Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)

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Pancreas outcomes between living and deceased kidney donor in pancreas after kidney transplantation patients.
(2018-11-01) Ferrer Fàbrega, Joana; Rovira Juarez, Jordi; Ventura Abreu Aguiarà, Pedro; Ferrer Marrades, Jorge Pedro; Revuelta Vicente, Ignacio; Paredes D; De Sousa-Amorim E; Rovira Sole, Jordina; Esmatjes Mompo, Enrique; García-Valdecasas Salgado, Juan Carlos; Campistol Plana, Josep M; Oppenheimer Salinas, Federico; Diekmann, Fritz; Ricart Batlle, Maria Teresa
Pancreas outcomes in pancreas after kidney transplantation (PAK) patients have been reported as being inferior to those of patients who receive simultaneous pancreas and kidney transplantation (SPK). The influence of the kidney donor (i.e. living versus deceased) has never been previously addressed.We retrospectively analysed all pancreas transplants performed in a single centre since 2007 and compared the outcomes between those patients who had previously received a living-donor kidney transplant (pancreas transplantation after living-donor kidney transplantation, PAldK; n?=?18) or a deceased-donor kidney transplant (pancreas transplantation after deceased-donor kidney transplantation, PAddK; n?=?28), using SPK (n?=?139) recipients as a reference.Pancreas survival was similar between all groups, but inferior for PAldK when including only those with a functioning graft at day 90 post-transplantation (P?=?0.004). Pancreas acute rejection was significantly increased in PAldK (67%; 1.8?±?1.4 episodes/graft) when compared with PAddK (25%) and SPK (32%) (P?<?0.05) patients. In a multivariate Cox regression model including known risk factors for pancreas rejection, PAldK was the only predictor of acute rejection (hazard ratio 6.82, 95% confidence interval 1.51-30.70, P?<?0.05). No association was found between donor-recipient HLA mismatches and graft rejection. Repeated HLA mismatches between kidney and pancreas donors (0 versus 1-6) did not correlate with pancreas graft rejection or survival in either PAK transplantation group (P?>?0.05).Pancreas graft outcomes are worse for PAldK when compared with PAddK and SPK patients.
Extracorporeal Photopheresis Improves Graft Survival in a Full-Mismatch Rat Model of Kidney Transplantation
(2023-01-12) Piñeiro, Gastón Julio; Lazo Rodriguez, Marta; Ventura Abreu Aguiarà, Pedro; Ramirez Bajo, Maria Jose; Bañon Maneus, Elisenda; Lozano Molero, Miguel; Cid Vidal, Joan; Hierro Garcia, Natalia; Cucchiari, David; Revuelta Vicente, Ignacio; Montagud Marrahí, Enrique; Palou Ribera, Eduard; Bayés Genís, Beatriz Enriqueta; Campistol Plana, Josep M; Diekmann, Fritz; Rovira Juarez, Jordi
Extracorporeal photopheresis (ECP) is an immunomodulatory therapy based on the infusion of autologous cellular products exposed to ultraviolet light (UV) in the presence of a photosensitizer. The study evaluates the ECP efficacy as induction therapy in a full-mismatch kidney transplant rat model. Dark Agouti to Lewis (DA-L) kidney transplant model has been established. ECP product was obtained from Lewis rat recipients after DA kidney graft transplantation (LewDA). Leukocytes of those LewDA rats were exposed to 8-methoxy psoralen, and illuminated with UV-A. The ECP doses assessed were 10 × 106 and 100 × 106 cells/time point. Lewis recipients received seven ECP infusions. DA-L model was characterized by the appearance of donor-specific antibodies (DSA) and kidney function deterioration from day three after kidney transplant. The dysfunction progressed rapidly until graft loss (6.1 ± 0.5 days). Tacrolimus at 0.25 mg/kg prolonged rat survival until 11.4 ± 0.7 days (p = 0.0004). In this context, the application of leukocytes from LewDA sensitized rats accelerated the rejection (8.7 ± 0.45, p = 0.0012), whereas ECP product at high dose extended kidney graft survival until 26.3 ± 7.3 days, reducing class I and II DSA in surviving rats. ECP treatment increases kidney graft survival in full-mismatch rat model of acute rejection and is a suitable immunomodulatory therapy to be explored in kidney transplantation.Copyright © 2023 Piñeiro, Lazo-Rodriguez, Ventura-Aguiar, Ramirez-Bajo, Banon-Maneus, Lozano, Cid, Hierro-Garcia, Cucchiari, Revuelta, Montagud-Marrahi, Palou, Bayés-Genís, Campistol, Diekmann and Rovira.
