e-Repositori UPF :: Articles (Departament de Medicina i Ciències de la Vida)

Enviaments recents

The role of digital rectal examination for early detection of significant prostate cancer in the era of magnetic resonance imaging
(MDPI, 2024) Morote, Juan; Paesano, Nahuel; Picola, Natàlia; Muñoz-Rodríguez, Jesús; Ruiz Plazas, Xavier; Muñoz-Rivero, Marta V.; Celma, Anna; García de Manuel, Gemma; Miró, Berta; Abascal-Junquera, José María; Servian, Pol; Méndez, Olga; Trilla, Enrique
The role of digital rectal examination (DRE) in the early detection of significant prostate cancer (PCa) is being questioned in the era of magnetic resonance imaging (MRI). However, some men with suspected PCa may still be identified solely through DRE, even with low serum prostate-specific antigen (PSA) levels. Additionally, most predictive models designed to improve significant PCa diagnostic pathways incorporate DRE findings. We assessed the role of DRE among 5005 men with serum PSA levels > 3.0 ng/mL and/or suspicious DRE findings, who underwent pre-biopsy MRI and targeted and/or systematic biopsies, as part of the significant PCa opportunistic screening program in Catalonia (Spain) between 2016 and 2023. Significant PCa, defined as grade group > 2, was detected in 2097 men (41.9%). Suspicion of PCa was based solely on DRE in 206 cases (4.1%) with significant PCa detected in 50 of them (2.4%). Two pathways using the Barcelona predictive models, before and after MRI, with and without DRE findings showed specificities of 52.8 and 38.7%, respectively (p < 0.001), after fixing sensitivity at 90%. Prostate biopsy was avoided in 35.1 and 26.7%, respectively (p < 0.001), while its efficacy increased from 52.8 to 58%. We conclude that DRE improved the effectiveness of an opportunistic significant PCa-screening program.
Quantification supports amyloid PET visual assessment of challenging cases: results from the AMYPAD diagnostic and patient management study
(Society of Nuclear Medicine and Molecular Imaging, 2025) Collij, Lyduine E.; Gispert López, Juan Domingo; AMYPAD Consortium
Several studies have demonstrated strong agreement between routine clinical visual assessment and quantification, suggesting that quantification approaches could support assessment by less experienced readers or in challenging cases. However, all studies to date have implemented a retrospective case collection, and challenging cases were generally underrepresented. Methods: We included all participants (n = 741) from the AMYPAD diagnostic and patient management study with available baseline amyloid PET quantification. Quantification was done with the PET-only AmyPype pipeline, providing global Centiloid and regional z scores. Visual assessment was performed by local readers for the entire cohort. From the total cohort, we selected a subsample of 85 cases for which the amyloid status based on the local reader's visual assessment and the Centiloid classification (cutoff = 21) was discordant or that were assessed with low confidence (i.e., ≤3 on a 5-point scale) by the local reader. In addition, concordant negative (n = 8) and positive (n = 8) scans across tracers were selected. In this sample (n = 101 cases; [18F]flutemetamol, n = 48; [18F]florbetaben, n = 53), the visual assessments and corresponding confidence by 5 certified independent central readers were captured before and after disclosure of the quantification results. Results: For the whole AMYPAD diagnostic and patient management study cohort, overall assessment by local readers highly agreed with Centiloid status (κ = 0.85, 92.3% agreement). This was consistently observed within disease stages (subjective cognitive decline-plus, κ = 0.82, 92.3% agreement; mild cognitive impairment, κ = 0.80, 89.8% agreement; dementia, κ = 0.87, 94.6% agreement). Across all central reader assessments in the challenging subsample, quantification of global Centiloid and regional z scores was considered supportive of visual reads in 70.3% and 49.3% of assessments, respectively. After disclosure of the quantitative results, we observed improvement in concordance across the 5 readers (baseline κ = 0.65, 65.3% agreement; κ after disclosure = 0.74, 73.3% agreement) and a significant increase in reader confidence (baseline mean (M) = 4.0 vs. M after disclosure = 4.34, Wilcoxon statistic (W) = 101,056, P < 0.001). Conclusion: In this clinical study enriched for challenging amyloid PET cases, we demonstrate the value of quantification to support visual assessment. After disclosure, both interreader agreement and confidence showed significant improvement. These results are important considering the arrival of antiamyloid therapies, which used the Centiloid metric for trial inclusion and target engagement. Moreover, quantification could support determination of amyloid-β status with high certainty, an important factor for treatment initiation.
