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Articles publicats en revistes (Patologia i Terapèutica Experimental)

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    Photocontrol of zebrafish behavior with a photoswitchable ligand of nicotinic acetylcholine receptors
    (Elsevier B.V., 2026-07-03) Papotto, Claudio; Pérez Pérez, Nayeli Fernanda; Gomila Juaneda, Alexandre; Sortino, Rosalba; Cases, Mercè; Lee, Hyojung; Calzaferri, Francesco; De Amici, Marco; Dallanoce, Clelia; Gorostiza Langa, Pau; Matera, Carlo
    The α7 nicotinic acetylcholine receptor (α7 nAChR) is a key modulator of neuronal and immunological signaling, and photopharmacology offers a route to control nicotinic transmission with high spatiotemporal precision. Here we report CPZ-2, a photoswitchable ligand inspired by a patented α7-active scaffold. CPZ-2 shows slow thermal relaxation, high photostability, and reversible photoswitching under one-photon irradiation, together with two-photon-induced photoisomerization monitored directly by HPLC–MS. Radioligand-binding competition performed on the trans-enriched state showed measurable displacement at α7 nAChRs and α1-containing receptors at 10 µM, with lower effects at α3β4 and α4β2 subtypes. Moreover, in wild-type zebrafish larvae, CPZ-2 modulated nicotine-evoked locomotion in a light-dependent manner after bath application. Finally, docking simulations in the α7 orthosteric site support a binding mode compatible with receptor engagement and suggest photostate-dependent differences in the orientation of the distal aromatic group relative to the C-loop region. Together, these data identify CPZ-2 as an uncharged, diffusible photoswitchable nicotinic ligand that combines robust one- and two-photon photochemistry with light-dependent modulation of nicotinic signaling in a wild-type vertebrate model.
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    Effect of a Probiotic Combination on Clinical and Microbiological Oral Parameters in Head and Neck Cancer Patients: A Randomised Clinical Trial
    (MDPI, 2025-07-25) Pereira-Riveros, Tanya; Jané Salas, Enric; Lozano Borbalas, Alicia; Rodrigo Aguilera, Felipe; Vinuesa Aumedes, Teresa
    Patients with head and neck cancer undergoing radiotherapy frequently experience xerostomia and disturbances in the oral bacterial balance, which can significantly impair their quality of life. This study investigated whether a 30-day daily intake of a probiotic combination could enhance salivary function and reduce disease-associated oral bacteria. Participants were randomly assigned to receive either probiotics or a placebo. By the end of the intervention, those in the probiotic group showed notable improvements in stimulated salivary flow and a reduction in overall bacterial counts, particularly Fusobacterium nucleatum. These results suggest that probiotics may represent a safe and effective approach to prevent or mitigate radiotherapy-induced oral complications. This study highlights the potential role of probiotics as a simple and supportive measure to improve oral health and overall well-being during cancer treatment recovery.
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    Comparative analysis of measurement methods for forefoot varus reliability: A systematic review and meta-analysis
    (Elsevier Ltd., 2026-06) Carrelero Camp, Sergi; Dalmau-Pastor, Miki; Simon de Blas, Clara; Vergés Salas, Carles; Planell i Mas, Elena de; Hernández-Secorún, Mar
    Background: Forefoot Varus is characterized by inversion of the metatarsal heads relative to the calcaneal bisector. It is present in 83.67 % of cases and contributes to overpronation and related foot/knee/hip pathologies. Despite multiple assessment methods, their reliability remains unclear. This systematic review evaluates the most reliable measurement technique. Methods: This systematic review and meta-analysis selected studies from several databases: PubMed, Scopus, Cochrane Library, Web of Science, and PEDro. The search strategies included keywords such as “forefoot”, “varus forefoot”, “supinatus forefoot”, “varus alignment of the foot-ankle complex” or “shank-forefoot” and their combinations were used. Studies published in the English, French, and Spanish language were included until July 4th, 2024. After identifying the articles, the methodological quality was assessed using the GRRAS checklist. The reported results were intra-class correlation coefficient, influence on gait, biomechanical factors, and pathologies. Results: This meta-analysis of 13 studies (n = 1238) found excellent intra-observer reliability for forefoot varus measurements (pooled ICC = 0.92, 95 %CI 0.89–0.94), with significant inter-observer differences (Q = 38.7, p < 0.001): goniometry showed ICCs of 0.56–0.68 (isolated forefoot or JIG shank-forefoot alignment goniometer) versus 0.81–0.91 (shank-forefoot alignment), while photogrammetry maintained consistently higher reliability (ICCs 0.90–0.93). Photogrammetry and goniometry demonstrated moderate correlation between methods (r = 0.71, 95 %CI 0.63–0.78) across predominantly healthy populations studies (76.9 %, mean age 31.5 ± 15.2 years). Conclusion: Photogrammetric and shank-forefoot alignment methods demonstrate excellent reliability (ICC >0.90) for forefoot varus assessment, while traditional goniometry shows inconsistent results. Standardized protocols are recommended to ensure cross-study comparability.