Impact of Mesenchymal Stromal Cells and Their Extracellular Vesicles in a Rat Model of Kidney Rejection
(2020-01-29) Rovira Sole, Jordina; Ramirez Bajo, Maria Jose; Rovira Juarez, Jordi; Lazo Rodriguez, Marta; Bañon Maneus, Elisenda; Tubita, Valeria; Moya Rull, Daniel; Hierro Garcia, Natalia; Ventura Abreu Aguiarà, Pedro; Oppenheimer Salinas, Federico; Campistol Plana, Josep M; Diekmann, Fritz
© Copyright © 2020 Ramirez-Bajo, Rovira, Lazo-Rodriguez, Banon-Maneus, Tubita, Moya-Rull, Hierro-Garcia, Ventura-Aguiar, Oppenheimer, Campistol and Diekmann. Background: Mesenchymal stromal cells (MSCs) from different sources possess great therapeutic potential due to their immunomodulatory properties associated with allograft tolerance. However, a crucial role in this activity resides in extracellular vesicles (EVs) and signaling molecules secreted by cells. This study aimed to evaluate the immunomodulatory properties of donor and recipient MSCs isolated from adipose tissue (AD) or bone marrow (BM) and their EVs on kidney outcome in a rat kidney transplant model. Methods: The heterotopic-kidney-transplant Fisher-to-Lewis rat model (F-L) was performed to study mixed cellular and humoral rejection. After kidney transplantation, Lewis recipients were assigned to 10 groups; two control groups; four groups received autologous MSCs (either AD- or BM- MSC) or EVs (derived from both cell types); and four groups received donor-derived MSCs or EVs. AD and BM-EVs were purified by ultracentrifugation. Autologous cell therapies were administered three times intravenously; immediately after kidney transplantation, 4 and 8 weeks, whereas donor-derived cell therapies were administered once intravenously immediately after transplantation. Survival and renal function were monitored. Twelve weeks after kidney transplantation grafts were harvested, infiltrating lymphocytes were analyzed by flow cytometry and histological lesions were characterized. Results: Autologous AD- and BM-MSCs, but not their EVs, prolonged graft and recipient survival in a rat model of kidney rejection. Autologous AD- and BM-MSCs significantly improved renal function during the first 4 weeks after transplantation. The amelioration of graft function could be associated with an improvement in tubular damage, as well as in T, and NK cell infiltration. On the other side, the application of donor-derived AD-MSC was harmful, and all rats died before the end of the protocol. AD-EVs did not accelerate the rejection. Contrary to autologous MSCs results, the single dose of donor-derived BM-MSCs is not enough to ameliorate kidney graft damage. Conclusion: EVs treatments did not exert any benefit in our experimental settings. In the autologous setting, BM-MSCs prompted as a potentially promising therapy to improve kidney graft outcomes in rats with chronic mixed rejection. In the donor-derived setting, AD-MSC accelerated progression to end-stage kidney disease. Further experiments are required to adjust timing and dose for better long-term outcomes.
Isolation of Extracellular Vesicles Derived from Mesenchymal Stromal Cells by Ultracentrifugation
(2020-12-20) Ramirez Bajo, Maria Jose; Bañon Maneus, Elisenda; Rovira Juarez, Jordi; Campistol Plana, Josep M; Diekmann, Fritz
Extracellular vesicles (EVs) are a heterogeneous group of membranous vesicles that differ on their biogenesis and release pathways, such as exosomes, microvesicles and apoptotic bodies. They are involved in cell-to-cell communication delivering signal molecules (proteins, nucleic acids, lipids, etc.) that can regulate different physiological processes, as well as the development and progression of several diseases. There are different methods and commercial kits to isolate EVs and depending on the methodology one could obtain EVs with different degrees of efficiency, purity and it can be more or less time-consuming. Then, the choice has to be according to the different advantages and disadvantages, and their use for downstream applications. Here, we describe the EVs isolation method from mesenchymal stromal cells by ultracentrifugation. This EVs isolation can be performed using common media and buffers, and only with the requirement of an analytical ultracentrifuge. Moreover, this method can be used to obtain large quantity of EVs with a good reproducibility for developing in vitro and in vivo experiments and studying their biological actions.
Chimeric HLA antibody receptor T cells for targeted therapy of antibody-mediated rejection in transplantation
(2023-10-01) Betriu Mendez, Sergi; Rovira Juarez, Jordi; Arana Aliaga, Carolt; Garcia Busquets, Ainhoa; Martinez Florensa, Mario; Ramirez Bajo, Maria Jose; Bañon Maneus, Elisenda; Lazo Rodriguez, Marta; Bartoló-Ibars A; Claas FHJ; Mulder A; Heidt S; Juan Otero, Manel; Bayés Genís, Beatriz Enriqueta; Campistol Plana, Josep M; Palou Ribera, Eduard; Diekmann, Fritz
The presence of donor-specific antibodies (DSA), mainly against HLA, increases the risk of allograft rejection. Moreover, antibody-mediated rejection (ABMR) remains an important barrier to optimal long-term outcomes after solid organ transplantation. The development of chimeric autoantibody receptor T lymphocytes has been postulated for targeted therapy of autoimmune diseases. We aimed to develop a targeted therapy for DSA desensitization and ABMR, generating T cells with a chimeric HLA antibody receptor (CHAR) that specifically eliminates DSA-producing B cells. We have genetically engineered an HLA-A2-specific CHAR (A2-CHAR) and transduced it into human T cells. Then, we have performed in vitro experiments such as cytokine measurement, effector cell activation, and cytotoxicity against anti-HLA-A2 antibody-expressing target cells. In addition, we have performed A2-CHAR-Tc cytotoxic assays in an immunodeficient mouse model. A2-CHAR expressing T cells could selectively eliminate HLA-A2 antibody-producing B cells in vitro. The cytotoxic capacity of A2-CHAR expressing T cells mainly depended on Granzyme B release. In the NSG mouse model, A2-CHAR-T cells could identify and eradicate HLA-A2 antibody-producing B cells even when those cells are localized in the bone marrow. This ability is effector:target ratio dependent. CHAR technology generates potent and functional human cytotoxic T cells to target alloreactive HLA class I antibody-producing B cells. Thus, we consider that CHAR technology may be used as a selective desensitization protocol or an ABMR therapy in transplantation.© 2023 The Authors. HLA: Immune Response Genetics published by John Wiley & Sons Ltd.