Risk factors and outcomes of ventilator-associated pneumonia in patients with traumatic brain injury: a systematic review and meta-analysis
(Elsevier, 2025) Prieto-Alvarado, Diego Enrique; Parada-Gereda, Henry M.; Molano Franco, Daniel; Martinez, Yamil Liscano; Rivas Tafurt, Giovanna Patricia; Masclans Enviz, Joan Ramon
Background: Ventilator-associated pneumonia (VAP) is a common complication in traumatic brain injury (TBI) patients, which increases morbidity and negatively affects outcomes. Risk factors and outcomes in these patients remain controversial. The aim of the present study is to explore the risk factors and clinical outcomes of patients with VAP and TBI. Methods: Two researchers conducted independent systematic literature searches of Pubmed, Cochrane Database, Scopus, Medline Ovid, Science Direct databases, published from inception to January 2024. The Newcastle-Ottawa scale was used to assess study quality. A meta-analysis was performed using a random-effects model when heterogeneity I2 > 50 % and a fixed-effects model when I2 < 50 %; in addition, a subgroup analysis was performed to explore VAP risk factors, and publication bias was assessed with the funnel plot and Begg's and Egger's tests. All results were considered statistically significant when p < 0.05. The certainty of the evidence was evaluated using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology. Results: Twelve studies were included in the meta-analysis with a total of 2883 patients. Male gender [OR 1.58 (95 % CI 1.23, 2.02) p < 0.05 I2 0 %] and abbreviated injury scale (head: H-AIS) [≥ 3 OR 2.79 (95 % CI 1.58, 4.93) p < 0.05 I2 0 %] increased the risk of VAP. After subgroup analysis, blood transfusion on admission [OR 1.97 (95 % CI 1.16-3.35) p ≤0.05 I2 5 %] and barbiturate infusion [OR 3.55 (95 % CI 2.01-6.30) p ≤0.05 I2 0 %] became risk factors. Prophylactic antibiotic use [OR 0.67 (95 % CI 0.51-0.88) p ≤0.05 I2 0 %] and younger age MD -3.29 (95 % CI -5.18, -1.40) p ≤0.05 I2 41 %] emerged as significant protective factors. In VAP patients ICU stay [MD 7.02 (95 % CI 6.05-7.99) p ≤0.05 I2 37 %], duration of mechanical ventilation [MD 5.79 (95 % CI 4.40, 7.18) p ≤0.05 I2 79 %] and hospital stay [MD 11.88 (95 % CI 8.71-15.05) p ≤0.05 I2 0 %] were significantly increased. The certainty of the evidence was moderate-high for the outcomes studied. Conclusions: Male gender, H-AIS ≥ 3, blood transfusion on admission, and barbiturate infusion were risk factors for VAP. In patients with VAP, ICU stay, duration of mechanical ventilation, hospital stay were significantly increased.
p53 efficiently suppresses tumor development in the complete absence of its cell-cycle inhibitory and proapoptotic effectors p21, Puma, and Noxa
(Elsevier, 2013) Valente, Liz J.; Gray, Daniel H. D.; Michalak, Ewa M.; Pinon-Hofbauer, Josefina; Egle, Alex; Scott, Clare L.; Janic, Ana; Strasser, Andreas
Activation of apoptosis through transcriptional induction of Puma and Noxa has long been considered to constitute the critical (if not sole) process by which p53 suppresses tumor development, although G1/S boundary cell-cycle arrest via induction of the CDK inhibitor p21 has also been thought to contribute. Recent analyses of mice bearing mutations that impair p53-mediated induction of select target genes have indicated that activation of apoptosis and G1/S cell-cycle arrest may, in fact, be dispensable for p53-mediated tumor suppression. However, the expression of Puma, Noxa, and p21 was not abrogated in these mutants, only reduced; therefore, the possibility that the reduced levels of these critical effectors of p53-mediated apoptosis and G1/S-cell-cycle arrest sufficed to prevent tumorigenesis could not be excluded. To resolve this important issue, we have generated mice deficient for p21, Puma, and Noxa (p21-/-puma-/-noxa-/- mice). Cells from these mice were deficient in their ability to undergo p53-mediated apoptosis, G1/S cell-cycle arrest, and senescence. Nonetheless, these animals remained tumor free until at least 500 days, in contrast to p53-deficient mice, which had all succumbed to lymphoma or sarcoma by 250 days. Interestingly, DNA lesions induced by y-irradiation persisted longer in p53-deficient cells compared to wild-type or p21-/-puma-/-noxa-/- cells, and the former failed to transcriptionally activate several p53 target genes implicated in DNA repair. These results demonstrate beyond a doubt that the induction of apoptosis, cell-cycle arrest, and possibly senescence is dispensable for p53-mediated suppression of spontaneous tumor development and indicate that coordination of genomic stability and possibly other processes, such as metabolic adaptation, may instead be critical.
