración física completa, puede ayudar a identificar algunos de ellos. La identificación de la causa en este conjunto de casos tiene un valor crucial en el asesoramiento clínico, el consejo genético-familiar y la anticipación pronóstica, así como en la realización o evitación de estudios complementarios y en el diseño del plan terapéutico.

Experimental and computational biophysics to identify vasodilator drugs targeted at TRPV2 using agonists based on the probenecid scaffold.

TRP channels are important pharmacological targets in physiopathology. TRPV2 plays distinct roles in cardiac and neuromuscular function, immunity, and metabolism, and is associated with pathologies like muscular dystrophy and cancer. However, TRPV2 pharmacology is unspecific and scarce at best. Using in silico similarity-based chemoinformatics we obtained a set of 270 potential hits for TRPV2 categorized into families based on chemical nature and similarity. Docking the compounds on available rat TRPV2 structures allowed the clustering of drug families in specific ligand binding sites. Starting from a probenecid docking pose in the piperlongumine binding site and using a Gaussian accelerated molecular dynamics approach we have assigned a putative probenecid binding site. In parallel, we measured the EC50 of 7 probenecid derivatives on TRPV2 expressed in Pichia pastoris using a novel medium-throughput Ca2+ influx assay in yeast membranes together with an unbiased and unsupervised data analysis method. We found that 4-(piperidine-1-sulfonyl)-benzoic acid had a better EC50 than probenecid, which is one of the most specific TRPV2 agonists to date. Exploring the TRPV2-dependent anti-hypertensive potential in vivo, we found that 4-(piperidine-1-sulfonyl)-benzoic acid shows a sex-biased vasodilator effect producing larger vascular relaxations in female mice. Overall, this study expands the pharmacological toolbox for TRPV2, a widely expressed membrane protein and orphan drug target.

Insights into the early transcriptomic response against watermelon mosaic virus in melon.

BACKGROUND: Watermelon mosaic virus (WMV) is one of the most prevalent viruses affecting melon worldwide. Recessive resistance to WMV in melon has previously been reported in the African accession TGR-1551. Moreover, the genomic regions associated to the resistance have also been described. Nevertheless, the transcriptomic response that might infer the resistance to this potyvirus has not been explored. RESULTS: We have performed a comparative transcriptomic analysis using mock and WMV-inoculated plants of the susceptible cultivar "Bola de oro" (BO) and a resistant RIL (Recombinant inbred line) derived from the initial cross between "TGR-1551" and BO. In total, 616 genes were identified as differentially expressed and the weighted gene co-expression network analysis (WGCNA) detected 19 gene clusters (GCs), of which 7 were differentially expressed for the genotype x treatment interaction term. SNPs with a predicted high impact on the protein function were detected within the coding regions of most of the detected DEGs. Moreover, 3 and 16 DEGs were detected within the QTL regions previously described in chromosomes 11 and 5, respectively. In addition to these two specific genomic regions, we also observde large transcriptomic changes from genes spread across the genome in the resistant plants in response to the virus infection. This early response against WMV implied genes involved in plant-pathogen interaction, plant hormone signal transduction, the MAPK signaling pathway or ubiquitin mediated proteolysis, in detriment to the photosynthetic and basal metabolites pathways. Moreover, the gene MELO3C021395, which coded a mediator of RNA polymerase II transcription subunit 33A (MED33A), has been proposed as the candidate gene located on chromosome 11 conferring resistance to WMV. CONCLUSIONS: The comparative transcriptomic analysis presented here showed that, even though the resistance to WMV in TGR-1551 has a recessive nature, it triggers an active defense response at a transcriptomic level, which involves broad-spectrum resistance mechanisms. Thus, this study represents a step forward on our understanding of the mechanisms underlaying WMV resistance in melon. In addition, it sheds light into a broader topic on the mechanisms of recessive resistances.

Internet of Things and citizen science as alternative water quality monitoring approaches and the importance of effective water quality communication.

The increasing demand for water and worsening climate change place significant pressure on this vital resource, making its preservation a global priority. Water quality monitoring programs are essential for effectively managing this resource. Current programs rely on traditional monitoring approaches, leading to limitations such as low spatiotemporal resolution and high operational costs. Despite the adoption of novel monitoring approaches that enable better data resolution, the public's comprehension of water quality matters remains low, primarily due to communication process deficiencies. This study explores the advantages and challenges of using Internet of Things (IoT) and citizen science as alternative monitoring approaches, emphasizing the need for enhancing public communication of water quality data. Through a systematic review of studies implemented on-field, we identify and propose strategies to address five key challenges that IoT and citizen science monitoring approaches must overcome to mature into robust sources of water quality information. Additionally, we highlight three fundamental problems affecting the water quality communication process and outline strategies to convey this topic effectively to the public.