Wnt pathway activation in long term remnant rat model
(2014-01-01) Bañon Maneus, Elisenda; Rovira Juarez, Jordi; Ramirez Bajo, Maria Jose; Moya Rull, Daniel; Hierro Garcia, Natalia; Takenaka, S; Diekmann, Fritz; Eickelberg, O; Konigshoff, M; Campistol Plana, Josep M
Progression of chronic kidney disease (CKD) is characterized by deposition of extracellular matrix. This is an irreversible process that leads to tubulointerstitial fibrosis and finally loss of kidney function. Wnt/ ?-catenin pathway was reported to be aberrantly activated in the progressive damage associated with chronic organ failure. Extensive renal ablation is an experimental model widely used to gain insight into the mechanisms responsible for the development of CKD, but it was not evaluated for Wnt/ ?-catenin pathway. This study aimed to elucidate if the rat 5/6 renal mass reduction model (RMR) is a good model for the Wnt/ ?-catenin activation and possible next modulation. RMR model was evaluated at 12 and 18 weeks after the surgery, when CKD is close to end-stage kidney disease demonstrated by molecular and histological studies. Wnt pathway components were analyzed at mRNA and protein level. Our results demonstrate that Wnt pathway is active by increase of ?-catenin at mRNA level and nuclear translocation in tubular epithelium as well as some target genes. These results validate the RMR model for future modulation of Wnt pathway, starting at shorter time after the surgery.
Enhanced Kidney Targeting and Distribution of Tubuloids During Normothermic Perfusion
(2025-09-05) Montagud Marrahí, Enrique; Rodriguez-Gonzalo, Adriana; López Aladid, Ruben; Luque, Yosu; Rabadan-Ros, Ruben; Cuadrado Payán, Elena; Bañon Maneus, Elisenda; Rovira Juarez, Jordi; Lazo Rodriguez, Marta; Aguila, Oriol; Arana Aliaga, Carolt; Garcia-Busquets, Ainhoa; Hierro, Natalia; Prudhomme, Thomas; Musquera Felip, Mireia; Xia, Yun; Diekmann, Fritz; Campistol, Josep M; Ramirez Bajo, Maria Jose
Tubuloids have become a promising tool for modeling and regenerating kidney disease, although their ability for integration and regeneration in vivo is not well documented. Here, we established, characterized, and compared human tubuloids using two optimized protocols: one involving prior isolation of tubular cells (Crude tubuloids) and the other involving prior isolation of proximal tubular cells (F4 tubuloids). Next, healthy rat-derived tubuloids were established using this protocol. Finally, we compared two strategies for delivering GFP tubuloids to a kidney host: 1) subcapsular/intracortical injection and 2) tubuloid infusion during normothermic preservation in a rat transplantation model and a discarded human kidney. F4 tubuloids achieved a higher level of differentiation state compared to Crude tubuloids. When analyzing tubuloid delivery to the kidney, normothermic perfusion was found to be more efficient than in vivo injection. Moreover, fully developed tubules were observed in the host parenchyma at 1 week and 1 month after infusion during normothermic perfusion represent a potential strategy to enhance the translatability of kidney regenerative therapies into clinical practice to condition kidney grafts and to treat kidney diseases.