Prenatal and postnatal alcohol exposure increases vulnerability to cocaine addiction in adult mice
(Wiley, 2020) Cantacorps Centellas, Lídia, 1991-; Montagud-Romero, Sandra; Luján Pérez, Miguel Ángel, 1991-; Valverde Granados, Olga
BACKGROUND AND PURPOSE: Alcohol exposure in utero may lead to a wide range of long-lasting morphological and behavioural deficiencies known as fetal alcohol spectrum disorders (FASD), associated with a higher risk of later developing neuropsychiatric disorders. However, little is known about the long-term consequences of cocaine use and abuse in individuals with FASD. This study aimed to investigate the effects of maternal binge alcohol drinking during prenatal and postnatal periods on cocaine reward-related behaviours in adult offspring. EXPERIMENTAL APPROACH: Pregnant C57BL/6 female mice were exposed to an experimental protocol of binge alcohol consumption (drinking-in-the-dark test) from gestation to weaning. Male offspring were subsequently left undisturbed until reaching adulthood and were tested for cocaine-induced motivational responses (conditioned place preference, behavioural sensitization and operant self-administration). Protein expression of dopamine- and glutamate-related molecules was assessed following cocaine-induced reinstatement. KEY RESULTS: The results show that prenatal and postnatal alcohol exposure enhanced the preference for the cocaine-paired chamber in the conditioned place preference test. Furthermore, early alcohol-exposed mice displayed attenuated cocaine-induced behavioural sensitization but also higher cocaine self-administration. Furthermore, alterations in glutamatergic excitability (GluA1/GluA2 ratio) and ¿FosB expression were found in the prefrontal cortex and the striatum of alcohol-exposed mice after cocaine-primed reinstatement. CONCLUSION AND IMPLICATIONS: Our findings demonstrate that maternal binge-like alcohol consumption during gestation and lactation alters sensitivity to the reinforcing effects of cocaine in adult offspring mice. Together, such data suggest that prenatal and postnatal alcohol exposure may underlie an enhanced susceptibility of alcohol-exposed offspring to develop drug addiction later in adulthood.
Behavioural and molecular effects of cannabidiolic acid in mice
(Elsevier, 2020) Alegre Zurano, Laia; Martín Sánchez, Ana; Valverde Granados, Olga
Background: cannabidiolic acid (CBDA) is one of the most abundant phytocannabinoid acids in the Cannabis Sativa plant. It has been shown to exert some therapeutic effects such as antiemetic, anti-inflammatory, anxiolytic or antidepressant, although some of them with controversy. Hypothesis/Purpose: assess the potential effects of CBDA on different behaviours and on the modulation of neuroinflammatory markers in the prefrontal cortex (PFC). Study Design: the effects of CBDA were evaluated on cognitive, emotional, motivational and nociceptive behaviours in male CD1 mice. Methods: acute and/or chronic CBDA treatment (0.001-1 mg/kg i.p.) was evaluated in cognitive, emotional and nociceptive behavioural models, using the Y-maze, spontaneous locomotor activity, social interaction test, elevated plus maze, hot-plate test, formalin test and tail-suspension test in mice. We also assessed the effects of CBDA on the rewarding responses of cocaine in the conditioned place preference paradigm. PFC was dissected after acute and chronic CBDA treatments to evaluate inflammatory markers. Results: acute CBDA induced antinociceptive effects in the hot plate test. A 10-days chronic CBDA treatment also showed an effect on despair-like behaviour in the tail suspension test. CBDA did not show any other effect in the remaining behavioural tests assayed, including the cocaine-induced conditioned place preference (CPP). Regarding the biochemical analysis, chronic CBDA treatment diminished peroxisome proliferator-activated receptor gamma (PPAR-γ) and increased interleukin-6 (IL-6) protein levels in PFC. Conclusion: these results show that CBDA has “in vivo” limited effects modulating mice behaviour and highlight the lack of agreement regarding its therapeutic potential.
The multiple functions of hindbrain boundary cells: Tinkering boundaries?