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    Detection of Dating Violence Among University Students in Health Sciences: A Multicentric Cross-Sectional Study in Spain and Colombia
    (Frontiers Media, 2026-06-26) Puig Llobet, Montserrat; Sanchez-Ortega, M. Aurelia; Prats Arimon, Marta; Agüera, Zaida; Rodríguez-Martín, Dolors; Moreno Arroyo, M. Carmen; Maestre, Elena; Lluch Canut, Ma. Teresa; Roldán Merino, Juan Francisco; Moreno Poyato, Antonio Rafael; Saz Roy, Mª Ángeles; Mantas Jiménez, Susana; Giménez Bonafé, Pepita; Vergés Bosch, Núria; Ferran Ferrer, Núria; Faure Carvallo, Adrien; Manzanares Céspedes, María Cristina; Astudillo-Rozas, Wilson; Rodríguez Ávila, Núria; Casanovas Cuellas, Cristina; Huertas Zurriaga, Ariadna; Torrubia Pérez, Elisabet; Mora López, Gerard; Vives Espelta, Judit; Sanromà Ortiz, Montserrat; Roca Llobet, Judith; Cogollo, Zuleima; Tuesca Molina, Rafael; Sánchez Balcells, Sara
    Introduction: Dating violence (DV) represents a critical public health challenge that disproportionately affects adolescents and young people. Among Health Sciences students, early detection is doubly important, both for their personal wellbeing and for their future role as frontline professionals in the identification of victims. The aim is to determine the prevalence and dynamics of dating violence (DV) among Health Sciences university students in Spain and Colombia, analyzing patterns of victimization and perpetration. Material and methods: This multicenter cross-sectional study included 511 Health Sciences students from eight universities in Spain and Colombia. DV was assessed using the Multidimensional Dating Violence Scale (EMVN) developed by García-Carpintero et al. (2018). The study was approved by the Research Ethics Committees of all participating institutions. Results: The findings reveal that control and surveillance, together with sexual violence, are the predominant dimensions, far exceeding physical violence. Digital control behaviors (“persistently sending messages through social media”) and subtle grooming behaviors (“giving unsolicited gifts or favors”) emerged as the most frequently reported indicators. The bivariate analysis revealed critical gaps: men reported significantly higher levels of perpetration of physical and sexual violence. In addition, the geographical context proved to be a determining factor, showing significant cultural variations in how the phenomenon manifests. Conclusions: The results highlight that dating violence in this population is predominantly psychological and related to control. It is imperative to integrate education on equality and awareness of “warning signs” into the academic curriculum to transform these students into professionals capable of breaking the cycle of violence. Implications: This pioneering study provides an international perspective on the vulnerability and perceptions of future health professionals. Its multicenter nature makes it possible to design intervention strategies adapted to specific sociocultural contexts, thereby strengthening the response capacity of health systems to gender-based violence.
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    Impaired expression of ecto-nucleotidases in human endometrial pathologies
    (Sercrisma International, 2019-09-09) Martín Satué, Mireia; Matias-Guiu, Xavier, 1958-; Rodríguez-Martínez, Aitor; Trapero Candela, Carla; Vidal, August; Gómez de Aranda, Immaculada; Fernandez-Montolí, M.A.; Piulats, Josep M.; Coroleu, Buenaventura; Barri, Pere; Tresserra, Francesc; Ponce Sebastià, Jordi
    The levels of extracellular ATP and its derivatives such as adenosine are impaired in the tissue microenvironment during tissue stress conditions such as hypoxia, infection, metabolic stress, tumor transformation and inflammation. Ecto-nucleotidases are the main regulators of extracellular ATP and adenosine levels. The aim of the present work is to upgrade our understanding of the role and location of ecto-nucleotidases in the context of two endometrial pathologies: cancer and endometriosis, as well as to investigate new diagnostic and treatment modalities based on the inhibition of ecto-nucleotidases' activities. We have analyzed by means of immunolabeling and in situ enzyme histochemistry human endometrial samples from: 1) endometrial tumors, and, 2) eutopic endometria as well as ectòpic endometriotic lesions from women with endometriosis. We have also studied endometrial cell cultures to evaluate the consequences of the overexpression of ecto-nucleotidases in their proliferative and invasive phenotypes. Ecto-nucleotidases showed impaired expression in pathological conditions when compared with non-pathological endometria. This altered pattern includes changes in expression levels and changes in protein localization, mainly a switch between epithelium and stroma. Overexpression of ecto-nucleotidases in endometrial cell cultures lead to changes in the proliferation and invasion rates. Impaired ecto-nucleotidases activities in endometrium might contribute to the pathogenesis and maintenance of endometrial pathologies with an inflammatory component such as cancer and endometriosis.