SF3B1 mutation-mediated sensitization to H3B-8800 splicing inhibitor in chronic lymphocytic leukemia
(EMBO Press, Rockefeller University Press, and Cold Spring Harbor Laboratory Press, 2023-08-10) López Oreja, Irene; Gohr, Andre; Playa-Albinyana, Heribert; Giró, Ariadna; Arenas Ríos, Fabián; Higashi, Morihiro; Tripathi, Rupal; López Guerra, Mónica; Irimia Martínez, Manuel; Aymerich Gregorio, Marta; Valcárcel Juárez, Juan; Bonnal, Sophie; Colomer Pujol, Dolors
Splicing factor 3B subunit 1 (SF3B1) is involved in pre-mRNA branch site recognition and is the target of antitumor-splicing inhibitors. Mutations in SF3B1 are observed in 15% of patients with chronic lymphocytic leukemia (CLL) and are associated with poor prognosis, but their pathogenic mechanisms remain poorly understood. Using deep RNA-sequencing data from 298 CLL tumor samples and isogenic SF3B1 WT and K700E-mutated CLL cell lines, we characterize targets and pre-mRNA sequence features associated with the selection of cryptic 39 splice sites upon SF3B1 mutation, including an event in the MAP3K7 gene relevant for activation of NF-κB signaling. Using the H3B-8800 splicing modulator, we show, for the first time in CLL, cytotoxic effects in vitro in primary CLL samples and in SF3B1-mutated isogenic CLL cell lines, accompanied by major splicing changes and delayed leukemic infiltration in a CLL xenotransplant mouse model. H3B-8800 displayed preferential lethality towards SF3B1- mutated cells and synergism with the BCL2 inhibitor venetoclax, supporting the potential use of SF3B1 inhibitors as a novel therapeutic strategy in CLL.
A novel patient-derived 3D model recapitulates mantle cell lymphoma lymph node signaling, immune profile and in vivo ibrutinib responses
(Springer Nature, 2023-04-08) Araujo Ayala, Ferran; Dobaño-López, Cèlia; Garcia Valero, Juan; Nadeu Prat, Ferran; Gava, Fabien; Faria, Carla; Norlund, Marine; Morin, Renaud; Bernes-Lasserre, Pascale; Serrat Aymerich, Neus; Playa-Albinyana, Heribert; Giménez Martínez, Rubén; Campo Güerri, Elias; Lagarde, Jean-Michel; López Guillermo, Armando; Giné Soca, Eva; Colomer Pujol, Dolors; Bezombes, Christine; Pérez Galán, Patricia
Mantle cell lymphoma (MCL), a rare and aggressive B-cell non-Hodgkin lymphoma, mainly develops in the lymph node (LN) and creates a protective and immunosuppressive niche that facilitates tumor survival, proliferation and chemoresistance. To capture disease heterogeneity and tumor microenvironment (TME) cues, we have developed the first patient-derived MCL spheroids (MCL-PDLS) that recapitulate tumor oncogenic pathways and immune microenvironment in a multiplexed system that allows easy drug screening, including immunotherapies. MCL spheroids, integrated by tumor B cells, monocytes and autologous T-cells self-organize in disc-shaped structures, where B and T-cells maintain viability and proliferate, and monocytes differentiate into M2-like macrophages. RNA-seq analysis demonstrated that tumor cells recapitulate hallmarks of MCL-LN (proliferation, NF-kB and BCR), with T cells exhibiting an exhaustion profile (PD1, TIM-3 and TIGIT). MCL-PDLS reproduces in vivo responses to ibrutinib and demonstrates that combination of ibrutinib with nivolumab (anti-PD1) may be effective in ibrutinib-resistant cases by engaging an immune response with increased interferon gamma and granzyme B release. In conclusion, MCL-PDLS recapitulates specific MCL-LN features and in vivo responses to ibrutinib, representing a robust tool to study MCL interaction with the immune TME and to perform drug screening in a patient-derived system, advancing toward personalized therapeutic approaches.
Chronic lymphocytic leukemia patient-derived xenografts recapitulate clonal evolution to Richter transformation
(Springer Nature, 2023-11-28) Playa-Albinyana, Heribert; Arenas Ríos, Fabián; Royo, Romina; Giró, Ariadna; López Oreja, Irene; Aymerich, Marta; López Guerra, Mónica; Frigola, Gerard; Beà Bobet, Sílvia M.; Delgado, Julio (Delgado González); Garcia-Roves, Pablo M.; Campo Güerri, Elias; Nadeu Prat, Ferran; Colomer Pujol, Dolors
Chronic lymphocytic leukemia (CLL) is a B-cell neoplasm with a heterogeneous clinical behavior. In 5-10% of patients the disease transforms into a diffuse large-B cell lymphoma known as Richter transformation (RT), which is associated with dismal prognosis. Here, we aimed to establish patient-derived xenograft (PDX) models to study the molecular features and evolution of CLL and RT. We generated two PDXs by injecting CLL (PDX12) and RT (PDX19) cells into immunocompromised NSG mice. Both PDXs were morphologically and phenotypically similar to RT. Whole-genome sequencing analysis at different time points of the PDX evolution revealed a genomic landscape similar to RT tumors from both patients and uncovered an unprecedented RT subclonal heterogeneity and clonal evolution during PDX generation. In PDX12, the transformed cells expanded from a very small subclone already present at the CLL stage. Transcriptomic analysis of PDXs showed a high oxidative phosphorylation (OXPHOS) and low B-cell receptor (BCR) signaling similar to the RT in the patients. IACS-010759, an OXPHOS inhibitor, reduced proliferation, and circumvented resistance to venetoclax. In summary, we have generated new RT-PDX models, one of them from CLL cells that mimicked the evolution of CLL to RT uncovering intrinsic features of RT cells of therapeutical value