(Elsevier, 2020) Pujades Corbi, Cristina
Embryonic boundaries were first described in Drosophila, and then in vertebrate embryos, as cellular interfaces between compartments. They display signaling properties and in vertebrates might allocate cells fated to different anatomical structures, or cells that will play different functions over time. One of the vertebrate embryonic structures with boundaries is the hindbrain, the posterior brain vesicle, which is transitory segmented upon morphogenesis. The hindbrain is formed by iterative units called rhombomeres that constitute units of gene expression and cell-lineage compartments. Rhombomeric cells are segregated by interhombomeric boundaries, which are prefigured by sharp gene expression borders. Hindbrain boundaries were first described as static groups of cells. However, later discoveries demonstrated the dynamic behavior of this specific cell population. They play distinct functional properties during brain morphogenesis that partially overlap on time, starting as a mechanical barrier to prevent cell intermingling, becoming a signaling hub, to finally constitute a group of proliferating progenitors providing differentiated neurons to the system. In this review, I try to give a more functional overview of this segmentation process and in particular of hindbrain boundaries. I will discuss the new challenges in the field on how to integrate cell fate specification and morphogenesis during brain embryonic development.
Metabolomics in COPD
(Elsevier, 2023) Gea Guiral, Joaquim; Enríquez Rodríguez, César Jessé; Pascual Guàrdia, Sergi, 1979-
The clinical presentation of chronic obstructive pulmonary disease (COPD) is highly heterogeneous. Attempts have been made to define subpopulations of patients who share clinical characteristics (phenotypes and treatable traits) and/or biological characteristics (endotypes), in order to offer more personalized care. Assigning a patient to any of these groups requires the identification of both clinical and biological markers. Ideally, biological markers should be easily obtained from blood or urine, but these may lack specificity. Biomarkers can be identified initially using conventional or more sophisticated techniques. However, the more sophisticated techniques should be simplified in the future if they are to have clinical utility. The -omics approach offers a methodology that can assist in the investigation and identification of useful markers in both targeted and blind searches. Specifically, metabolomics is the science that studies biological processes involving metabolites, which can be intermediate or final products. The metabolites associated with COPD and their specific phenotypic and endotypic features have been studied using various techniques. Several compounds of particular interest have emerged, namely, several types of lipids and derivatives (mainly phospholipids, but also ceramides, fatty acids and eicosanoids), amino acids, coagulation factors, and nucleic acid components, likely to be involved in their function, protein catabolism, energy production, oxidative stress, immune-inflammatory response and coagulation disorders. However, clear metabolomic profiles of the disease and its various manifestations that may already be applicable in clinical practice still need to be defined.
Decoding p53 tumor suppression: a crosstalk between genomic stability and epigenetic control?
(Nature Research, 2025) Janic, Ana; Abad Cortel, Etna; Amelio, Ivano
Genomic instability, a hallmark of cancer, is a direct consequence of the inactivation of the tumor suppressor protein p53. Genetically modified mouse models and human tumor samples have revealed that p53 loss results in extensive chromosomal abnormalities, from copy number alterations to structural rearrangements. In this perspective article we explore the multifaceted relationship between p53, genomic stability, and epigenetic control, highlighting its significance in cancer biology. p53 emerges as a critical regulator of DNA repair mechanisms, influencing key components of repair pathways and directly participating in DNA repair processes. p53 role in genomic integrity however extends beyond its canonical functions. p53 influences also epigenetic landscape, where it modulates DNA methylation and histone modifications. This epigenetic control impacts the expression of genes involved in tumor suppression and oncogenesis. Notably, p53 ability to ensure cellular response to DNA demethylation contributes to the maintenance of genomic stability by preventing unscheduled transcription of repetitive non-coding genomic regions. This latter indicates a causative relationship between the control of epigenetic stability and the maintenance of genomic integrity in p53-mediated tumor suppression. Understanding these mechanisms offers promising avenues for innovative therapeutic strategies targeting epigenetic dysregulation in cancer and emphasizes the need for further research to unravel the complexities of this relationship. Ultimately, these insights hold the potential to transform cancer treatment and prevention strategies.