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    New method to simultaneously characterize the expression and in situ activity of ecto-nucleotidase in human tissues
    (Sercrisma International, 2017) Villamonte-Román, María; Torrejón-Escribano, Benjamín; Vidal-Bel, August; Ponce Sebastià, Jordi; Matias-Guiu, Xavier, 1958-; Martín Satué, Mireia
    Introduction: Extracellular nucleotides, such as ATP, and nucleosides, such as adenosine, act as autocrine and paracrine molecules that have multiple roles in virtually all organs and tissues, including female reproductive organs. Extracellular ATP and adenosine levels are regulated by the action of ecto-nucleotidases that hydrolyse ATP to adenosine. The aim of the present study was to set up a new method to simultaneously localize the cellular distribution and in situ activity of ecto-nucleotidases in tissue sections. We used this method to characterize the expression of ecto-nucleotidases in human oviducts. Material and Methods: Cryosections of non-pathological human oviducts were obtained from salpingectomy at the Service of Gynecology of Bellvitge Hospital. Samples were incubated with the following primary antibodies against human enzymes: anti-nucleoside triphosphate diphosphohydrolase 1 (NTPDase1/CD39), anti-NTPDase2, and anti-placental alkaline phosphatase (PLAP). In situ activity reactions were performed on the same slides using the Wachstein/Meisel lead phosphate method with ATP or ADP as substrate. For alkaline phosphatase activity, the BCIP/NBT revealing reagent was used. The sections were then incubated with the appropriate Alexa Fluor-conjugated secondary antibodies and mounted with Prolong Gold antifade with DAPI medium. Results: NTPDase1 was expressed in the smooth muscle and endothelial cells, coinciding with localization of ADPase activity. NTPDase2 was largely expressed and active (ATPase activity) in ciliated cells and in connective tissue. PLAP was immunodetected and active in luminal epithelium. Conclusions: We found that this new method is specific, sensitive, and useful with diferent tissues. Our results show that ecto-nucleotidases are abundantly present in human oviducts where these enzymes work in concert to metabolize extracellular ATP to adenosine. This study contributes to knowledge of purinergic signaling by ecto-nucleotidases in the female reproductive system.
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    Ecto-nucleotidase expression and activity in endometrioid-type endometrial carcinoma cell lines
    (Sercrisma International, 2017-09-08) Rodríguez-Martínez, Aitor; Matias-Guiu, Xavier, 1958-; Martín Satué, Mireia
    Introduction: ATP and adenosine are known for their role in promoting an immunosuppressive environment at the tumor site. It is known that some ecto-nucleotidases, proteins that handle the hydrolysis of tri-, di- and monophosphate nucleotides, are overexpressed in endometrial tumor tissues although the mechanisms underlying these processes remain controversial. In the present study we characterized, with cytochemistry and i mmunofluorescence, the ecto-nucleotidase profiles in endometrioid-type endometrial carcinoma cell lines. Furthermore, we have developed a new approach capable of simultaneously detecting both alkaline phosphatase expression and activity. Materials and methods: Cell lines: 3 endometrioid endometrial carcinoma cell lines (Ishikawa, HEC-1B and ECC-1) were used for cytochemistry and immunofluorescence experiments. In situ ecto-nucleotidase enzyme activities: ATPase, ADPase, and AMPase activity experiments were performed in all cell lines, based on the Wachstein/Meisel technique. Immunofluorescence experiments: cell immunolabeling was performed using primary antibodies against different members of the ecto-nucleotidases: anti-ectonucleoside triphosphate diphosphohydrolase 2 (E-NTPDase2), anti-E-NTPDase3, anti-CD73, and anti-placental-like alkaline phosphatase (PLAP). Alkaline phosphatase immunoactivity assay: for the detection of both activity and al kaline phosphatase expression we developed a combinatorial assay in which enzyme activity can be co-visualized with protein expression. Immunofluorescence followed by an activity assay was performed on AP-expressing cells. Results: Cytochemistry enzyme assays showed moderate ATPase activity in both Ishikawa and ECC-1 cell lines. Moderate ADPase activity was found in ECC-1 cells and high AMPase activity was detected in HEC-1B cells. In immunolabeling experiments we found NTPDase2 protein expression in all three cell lines, with NTPDase3 expression restricted to ECC-1 cells. CD73 was detected in all three cell lines. Moderate alkaline phosphatase activity and protein expression were found in Ishikawa and ECC-1 cells. A wide differential range of activities and ecto-nucleotidase expression among the studied cell lines was observed. NTPDase2 and NTPDase3 expression correlated with ATPase activity. CD73 protein expression coincided with the high AMPase activity shown with HEC-1B. Conclusions: Ishikawa, HEC-1B, and ECC-1 cell lines represent a useful cell model for the study of ecto-nucleotidases in the context of endometrioid-type endometrial carcinoma.