The PADRIS-PRESTO Cohort: A Comprehensive Population-Based Study on Mental Health in Catalonia
(Cambridge University Press (CUP), 2025-12-01) De Prisco, Michele; Oliva, Vincenzo; Fico, Giovanna; Mas, Ariadna; Valenzuela-Pascual, Clàudia; Montejo Egido, Laura; Bort, Marta; Sommerhof, Constanza; Bortolozzi, Analia; Miquel Rio, Lluís; Vilella, Elisabet; Forte, Maria Florencia; Fortea, Lydia; Fernández-Plaza, Tábatha; Giménez Palomo, Anna; Sagué-Vilavella, Maria; Madero Gómez, Santiago; Llorca-Bofí, Vicent; Bioque Alcázar, Miquel; Grande i Fullana, Iria; Murru, Andrea; Pacchiarotti, Isabella; Cavero Álvarez, Myriam; Blanch Andreu, Jordi; Viñas-Bardolet, Clara; Aparicio-Nogué, Vicenç; Martínez-Cerdá, Juan Francisco; Parellada Rodón, Eduard; Martínez-Arán, Anabel, 1971-; Radua, Joaquim; Vieta i Pascual, Eduard, 1963-; Hidalgo Mazzei, Diego; Anmella, Gerard
Background: Mental disorders affect nearly 970 million people worldwide, impacting individuals and healthcare systems. Large population databases offer insights often unattainable in smaller studies, but their findings may not always generalize across diverse regions. To address this, we introduce a European cohort from Catalonia, Spain, allowing for comparisons between individuals with mental disorders and the general population. Methods: Data were obtained from the “Programa d’analítica de dades per a la recerca i la innovació en salut” (PADRIS). The cohort included all individuals who accessed public specialized mental health services between 2015 and 2019, with retrospective follow-up extending to 2010. These individuals, referred to as cases, were matched by age, sex, and health region with controls, individuals who had no interactions with mental health services during the same period. Sociodemographic and clinical characteristics, including psychiatric diagnoses, comorbidities, smoking status, healthcare utilization, and prescribed treatments, were analyzed. Results: The study included 1,421,510 individuals (mean age: 41.6±22.1; 53.6% female), with 473,812 cases and 947,698 controls. Cases were more likely to be exempt from income reporting, be ever-smokers, and have musculoskeletal comorbidities. A total of 1,547,374 psychiatric diagnoses were recorded, with anxiety (31.38%) and mood disorders (18.83%) being the most frequent. Over the follow-up, 76.2 million primary care visits and 67.1 million prescriptions were recorded. Conclusions: This cohort enhances our understanding of mental health service use, diagnostic trends, and treatment patterns in Catalonia. The insights derived from this cohort have the potential to inform mental health policies, improving outcomes within and beyond the region.
A review of vancomycin, gentamicin and amikacin population pharmacokientic models in neonates and infants.
(Springer Nature Switzerland, 2025-01-15) Albanell Fernández, Marta; Bastida Fernández, Carla; Rodríguez Reyes, Montse; Soy Muner, Dolors
Abstract Population pharmacokinetic (popPK) models are an essential tool when implementing therapeutic drug monitoring (TDM) and to overcome dosing challenges in neonates in clinical practice. Since vancomycin, gentamicin, and amikacin are among the most prescribed antibiotics for the neonatal population, we aimed to characterize the popPK models of these antibiotics and the covariates that may influence the pharmacokinetic parameters in neonates and infants with no previous pathologies. We searched the PubMed, Embase, Web of Science, and Scopus databases and the bibliographies of relevant articles from inception to the beginning of February 2024. The search identified 2064 articles, of which 68 met the inclusion criteria (34 for vancomycin, 21 for gentamicin, 13 for amikacin). A one-compartment popPK model was more frequently used to describe the pharmacokinetics of the three antibiotics (91.2% vancomycin, 76.9% gentamicin, 57.1% amikacin). Pharmacokinetic parameter (mean ± standard deviation) values calculated for a “typical” neonate weighing 3 kg were as follows: clearance (CL) 0.34 ± 0.80 L/h for vancomycin, 0.27 ± 0.49 L/h for gentamicin, and 0.19 ± 0.07 L/h for amikacin; volume of distribution (V d): 1.75 ± 0.65 L for vancomycin, 1.54 ± 0.53 L for gentamicin, and 1.67 ± 0.27 L for amikacin for one compartment models. Total body weight, postmenstrual age, and serum creatinine were common predictors (covariates) for describing the variability in CL, whereas only total body weight predominated for V d. A single universal popPK model for each of the antibiotics reviewed cannot be implemented in the neonatal population because of the significant variability between them. Body weight, renal function, and postmenstrual age are important predictors of CL in the three antibiotics, and total body weight for V d. TDM represents an essential tool in this population, not only to avoid toxicity but to attain the desired pharmacokinetic/pharmacodynamic index. The characteristics of the neonatal population, coupled with the lack of prospective studies and external validation of most models, indicate a need to continue investigating the pharmacokinetics of these antibiotics in neonates.