A novel mismatch repair deficient lung adenocarcinoma model for immunotherapy research
(Elsevier, 2025) Zadra, Ivan; Abad Cortel, Etna; Krasko, Anastasia; Cerdán Porqueras, Víctor; Subirana-Granés, Marc; Reyes, Diana; Borredat Díaz, Pablo; Pasquali, Lorenzo; Aramburu, José (Aramburu Beltrán); López Rodríguez, M. Cristina; Janic, Ana
Immunotherapy has revolutionised cancer treatment, yet responses vary significantly based on tumour characteristics and microenvironment. Here, we developed and analysed subcutaneous and orthotopic immunocompetent mice models of mismatch repair-deficient (dMMR) lung adenocarcinoma (LUAD) by selectively ablating Mlh1. Subcutaneous tumours demonstrated partial sensitivity to anti-PD-1 therapy, whereas orthotopic tumours exhibited robust responses, with substantial reductions in tumour burden. Although both models displayed to some extent a robust immune microenvironment, they differed in immune cell infiltration patterns following anti-PD-1 treatment, underscoring the critical influence of anatomical site and tumour context in shaping immunotherapy outcomes. Furthermore, the use of clonal cell lines with enriched neoantigen frequency in the orthotopic model highlighted the role of clonal heterogeneity in modulating therapeutic efficacy. Together, our findings emphasise the relevance of orthotopic models for preclinical evaluation and suggest that they more accurately reflect clinical responses to immune checkpoint blockade in dMMR LUAD.
Thermal evolution of gene expression profiles in Drosophila subobscura
(BioMed Central, 2007) Laayouni, Hafid, 1968-; García-Franco, Francisco; Chávez-Sandoval, Blanca E.; Trotta, Vincenzo; Beltran, Sergi; Corominas Guiu, Montserrat; Santos, Mauro
Background: Despite its pervasiveness, the genetic basis of adaptation resulting in variation directly or indirectly related to temperature (climatic) gradients is poorly understood. By using 3-fold replicated laboratory thermal stocks covering much of the physiologically tolerable temperature range for the temperate (i.e., cold tolerant) species Drosophila subobscura we have assessed whole-genome transcriptional responses after three years of thermal adaptation, when the populations had already diverged for inversion frequencies, pre-adult life history components, and morphological traits. Total mRNA from each population was compared to a reference pool mRNA in a standard, highly replicated two-colour competitive hybridization experiment using cDNA microarrays. Results: A total of 306 (6.6%) cDNA clones were identified as 'differentially expressed' (following a false discovery rate correction) after contrasting the two furthest apart thermal selection regimes (i.e., 13°C vs. 22°C), also including four previously reported candidate genes for thermotolerance in Drosophila (Hsp26, Hsp68, Fst, and Treh). On the other hand, correlated patterns of gene expression were similar in cold- and warm-adapted populations. Analysis of functional categories defined by the Gene Ontology project point to an overrepresentation of genes involved in carbohydrate metabolism, nucleic acids metabolism and regulation of transcription among other categories. Although the location of differently expressed genes was approximately at random with respect to chromosomes, a physical mapping of 88 probes to the polytene chromosomes of D. subobscura has shown that a larger than expected number mapped inside inverted chromosomal segments. Conclusion: Our data suggest that a sizeable number of genes appear to be involved in thermal adaptation in Drosophila, with a substantial fraction implicated in metabolism. This apparently illustrates the formidable challenge to understanding the adaptive evolution of complex trait variation. Furthermore, some clustering of genes within inverted chromosomal sections was detected. Disentangling the effects of inversions will be obviously required in any future approach if we want to identify the relevant candidate genes.
Implementation of community screening strategies for depression
(Nature Research, 2024) Arias de la Torre, Jorge; Ronaldson, Amy; Vilagut Saiz, Gemma, 1975-; Martinez-Alés, Gonzalo; Dregan, Alex; Bakolis, Ioannis; Valderas Martínez, José María; Molina, Antonio J.; Martín, Vicente; Bellón, Juan Ángel; Alonso Caballero, Jordi
Astroglial reactivity is a key modulator of Alzheimer's disease pathological progression
(Oxford University Press, 2024) Pelkmans, Wiesje; Gispert López, Juan Domingo
This scientific commentary refers to 'Association of glial fibrillary acid protein, Alzheimer's disease pathology and cognitive decline' by Peretti et al. (https://doi.org/10.1093/brain/awae211).