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    Editorial: Purinergic pharmacology, Volume II
    (Frontiers Media, 2023-05-16) Ciruela Alférez, Francisco; Jacobson, Kenneth A.
    Extracellular purine nucleotides and nucleosides serve as crucial signalling molecules, acting as neurotransmitters and neuromodulators. Tightly regulated extracellular levels of adenosine 5′-triphosphate (ATP) and adenosine, which are controlled by various enzymes and transporters, activate a variety of purinergic receptors. These receptors, which appear early in evolution, are among the most abundant receptors in living organisms and regulate numerous physiological processes, making them attractive therapeutic targets for a wide range of diseases. While P1 (adenosine) receptors are selective for adenosine, the breakdown product of ATP, P2 receptors respond to purine and pyrimidine nucleotides. Importantly, purinergic receptors, including both G protein-coupled receptors (ARs and P2YRs) and ligand-gated ion channel receptors (P2XRs), are involved in a multitude of neuronal and non-neuronal mechanisms, such as pain, immune responses, exocrine and endocrine secretion, platelet aggregation, endothelium-mediated vasodilatation, and inflammation. However, since purinergic receptors are widely distributed throughout the body, it is challenging to develop drugs that selectively target specific receptor subtypes without causing unwanted side effects. Additionally, extracellular levels of purines and pyrimidines can also vary greatly, leading to the simultaneous activation of different purinergic receptors in response to oscillating concentrations of endogenous purines. Consequently, through these different subtypes of P1 and P2 receptors, cells integrate extracellular purine responses, harmonising short- and long-term purinergic signalling. Therefore, the selectivity of drugs is a crucial goal in the field of purinergic pharmacology. For decades, medicinal chemists have been developing potent and selective synthetic agonists and antagonists for purinergic receptors, as well as allosteric modulators that allow for event-responsive and temporally specific manipulation of the endogenous purinergic system. Additionally, modulation of the metabolism and uptake of extracellular purine nucleotides and nucleosides can also regulate purinergic processes. Overall, the field of purinergic pharmacology is rapidly expanding and presents exciting opportunities for pharmacotherapeutic development.
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    Macrolide resistance determinants and their associations in streptococci from selected livestock and wildlife species from Catalonia, Northeast Spain
    (American Society for Microbiology, 2026-03-16) López de Egea, Guillem; González-Díaz, Aida; Aragon, Virginia; Cabezón Ponsoda, Òscar; Guédon, Gérard; Berbel, Dàmaris; Cadenas Jiménez, Irene; Espunyes, Johan; Planellas, Marta; Domínguez Luzón, Ma. Ángeles (María Ángeles); Leblond Bourget, Nathalie; Ardanuy Tisaire, María Carmen
    The increasing macrolide resistance in Streptococcus spp. causing human and animal infections in the last decades is a concern for global health. The objectives of this study were to analyze the macrolide resistance rates of Streptococcus spp. from animals and their resistance determinants. We conducted a retrospective study of an animal Streptococcus collection (307 isolates) from farm, wild animals, and pets in Catalonia, Northeast Spain. Identification was done by MALDI-TOF, and antimicrobial susceptibility to erythromycin and clindamycin was assessed by disk diffusion (EUCAST). Resistant strains were further tested for susceptibility to other antimicrobial agents using disk diffusion and microdilution methods. Selected isolates (n = 50) were subjected to whole-genome sequencing (WGS). Mobile genetic elements (MGEs), such as integrative and conjugative elements (ICEs) and integrative and mobilizable elements (IMEs), were identified using ICEscreen. Streptococcal strains were mainly isolated from domestic swine (50.5%) and wild boars (19.2%), with S. suis (54.4%) and S. hyovaginalis (14%) the predominant species. The macrolide resistance phenotypes found were MLSB (n = 145), M (n = 6), and L (n = 30). Macrolide (84.5%) and lincosamide (94.8%) resistance rates from swine strains were higher than those from other animals (13.2% and 18.4%, respectively, P < 0.001). The predominant resistant genes found were erm(B) (n = 38), tet(O) (n = 28), vga(F) (n = 20), and lnu(B)-lsa(E) (n = 10), and were mostly associated with ICEs or defective ICEs (dICEs) belonging to the Tn5252 family. Animal streptococci presented high macrolide resistance rates, especially concerning swine strains, associated with a variety of resistance determinants. MGEs were the main carriers of resistance determinants and contributors to its spread.