Clonal tracing with somatic epimutations reveals dynamics of blood ageing
(Springer Nature, 2025-05-21) Scherer, Michael; Singh, Indranil; Braun, Martina Maria; Szu Tu, Chelsea; Sánchez Sánchez, Pedro; Lindenhofer, Dominik; Jakobsen, Niels Asger; Körber,Verena; Kardorff, Michael; Nitsch, Lena; Kautz, Pauline; Rühle, Julia; Bianch, Agostina; Cozzuto, Luca; Frömel, Robert; Beneyto Calabuig, Sergi; Lareau, Caleb; Satpathy, Ansuman T.; Beekman, Renée; Steinmetz, Lars M.; Raffel, Simon; Ludwig, Leif S.; Vyas, Paresh; Rodríguez Fraticelli, Alejo E.; Velten, Lars
Current approaches used to track stem cell clones through differentiation require genetic engineering1,2 or rely on sparse somatic DNA variants3,4, which limits their wide application. Here we discover that DNA methylation of a subset of CpG sites reflects cellular differentiation, whereas another subset undergoes stochastic epimutations and can serve as digital barcodes of clonal identity. We demonstrate that targeted single-cell profiling of DNA methylation5 at single-CpG resolution can accurately extract both layers of information. To that end, we develop EPI-Clone, a method for transgene-free lineage tracing at scale. Applied to mouse and human haematopoiesis, we capture hundreds of clonal differentiation trajectories across tens of individuals and 230,358 single cells. In mouse ageing, we demonstrate that myeloid bias and low output of old haematopoietic stem cells6 are restricted to a small number of expanded clones, whereas many functionally young-like clones persist in old age. In human ageing, clones with and without known driver mutations of clonal haematopoieis7 are part of a spectrum of age-related clonal expansions that display similar lineage biases. EPI-Clone enables accurate and transgene-free single-cell lineage tracing on hematopoietic cell state landscapes at scale.
Decreased practice effects in cognitively unimpaired amyloid betapositive individuals: a multicenter, longitudinal, cohort study
(John Wiley & Sons, 2025-03-01) Tort Merino, Adrià; Pérez Millan, Agnès; Falgàs Martínez, Neus; Borrego Écija, Sergi; Esteller, Diana; Bosch, Bea; Castellví, Magdalena; Juncà Parella, Jordi; Val Guardiola, Andrea; Fernández Villullas, Guadalupe; Antonell Boixader, Anna, 1978-; Sanchez-Saudinos, María Belén; Rubio Guerra, Sara; Zhu, Nuole; García Martínez, María; Pozueta, Ana; Estanga, Ainara; Ecay Torres, Mirian; Lopez de Luis, Carolina; Tainta, Mikel; Altuna, Miren; Rodriguez Rodriguez, Eloy; Sanchez Juan, Pascual; Martinez Lage, Pablo; Lleo, Alberto; Fortea, Juan; Illán Gala, Ignacio; Balasa, Mircea; Lladó Plarrumaní, Albert; Rami González, Lorena; Sanchez Valle, Raquel
INTRODUCTION We aimed to determine whether cognitively unimpaired (CU) amyloid- beta-positive (A beta+) individuals display decreased practice effects on serial neuropsychological testing. METHODS We included 209 CU participants from three research centers, 157 A beta- controls and 52 A beta+ individuals. Participants underwent neuropsychological assessment at baseline and annually during a 2-year follow-up. We used linear mixed-effects models to analyze cognitive change over time between the two groups, including time from baseline, amyloid status, their interaction, age, sex, and years of education as fixed effects and the intercept and time as random effects. RESULTS The A beta+ group showed reduced practice effects in verbal learning (beta = -1.14, SE = 0.40, p = 0.0046) and memory function (beta = -0.56, SE = 0.19, p = 0.0035), as well as in language tasks (beta = -0.59, SE = 0.19, p = 0.0027). DISCUSSION Individuals with normal cognition who are in the Alzheimer's continuum show decreased practice effects over annual neuropsychological testing. Our findings could have implications for the design and interpretation of primary prevention trials. Highlights This was a multicenter study on practice effects in asymptomatic A beta+ individuals. We used LME models to analyze cognitive trajectories across multiple domains. Practice-effects reductions might be an indicator of subtle cognitive decline. Implications on clinical and research settings within the AD field are discussed.