Prognostic value of PARP1 and PARP2 copy number alterations in prostate cancer
(Elsevier, 2025) Segalés Tañà, Laura, 1994-; Bellmunt Molins, Joaquim, 1959-; Perera Bel, Júlia; Vargas-Parra, Gardenia; Juanpere, Nuria; Lopez-Segura, David; Rodriguez-Vida, Alejo; Colomo Saperas, Luis Alberto; Cecchini Rosell, Lluís; Lloreta, Josep, 1958-; Yélamos López, José; Fumadó Ciutat, Lluis; Hernández Llodrà, Silvia
PARP1/2 have overlapping yet nonredundant biological functions in DNA repair and androgen receptor-transcriptional regulation. Studies on PARP alterations in human tumors have yielded conflicting results. In prostate cancer (PCa), PARP1/2 protein overexpression has been related to androgen deprivation therapy resistance, biochemical recurrence, and progression to metastases. PARP inhibitors have been approved for treating metastatic castration-resistant PCa with homologous recombination repair gene mutations. However, the significance of PARP1/2 genomic alterations is not fully studied. We aimed to analyze PARP1/2 alterations in PCa, assess their value as prognostic markers, and explore their relevance for potential therapeutic stratification. PARP1/2 copy number status was evaluated in 121 PCa primary tumors using real-time PCR. In 29 of them, a regional pelvic lymph node involvement was also analyzed. BRCA1/2 somatic mutations were analyzed in 24 PCa cases. Relationship with clinicopathological features, progression to metastases, and prostate-specific antigen recurrence was assessed. PARP1 loss and PARP2 gain were detected in 34.7% and 32.2% of primary tumors, respectively, with a high frequency of co-occurrence (P < .001). Both alterations were statistically associated with locally advanced disease at the time of diagnosis (P = .036; P = .006), metastatic dissemination (P = .014; P = .003), and other aggressive clinicopathological characteristics (such as the presence of Gleason pattern 5, high-grade, and high-stage). Cases with exclusive PARP2 gain had the shortest time to prostate-specific antigen recurrence, whereas double wt patients displayed the best outcome (P = .007). In 29 paired primary tumors and regional pelvic lymph node involvement, PARP1 loss showed strong concordance (P = .001), whereas PARP2 gain did not (P = .411). In conclusion, loss of PARP1 and gain of PARP2 show strong co-occurrence and are associated with clinicopathological characteristics of aggressiveness. PARP2 alterations appear to have a particularly significant impact on disease prognosis. Furthermore, these data suggest that the analysis of PARP1/2 copy number status could be useful in predicting PCa outcomes. Its role in therapy warrants further evaluation.
Prenatal alcohol exposure dysregulates the expression of clock genes and alters rhythmic behaviour in mice
(Royal Society, 2025) Reina-Campos, Maria; Gallego-Landin, Ines; Medrano, Mireia; García Baos, Alba; Valverde Granados, Olga
Foetal alcohol spectrum disorders (FASDs) refer to a range of adverse physical, behavioural and cognitive effects caused by perinatal alcohol exposure. While cognitive impairments are well documented, FASD has also been associated with sleep disturbances and circadian rhythm disruptions. This study aimed to examine the effects of perinatal alcohol exposure on circadian rhythms at behavioural and gene expression levels across two developmental stages (adolescence and adulthood) in both male and female mice. Using a validated prenatal and lactation alcohol exposure (PLAE) protocol, we assessed circadian patterns of locomotor activity under free-running conditions and spatial memory performance during adolescence and adulthood. Additionally, we evaluated the impact of PLAE on circadian expression of clock and non-circadian genes involved in neurotransmission across key brain regions, including the medial prefrontal cortex and hippocampus. PLAE altered circadian rhythmicity and impaired spatial memory. Gene expression analyses revealed disrupted oscillatory patterns in clock genes and in genes related to plasticity and cognition, including those from the expanded endocannabinoid system (e.g. Cnr1, Dagla, Faah) and other neurotransmitter systems (e.g. Oprm1, Slc17a8, Drd1, Gabra1). These findings underscore the impact of early alcohol exposure on biological rhythms and neurobehavioural function, highlighting circadian dysregulation as a contributing factor to FASD.