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    Fibroblastic aspartoacylase suppresses TGFβ-mediated responses and cancer progression
    (Springer Nature, 2026-06-16) Astobiza, Ianire; Capó-Serra, Catalina; Viera, Cristina; Rodriguez, Javier; Carnicero, Patricia; Juliá, Miguel; Martinez, Ainara; Pérez-López, Carmen; Subijana, María; Ortiz-Sanz, Carolina; Garcia-Longarte, Saioa; Mendizabal, Isabel; Kay, Emily J.; Riera-Domingo, Carla; Rivis, Silvia; Carlevaris, Onintza; Egia-Mendikute, Leire; Cascais, Sara; Martín-Martín, Natalia; Fernandez-Ruiz, Sonia; Torrano, Veronica; Crespo, Jana R.; Pujana-Vaquerizo, Mikel; Espinet, Elisa; Trumpp, Andreas; Eiro, Noemi; Vizoso, Francisco J.; Vivancos, Ana; Seoane, Joan; Gonzalo, David; Rey, Sofía; Santos-Martín, Aida; Ugalde-Olano, Aitziber; Manini, Claudia; López, Jose I.; Cabrera, Diana; Van Liempd, Sebastian M.; Falcon-Perez, Juan M.; Gomis Cabré, Roger; Palazón, Asís
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    Regulatory elements in the Sox9 locus license the initiation of pancreatic ductal adenocarcinoma
    (Elsevier, 2026-04-28) Ballester Frago, Marta; Kurilla, Anita; Dai, Yifan; Bergara Muguruza, Leire; Radke, Katarzyna; Maurer, Hans Carlo; Espinet, Elisa; Høj, Kristina; Marisch Delgado, Aida; Seymour, Philip A.; Omar, Saynab; Rift, Charlotte Vestrup; Hasselby, Jane; Klausen, Pia; Vilmann, Peter; Castellanos-Rubio, Ainara; Santin, Izortze; Sandelin, Albin; Arnes, Luis
    Cellular plasticity enables tissue regeneration but can be hijacked by oncogenic programs. In the pancreas, Kras acts on tissue-specific enhancers to lock regeneration into a pro-inflammatory state that drives cancer initiation. Enhancer transcription, an early event during cell state transitions, generates long noncoding RNAs (lncRNAs) that influence transcription and genome organization, yet their roles in pancreatic regeneration remain unclear. We profiled epithelial lncRNAs and their targets during pancreatic ductal adenocarcinoma (PDAC) precursor formation, focusing on those transcribed from enhancers near cell identity regulators. LINC00673, expressed from a Sox9-associated super-enhancer during development, is reactivated in PDAC. Conditional deletion of LINC00673 accelerates acinar-to-ductal metaplasia resolution and impairs PDAC initiation. Moreover, LINC00673 harbors a variant associated with PDAC risk. In addition, our data are consistent with a contribution of transcribed super-enhancers to long-range gene regulation during pancreatic cancer initiation. These findings reveal a regulatory layer linking developmental enhancer activity, cellular plasticity, and pancreatic disease progression.
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    Impaired α-Synuclein aggregate clearance in neuronal cells drive their spread to microglia through tunneling nanotubes
    (Nature Publishing Group, 2026-03-12) Chakraborty, Ranabir; Palese, Francesca; Samella, Philippa; Testa, Veronica; Montero-Muñoz, Jara; Syan, Sylvie; Nonaka, Takashi; Hasegawa, Masato; Consiglio, Antonella; Zurzolo, Chiara
    Tunneling nanotubes (TNTs) play a crucial role in intercellular communication, enabling transfer of molecular cargoes over long distances between connected cells. Previous studies have demonstrated efficient, directional transfer of α-Synuclein (α-Syn) aggregates from neurons to microglia, with endosomal trafficking and lysosomal processing identified as the primary events following α-Syn internalization. Using human neuronal and microglial cell lines, we show that microglia exhibit higher lysosomal turnover, particularly through lysophagy, whereas neuronal lysosomes display compromised degradative capacity and impaired autophagic flux upon α-Syn exposure, resulting in compromised aggregate clearance. Such a response to α-Syn aggregates is also conserved in human iPSC-derived neurons and microglia. Moreover, perturbing aggregate clearance via autophagy inhibition enhances TNT-mediated transfer of α-Syn from neuronal cells to microglia. Microglia co-cultured with α-Syn-containing neurons upregulate autophagy flux, enabling efficient degradation of the transferred aggregates. These results highlight dysfunctional autophagy in neurons as a key driver outsourcing α-Syn aggregates to microglia.
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    Bilateral equalization of synaptic output in olfactory glomeruli of Xenopus tadpoles
    (eLife Sciences, 2026-05-15) Casas, Marta; Terni, Beatrice; Llobet Berenguer, Artur, 1972-
    Odorants stimulate olfactory sensory neurons (OSNs) to create a bilateral sensory map defined by a set of glomeruli present in the left and right olfactory bulbs. Using Xenopus tropicalis tadpoles, we challenged the notion that glomerular activation is exclusively determined ipsilaterally. Glomerular responses evoked by unilateral stimulation were potentiated following transection of the contralateral olfactory nerve. The gain of function was observed as early as 2 hr after injury and faded away with a time constant of 4 days. Potentiation was mediated by the presence of larger and faster calcium transients driving glutamate release from OSN axon terminals. The cause was the reduction of the tonic presynaptic inhibition exerted by dopamine D2 receptors. Inflammatory mediators generated by injury were not involved. These findings reveal the presence of a bilateral modulation of glomerular output driven by dopamine that compensates for imbalances in the number of operative OSNs present in the two olfactory epithelia. Considering that the constant turnover of OSNs is an evolutionarily conserved feature of the olfactory system and determines the innervation of glomeruli, the compensatory mechanism described here may represent a general property of the vertebrate olfactory system to establish an odor map.