One-stage knee replacement shows similar healing rates in patients with negative or positive preoperative cultures: a retrospective cohort study
(Copernicus Publications, 2025-07-25) Sabater Martos, Marta; Morata Ruiz, Laura; Segur Vilalta, Josep Maria; Soriano Viladomiu, Alex; Martínez Pastor, Juan Carlos
Treatment of chronic periprosthetic joint infections (PJIs) involves prosthesis removal, reimplantation, and antibiotic treatment. This process can be performed as a two-stage replacement or a one-stage replacement. One-stage replacement is classically performed only in patients who meet very strict criteria. The objective of this study was to analyse the healing and failure rates of one-stage knee replacement in patients with positive preoperative cultures and in those with negative preoperative cultures. Secondarily, we analysed the healing rate in patients with a sinus tract. Material and methods: We included 56 patients diagnosed with likely or confirmed PJI who underwent one-stage knee replacement in our centre between January 2016 and December 2021, with a minimum follow-up of 1 year. We evaluated the differences between cases with positive and negative preoperative cultures. Survival differences were assessed according to preoperative culture positivity and the presence of a sinus tract. Results: Preoperative cultures had positive results in 43 patients (76.8 %) and negative results in 13 patients (23.2 %). The overall failure rate was 12.5 % (seven patients), with one of these patients having had negative preoperative cultures. Of the 49 patients (87.5 %) with good results, 12 had negative preoperative cultures, and 37 had positive cultures (p = 1.00). Only 6 (10.7 %) of the 56 patients studied presented with a sinus tract. The differences in terms of healing and failure rates between patients with and without a sinus tract were not statistically significant (p = 0.57). Discussion: Using less strict criteria for patients, such as allowing preoperative negative cultures or the presence of a sinus tract, produced similar results to those for patients with only positive cultures or intact soft tissue.
Thinner and wiser? Prospects of GLP-1 agonists in psychiatry
(Elsevier B.V., 2025-05-22) Vieta i Pascual, Eduard, 1963-; Oliva, Vincenzo
In recent years, growing scientific attention has converged on the intricate, bidirectional relationship between physical health and mental well-being. Chronic inflammation, disruptions in the gut–brain axis and microbiota, and metabolic alterations such as obesity and type 2 diabetes have all been implicated in the pathophysiology of neuropsychiatric disorders. These insights are not merely academic—they are transforming how we approach, frame, and treat neuropsychiatric disorders.
Eye-tracking metrics during image viewing as possible biomarkers of cognitive alterations: A systematic review and meta-analysis in people with bipolar disorder
(Elsevier B.V., 2025-05-06) De Prisco, Michele ; Oliva, Vincenzo; Fico, Giovanna; Kjærstad, Hanne Lie; Woznica Miskowiak, Kamilla; Anmella, Gerard; Hidalgo Mazzei, Diego; Murru, Andrea; Vieta i Pascual, Eduard, 1963-; Radua, Joaquim
Eye-tracking metrics, such as fixation latency, fixation count, saccade amplitude, and gaze duration, are emerging digital biomarkers that can enhance our understanding of cognitive and emotional alterations in mental disorders. For bipolar disorder (BD), eye-tracking offers a promising approach to investigate the mechanisms underlying the deficits in attention, inhibitory control, and emotion processing. This meta-analysis examined the differences in eye-tracking metrics in individuals with BD compared to healthy controls (HCs) or individuals with other psychiatric conditions, while observing images with emotional or non-emotional content. A comprehensive search of the PubMed/MEDLINE, Scopus, and PsycINFO databases was conducted from inception to August 20, 2024. Studies investigating differences in eye-tracking metrics using an image viewing paradigm were reviewed, and meta-analyses were performed. Ten studies met the inclusion criteria: BD (n = 337) was compared to HCs (n = 352) in all ten studies, to major depressive disorder (n = 60) in two studies, and to schizophrenia (n = 22) in one study. Meta-analyses were only feasible for comparisons between BD and HCs. Individuals with BD exhibited higher latency for the first fixation, a reduced number of fixations, shorter gaze duration, and lower saccadic peak velocity and amplitude. Additionally, they showed shorter fixation durations only when viewing images with negative content. This report provides valuable insights into the cognitive and emotional difficulties faced by individuals with BD, which can guide the development of more targeted and effective assessments and interventions for this population.
Systems biology drug screening identifies statins as enhancers of current therapies in chronic lymphocytic leukemia
(Nature Publishing Group, 2020-12-17) Gimenez, Neus; Tripathi, Rupal; Giró, Ariadna; Rosich, Laia; López Guerra, Mónica; López Oreja, Irene; Playa-Albinyana, Heribert; Arenas Ríos, Fabián; Mas, José Manuel; Pérez Galán, Patricia; Delgado, Julio (Delgado González); Campo Güerri, Elias; Farrés, Judith; Colomer Pujol, Dolors
Chronic lymphocytic leukemia (CLL) is a B lymphoid malignancy highly dependent on the microenvironment. Despite new targeted therapies such as ibrutinib and venetoclax, disease progression and relapse remain an issue. CLL cell interactions with the supportive tissue microenvironment play a critical role in disease pathogenesis. We used a platform for drug discovery based on systems biology and artificial intelligence, to identify drugs targeting key proteins described to have a role in the microenvironment. The selected compounds were screened in CLL cell lines in the presence of stromal cells to mimic the microenvironment and validated the best candidates in primary CLL cells. Our results showed that the commercial drug simvastatin was the most effective and selective out of the tested compounds. Simvastatin decreased CLL cell survival and proliferation as well as cell adhesion. Importantly, this drug enhanced the antitumor effect of venetoclax and ibrutinib. We proposed that systems biology approaches combined with pharmacological screening could help to find new drugs for CLL treatment and to predict new combinations with current therapies. Our results highlight the possibility of repurposing widely used drugs such as statins to target the microenvironment and to improve the efficacy of ibrutinib or venetoclax in CLL cells.