Factors influencing the attrition rate of a 10-week multimodal rehabilitation program in patients after lung transplant: a neural network analysis
(MDPI, 2024) Dávalos Yerovi, Vanesa; Sánchez-Rodríguez, María Dolores; Gómez-Garrido, Alba; Launois, Patricia; Tejero Sánchez, Marta; Pujol-Blaya, Vicenta; Curbelo Peña, Yulibeth; Donohoe, Owen; Marco Navarro, Ester
Background/Objectives: Despite the effectiveness of exercise and nutritional interventions to improve aerobic capacity and quality of life in lung transplant (LT) recipients, their compliance is low. Strategies to reduce the high attrition rate (participants lost over time) is a major challenge. Artificial neural networks (ANN) may assist in the early identification of patients with high risk of attrition. The main objective of this study is to evaluate the usefulness of ANNs to identify prognostic factors for high attrition rate of a 10-week rehabilitation program after a LT. Methods: This prospective observational study included first-time LT recipients over 18 years of age. The main outcome for each patient was the attrition rate, which was estimated by the amount of missing data accumulated during the study. Clinical variables including malnutrition, sarcopenia, and their individual components were assessed at baseline. An ANN and regression analysis were used to identify the factors determining a high attrition rate. Results: Of the 41 participants, 17 (41.4%) had a high rate of attrition in the rehabilitation program. Only 23 baseline variables had no missing data and were included in the analysis, from which a low age-dependent body mass index (BMI) was the most important conditioning factor for a high attrition rate (p = 7.08 × 10), followed by end-stage respiratory disease requiring PT (p = 0.000111), low health-related quality-of-life (HRQoL) (p = 0.0009078), and low handgrip strength (p = 0.023). Conclusions: The prevalence of high attrition rate in LT recipients is high. The profile of patients with a high probability of attrition includes those with chronic obstructive pulmonary disease, low BMI and handgrip strength, and reduced HRQoL.
Epigenetic age and long-term cancer risk following a stroke
(BioMed Central, 2024) Suárez-Pérez, Antoni; Macias-Gómez, Adrià; Fernández-Pérez, Isabel; Vallverdú-Prats, Marta; Cuadrado-Godia, Elisa; Giralt-Steinhauer, Eva; Campanale, Maia; Guisado-Alonso, Daniel; Rodríguez-Campello, Ana; Jiménez-Balado, Joan; Jiménez Conde, Jordi; Ois Santiago, Angel Javier
Background: The association between increased cancer risk following a cerebrovascular event (CVE) has been previously reported. We hypothesize that biological age (B-age) acceleration is involved in this association. Our study aims to examine B-age as a novel contributing factor to cancer development post-CVE. Methods: From our prospective stroke registry (BasicMar), we selected 940 cases with epigenetic data. For this study, we specifically analyzed 648 of these patients who had available data, no prior history of cancer, and a minimum follow-up of 3 months. The primary outcome was cancer incidence. B-age was estimated using DNA methylation data derived from whole blood samples obtained within 24 h of stroke onset, employing various epigenetic clocks (including Hannum, Horvath, PhenoAge, Zhang, Zhang, and the mitotic epiTOC). Extrinsic epigenetic age acceleration (EEAA) was calculated as the residuals from the regression of B-age against chronological age (C-age). For epiTOC, the age-adjusted values were obtained by regressing out the effect of age from the raw epiTOC measurements. Estimated white cell counts were derived from DNA methylation data, and these cell fractions were used to compute the intrinsic epigenetic age acceleration (IEAA). Subsequently, we evaluated the independent association between EEAA, IEAA, and cancer incidence while controlling for potential confounding variables. Results: Among 648 patients with a median follow-up of 8.15 years, 83 (12.8%) developed cancer. Cox multivariable analyses indicated significant associations between Hannum, Zhang, and epiTOC EEAA and the risk of cancer after CVE. After adjusting for multiple testing and competing risks, EEAA measured by Hannum clock maintained an independent association with cancer risk. Specifically, for each year increase in Hannum's EEAA, we observed a 6.0% increased incidence of cancer (HR 1.06 [1.02-1.10], p value = 0.002). Conclusions: Our findings suggest that epigenetic accelerated aging, as indicated by Hannum's EEAA, may play a significant role in the increased cancer risk observed in CVE survivors.
The evolution of facultative symbiosis in stony corals
(Nature Research, 2025) Levy, Shani; Grau Bové, Xavier; Kim, Iana V.; Najle, Sebastián R.; Ksiezopolska, Ewa; Elek, Anamaria; Montes-Espuña, Laia; Montgomery, Sean A.; Mass, Tali; Sebé-Pedrós, Arnau
Most stony corals are obligate symbionts that are dependent on nutrients provided by the photosynthetic activity of dinoflagellates residing within specialized cells1. Disruption of this symbiotic consortium leads to coral bleaching and, ultimately, mortality2. However, a few coral species exhibit facultative symbiosis, allowing them to survive extended periods of bleaching3,4. Despite this resilience, the underlying biological mechanisms remain poorly understood. Here we investigate the genomic and cellular basis of facultative symbiosis in Oculina patagonica, a thermotolerant Mediterranean coral5,6. We sequenced and annotated a chromosome-scale genome of O. patagonica and built cell atlases for this species and two obligate symbiotic corals. Comparative genomic analysis revealed karyotypic and syntenic conservation across all scleractinians, with species-specific gene expansions primarily driven by tandem duplications. Single-cell transcriptomic profiling of symbiotic and naturally aposymbiotic wild specimens identified an increase in phagocytic immune cells and a metabolic shift in gastrodermal gene expression from growth-related functions to quiescent, epithelial-like states. Cross-species comparison of host cells uncovered Oculina-specific metabolic and signalling adaptations indicative of an opportunistic, dual-feeding strategy that decouples survival from symbiotic state.