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    Generation of gene-corrected human isogenic iPSC lines from hypertrophic cardiomyopathy patients harboring PRKAG2 mutation (c.2084A>G, p.His530Arg) using prime editing
    (Elsevier B.V., 2026-05-01) Lu, Zijun; Qiu, Zhichao; Zhang, Yao; Yang, Hao; Yang, Yuan; Liang, Zhuobin; Zhang, Joe Z.
    PRKAG2 cardiac syndrome is a rare inherited cardiomyopathy characterized by clinical manifestations such as abnormal cardiac hypertrophy, glycogen storage, and arrhythmias. We derived two human induced pluripotent stem cell (iPSC) lines carrying a heterozygous PRKAG2 missense mutation (c.2084A>G, p.His530Arg) from two patients with hypertrophic cardiomyopathy. Using Prime Editing, we precisely corrected this mutation in patient-specific iPSCs. This approach enables a valuable resource for advancing precision medicine research in PRKAG2 cardiac syndrome.
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    Gut microbiome shift in long COVID: impact of disease and montelukast treatment
    (International Society of Global Health, 2026-05-15) Domínguez Luzón, Ma. Ángeles (María Ángeles); Martí Martí, Sara; Camps Massa, Paula; Pérez-Mormeneu, Judit; Guevara-Nuñez, Daiana; Saiz Escobedo, Lucía; Calatayud, Laura; González-Díaz, Aida; Sanllorente, Albert; Vicens-Zygmunt, Vanesa; Santos Pérez, Salud; Morros Pedrós, Rosa; Salvador González, Betlem
    Background: Long COVID-19 is a post-infectious syndrome with persistent symptoms that can involve multiple organ systems. Evidence suggests that SARS-CoV-2 infection may disrupt gut microbiome composition, potentially contributing to long-term effects. As treatment remains symptom-based, interest has grown in repurposing drugs like montelukast. However, non-antibiotic medications may also alter gut microbial communities, raising questions about their impact. Here, we compare gut microbiota between long COVID patients and healthy controls and examine how montelukast treatment affects microbial composition. Methods: We analysed stool samples from long COVID patients and healthy controls using 16S rRNA gene sequencing (Illumina MiSeq). We evaluate alpha (Shannon) and beta (Bray–Curtis) diversity, followed by relative abundance and linear discriminant effect size analysis, to identify differentially abundant taxa. This proof-of-concept study included a cross-sectional comparison and a longitudinal analysis of montelukast-treated patients vs. placebo. Results: Cross-sectional analysis revealed a significant structural reorganisation of the gut microbial community in long COVID patients, although overall species richness was largely maintained. Linear discriminant effect size analysis revealed that this architectural shift was driven by an enrichment of Firmicutes (Agathobacter and Faecalibacterium genera) in the long COVID group, while healthy controls were characterised by higher abundances of the phyla Verrucomicrobiota and Actinobacteriota, as well as genera Alistipes and Akkermansia. Longitudinal analysis demonstrated that the broader community structure remained stable in both groups; however, montelukast treatment led to a specific enrichment of the genus Dialister, suggesting targeted and potentially transient effects without disrupting the overall microbial landscape. Conclusions: Long COVID is characterised by a significant restructure of the gut ecosystem. This qualitative dysbiosis reflects a shift in homeostatic balance, where the core microbial community remains present, but its proportions are altered. Short-term montelukast treatment shows a minimal impact on the microbial landscape, suggesting treatment does not further destabilise the gut environment. These findings highlight the specific and targeted nature of gastrointestinal involvement in long COVID.
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    Good Short- and Mid-term Outcome After Cross-Linked Hyaluronic Acid Infiltration for Hallux Rigidus: A Case Report
    (SAGE Publications, 2024) Capell Morera, Annabel; Planell i Mas, Elena de; Pérez Palma, Laura; Manzanares Céspedes, María Cristina
    We report a first case of hallux rigidus successfully treated in an elderly patient by intra-articular infiltration of cross-linked hyaluronicacid (HA) 21 mg/mL with mannitol (Desirial Plus) and review the previous literature on the different compositions of HA infiltrative treatmentapplied to hallux rigidus. A 77-year-old female patient with moderate unilateral pain of 6 months of evolution and stiffness of the movement of thefirst metatarsophalangeal joint of the left foot, corresponding to grade 2 of the classification proposed by Coughlin and Shurnas. The objectiveof the study was to perform a pilot test to (a) evaluate the correct technique of intra-articular infiltration as well as (b) the use of a commercialcross-linked HA 21 mg/mL with mannitol, to a voluntary patient diagnosed with hallux rigidus. A single cross-linked HA infiltration is applied tothe first metatarsophalangeal joint with an administered amount of 1 mL. The loaded dorsiflexion, the unloaded dorsiflexion, and the unloadedplantarflexion angles of the first metatarsophalangeal joint improved from 15°, 20°, and 10°, respectively, before injection to 45°, 52°, and 22°,respectively, at 14 days after injection. Moreover, these improvements maintained until the final follow-up (400 days). The intensity of pain,according to the visual analog scale, improved from 7 of 10 before the injection, passing through 4 of 10 at 14 days after the injection, to 1 of 10at 60 days after the injection. Cross-linked HA 21 mg/mL with mannitol improves symptomatology, joint mobility of the first metatarsophalangealjoint, and quality of life in the patient with stiff hallux submitted to the pilot test. These effects have been maintained for more than 14 months.
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    Cyclooxygenase-2 protein expression modulates cell proliferation and apoptosis in solid ameloblastoma and odontogenic keratocyst. An immunohistochemical study
    (John Wiley & Sons, 2021-08-16) Escobar, Enrico; Peñafiel, Cristian; Gómez Valenzuela, Fernán; Chimenos Küstner, Eduardo; Pérez Tomás, Ricardo E.
    Background: Cyclooxygenase-2 protein is a critically important mediator in inflammation that influences proliferation, apoptosis, angiogenesis, and metastasis. Previous works showed a relationship between cyclooxygenase-2 and tumourigenesis in humans and animal models. In epithelial odontogenic tumours and cysts, increased cell proliferation and survival have been linked to its pathogenesis and tumour development. The aim of the present study was to analyze the immunohistochemical expression of cyclooxygenase-2 in solid ameloblastoma and odontogenic keratocyst and its association with proteins related to cell proliferation and apoptosis. Methods: This study was conducted on 40 cases from the Pathological Anatomy Service, University of Chile. The cases were diagnosed as solid ameloblastoma (n=21) and odontogenic keratocyst (n=19) according to WHO 2017. Slides prepared from paraffin-embedded sections were immunohistochemically stained for cyclooxygenase-2, cyclin D1, Ki-67, p63, and Bcl- 2. Statistical evaluation was performed by the Shapiro-Wilk test, ANOVA Mann-Whitney test, and Spearman's correlation coefficient (P < 0.05). Results: There were significant differences in the immunoexpression of cyclin D1, Ki-67, and Bcl-2 between solid ameloblastoma and odontogenic keratocyst. Likewise, there was a significant difference in the immunoexpression of p63 between follicular and plexiform histological types/subtypes of solid ameloblastoma. Lastly, there were statistical associations between cyclooxygenase-2 and Ki-67 for solid ameloblastoma and between cyclooxygenase-2 and p63 for odontogenic keratocyst. Conclusion: A high level of cyclooxygenase-2 is related to increased cell survival and proliferative activity in solid ameloblastoma and odontogenic keratocyst. This event might contribute to tumoural progression and local invasiveness in these lesions.
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    Remote local photoactivation of morphine produces analgesia without opioid-related adverse effects
    (Blackwell, 2021-08-06) López-Cano, Marc; Font Díaz, Joan; Aso Pérez, Ester; Sahlholm, Kristoffer; Cabré, Gisela; Giraldo, Jesús; Koninck, Yves de; Hernando, Jordi; Llebaria Soldevila, Amadeu; Fernández Dueñas, Víctor; Ciruela Alférez, Francisco
    Background and purpose: Opioid-based drugs are the gold standard medicines for pain relief. However, tolerance and several side effects (i.e. constipation and dependence) may occur upon chronic opioid administration. Photopharmacology is a promising approach to improve the benefit/risk profiles of these drugs. Thus, opioids can be locally activated with high spatiotemporal resolution, potentially minimizing systemic-mediated adverse effects. Here, we aimed at developing a morphine photo-derivative (photocaged morphine), which can be activated upon light irradiation both in vitro and in vivo. Experimental approach: Light-dependent activity of pc-morphine was assessed in cell-based assays (intracellular calcium accumulation and electrophysiology) and in mice (formalin animal model of pain). In addition, tolerance, constipation and dependence were investigated in vivo using experimental paradigms. Key results: In mice, pc-morphine was able to elicit antinociceptive effects, both using external light-irradiation (hind paw) and spinal cord implanted fibre-optics. In addition, remote morphine photoactivation was devoid of common systemic opioid-related undesired effects, namely, constipation, tolerance to the analgesic effects, rewarding effects and naloxone-induced withdrawal. Conclusion and implications: Light-dependent opioid-based drugs may allow effective analgesia without the occurrence of tolerance or the associated and severe opioid-related undesired effects.