Neurodevelopmental disorders: 2024 update
(University of Münster, 2024) Martínez de Lagrán Cabredo, María; Bascón-Cardozo, Karen; Dierssen, Mara
Neurodevelopmental disorders encompass a range of conditions such as intellectual disability, autism spectrum disorder, rare genetic disorders and developmental and epileptic encephalopathies, all manifesting during childhood. Over 1,500 genes involved in various signaling pathways, including numerous transcriptional regulators, spliceosome elements, chromatin-modifying complexes and de novo variants have been recognized for their substantial role in these disorders. Along with new machine learning tools applied to neuroimaging, these discoveries facilitate genetic diagnoses, providing critical insights into neuropathological mechanisms and aiding in prognosis, and precision medicine. Also, new findings underscore the importance of understanding genetic contributions beyond protein-coding genes and emphasize the role of RNA and non-coding DNA molecules but also new players, such as transposable elements, whose dysregulation generates gene function disruption, epigenetic alteration, and genomic instability. Finally, recent developments in analyzing neuroimaging now offer the possibility of characterizing neuronal cytoarchitecture in vivo, presenting a viable alternative to traditional post-mortem studies. With a recently launched digital atlas of human fetal brain development, these new approaches will allow answering complex biological questions about fetal origins of cognitive function in childhood. In this review, we present ten fascinating topics where major progress has been made in the last year.
Effect of bariatric surgery on HDL-mediated cholesterol efflux capacity
(Frontiers, 2024) Castañer, Olga; Pérez Vega, Karla Alejandra; Álvarez, Sara; Vázquez, Susana; Casajoana, Anna; Blanchart, Gemma; Gaixas, Sònia; Schröder, Helmut, 1958-; Zomeño Fajardo, Maria Dolores; Subirana Cachinero, Isaac; Muñoz Aguayo, Daniel; Fitó Colomer, Montserrat; Benaiges Foix, David; Goday Arno, Alberto; Oliveras, Anna
Background: Bariatric surgery (BS) is the most effective intervention for severe obesity, leading to sustained weight loss, reduced obesity-related comorbidities, and cardiovascular mortality. Aim: To assess changes in high-density lipoprotein (HDL) functions [cholesterol efflux capacity (CEC) and anti-inflammatory capacity] at different follow-up times in patients with severe obesity undergoing BS. Methods: A prospective observational study within a cohort of consecutively enrolled patients with severe obesity scheduled to undergo BS. In total, 62 participants (77% women), with a mean age of 42.1 years (SD 9.33 years) underwent BS. Regarding the surgical procedure, 27 (43.5%) underwent sleeve gastrectomy and 35 (56.5%) Roux-en-Y gastric bypass. All patients were evaluated preoperatively and at 1, 3, 6, and 12 months after surgery. Results: A decrease in body mass index and an improvement in the systemic lipid profile, indicated by reductions in total cholesterol, low-density lipoprotein cholesterol (LDLc), and remnant cholesterol, and an increase in HDL cholesterol (HDLc) was observed (all p trend < 0.001). Time-series comparisons vs. baseline showed that, in general, anthropometric measures, glycemia, total cholesterol, LDLc, and remnant cholesterol decreased at all follow-ups, whereas HDLc and triglyceride concentrations significantly improved vs. baseline from 6 months, reaching at 12 months the highest HDLc levels (29.6%, p < 0.001) and the lowest circulating triglycerides (-30%, p < 0.001). Although HDL's anti-inflammatory ability worsens after surgery, the HDL-mediated CEC linearly increased after surgery (for both p trend < 0.013). Conclusion: BS improves the lipid profile both quantitatively and qualitatively after 1 year, specifically enhancing HDL-mediated cholesterol efflux capacity, which may contribute to a reduced cardiovascular risk in individuals with severe obesity.

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