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    Bifunctional carbazole derivatives for simultaneous therapy and fluorescence imaging in prion disease murine cell models
    (Elsevier Masson SAS, 2022-11-21) Staderini, Matteo; Vanni, Silvia; Colini Baldeschi, Arianna; Giachin, Gabriele; Zattoni, Marco; Celauro, Luigi; Ferracin, Chiara; Bistaffa, Edoardo; Moda, Fabio; Pérez, Daniel I.; Martínez, Ana; Martín, M. Antonia; Martín Cámara, Olmo; Cores, Ángel; Bianchini, Giulia; Kammerer, Robert; Menéndez, J. Carlos; Legname, Giuseppe; Bolognesi, Maria Laura
    Prion diseases are characterized by the self-assembly of pathogenic misfolded scrapie isoforms (PrPSc) of the cellular prion protein (PrPC). In an effort to achieve a theranostic profile, symmetrical bifunctional carbazole derivatives were designed as fluorescent rigid analogues of GN8, a pharmacological chaperone that stabilizes the native PrPC conformation and prevents its pathogenic conversion. A focused library was synthesized via a four-step route, and a representative member was confirmed to have native fluorescence, including a band in the near-infrared region. After a cytotoxicity study, compounds were tested on the RML-infected ScGT1 neuronal cell line, by monitoring the levels of protease-resistant PrPSc. Small dialkylamino groups at the ends of the molecule were found to be optimal in terms of therapeutic index, and the bis-(dimethylaminoacetamido)carbazole derivative 2b was selected for further characterization. It showed activity in two cell lines infected with the mouse-adapted RML strain (ScGT1 and ScN2a). Unlike GN8, 2b did not affect PrPC levels, which represents a potential advantage in terms of toxicity. Amyloid Seeding Assay (ASA) experiments showed the capacity of 2b to delay the aggregation of recombinant mouse PrP. Its ability to interfere with the amplification of the scrapie RML strain by Protein Misfolding Cyclic Amplification (PMCA) was shown to be higher than that of GN8, although 2b did not inhibit the amplification of human vCJD prion. Fluorescent staining of PrPSc aggregates by 2b was confirmed in living cells. 2b emerges as an initial hit compound for further medicinal chemistry optimization towards strain-independent anti-prion compounds.
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    Somatic mutations in cervicovaginal samples: assessing their role in ovarian cancer detection and prognosis
    (Elsevier, 2026-02-23) Pelegrina, Beatriz; Paytubi Casabona, Sònia; Benavente, Yolanda; Marín, Fátima; López-Querol Marta; Onieva, Irene; Frias Gomez, Jon; Pavon Diaz, Claudia; Martínez García, Jose Manuel; Fernandez Gonzalez, Sergi; Dorca Duch, Eduard; Vidal-Bel, August; Barahona, Marc; Pérez Escanilla, Yolanda; Brunet, Joan; Pineda, Marta; Pijuan, Lara; Ponce i Sebastià, Jordi ; Matias-Guiu, Xavier, 1958-; Alemany i Vilches, Laia; Costas, Laura
    Background: Most patients with ovarian cancer are diagnosed at a late stage because of the lack of early stage symptoms or effective screening methods. To address this issue, we evaluated the presence of DNA somatic variants in cervicovaginal samples to aid the detection and prognosis of ovarian cancer. Methods: We employed next-generation sequencing (NGS) with molecular identifiers to analyze samples from a case-control study involving women diagnosed with ovarian cancer and age-matched controls. The study included Pap smear samples from 43 patients with ovarian cancer and 99 controls, 27 paired vaginal self-samples, 16 endometrial aspirates, and 13 tumor samples from cases, for a total of 198 samples. Results: Pathogenic and likely pathogenic variants were identified in 25.6 % (11/43, 95 % confidence interval -CI-:13.5–41.2) of Pap smear samples from patients with ovarian cancer. These variants were also found in 33.3 % of the control samples, leading to a specificity of 66.7 % (66/99, 95 %CI:56.5–75.8 %). Among the paired samples, we observed pathogenic and likely pathogenic variants in 14.3 % (2/14, 95 %CI:1.78–42.8) of the vaginal samples, 77.8 % (7/9, 95 %CI:40.0–97.2) of the endometrial aspirates, and 69.2 % (9/13, 95 %CI:39.6–90.9) of the tumor samples. In the age- and stage-adjusted survival models, women with variants detected in Pap smear samples had poorer overall survival than those without variants (hazard ratio -HR-=4.27, 95 %CI:1.06–17.23; P = 0.041). Conclusions: DNA somatic variants in cervicovaginal samples have limited diagnostic value for detecting ovarian cancer. However, their presence may have prognostic significance, warranting further investigation. Future research could explore multimodal strategies that integrate molecular markers with imaging or other approaches to improve early detection.