Updating the classification and routine diagnosis of NSAID hypersensitivity reactions: A WAO Statement
(Elsevier Inc., 2025-08-01) Romano, Antonio; Valluzzi, Rocco L.; Alvarez Cuesta, Emilio; Ansotegui, Ignacio; Asero, Riccardo; Barbaud, Annick; Bartra Tomàs, Joan; Bavbek, Sevim; Cahilli, Katherine N.; Demoly, Pascal; Doña, Inmaculada; Guzmán Meléndez, Maria A.; Kidon, Mona; Li, Lily; Madrigal Burgaleta, Ricardo; Makowska, Joanna; Park, Hae-Sim; Picado Vallés, César; Sanak, Marek; Taniguchi, Masami; White, Andrew A.; Atanaskovic-Markovic, Marina; Attanasi, Marina; Aun, Marcelo Vivolo; Berges Gimeno, Maria Pilar; Bernal Rubio, Lorena; Brockow, Knut; Bustamante, Lucrecia; Caffarelli, Carlo; Chang, Yoon Seok; Chikhladze, Manana; Ensina, Luis Felipe; Fernandes, Brayan N.; Garvey, Lene Heise; Giavina Bianchi, Pedro; Gómes, Eva; Kuyucu, Semanur; Labella, Marina; Mayorga, Cristobalina; Mori, Francesca; Pagani, Mauro; Palma Pino, Valeria; Parisi, Claudio A. S.; Phillips, Elizabeth; Powell, Elizabeth; Ramien, Michelle; Savic, Louise; Solano Solares, Emilio; Tanno, Luciana Kase; Vázquez Revuelta, Paula; Watts, Timothy; Yamaguchi, Masao
Hypersensitivity reactions to non-steroidal anti-inflammatory drugs (NSAIDs) have been classified as immediate (or acute) and delayed. Immediate reactions can be further classified into 4 clinical types: NSAID-exacerbated respiratory disease (N-ERD), NSAID-exacerbated cutaneous disease (NECD), NSAID-induced urticaria/angioedema (NIUA), and single NSAID-induced urticaria/angioedema/anaphylaxis (SNIUAA). Specifically, the NIUA type references reactions to ≥2 NSAIDs belonging to different chemical groups, involving urticaria and/or angioedema in patients with no underlying chronic spontaneous urticaria. However, there are patients meeting cross-reactive criteria for NIUA phenotype who report reactions that involve 2 organ systems (eg, cutaneous and respiratory; cutaneous and gastrointestinal) and have been termed “blended”. In pediatrics, this type of reaction is recognized and has been termed NSAID-induced urticaria/angioedema/anaphylaxis (NIUAA), an acronym we suggest be extended now to adults. There are small subgroups of N-ERD patients who also report skin symptoms and, alternatively, NECD patients who report respiratory symptoms. These 2 subgroups could be diagnosed as having mixed N-ERD and mixed NECD, respectively. In fact, they are patients suffering from N-ERD or NECD who have had reactions consistent with anaphylaxis. In the current classifications of NSAID hypersensitivity, the reactions in which NSAIDs act as aggravating factors or cofactors in subjects with sensitization to foods are not included. Recently, this type of reactions has been defined as NSAID-exacerbated food allergy (NEFA) and NSAID-induced food allergy (NIFA), respectively. This Statement of the World Allergy Organization (WAO) aims to update both the classification of hypersensitivity reactions to NSAIDs and their diagnosis, addressing the novel issues.
Maternal stress, anxiety, well-being, and sleep quality in pregnant women throughout gestation
(MDPI, 2023-11-26) Martín Asuero, Andrés; Pascal Capdevila, Rosalia; Casas, Irene; Genero, Mariona; Nakaki, Ayako; Youssef, Lina; Larroya, Marta; Benitez, Leticia; Gomez, Yvan; Martínez-Arán, Anabel, 1971-; Morilla, Ivette; Oller-Guzmán, Teresa M.; Vieta i Pascual, Eduard, 1963-; Crispi Brillas, Fàtima; Gratacos, Eduard; Gómez Roig, Ma. Dolores; Crovetto, Francesca
Background: Maternal stress, anxiety, well-being, and sleep quality during pregnancy have been described as influencing factors during pregnancy. Aim: We aimed to describe maternal stress, anxiety, well-being, and sleep quality in pregnant women throughout gestation and their related factors. Methods: A prospective study including pregnant women attending BCNatal, in Barcelona, Spain (n = 630). Maternal stress and anxiety were assessed by the Perceived Stress Scale (PSS) and State-Trait Anxiety Inventory (STAI)-validated questionnaires. Maternal well-being was assessed using theWorld Health OrganizationWell-Being Index Questionnaire (WHO-5), and sleep quality was assessed using the Pittsburgh Sleep Quality Index Questionnaire (PSQI). All questionnaires were obtained twice during the second and third trimester of pregnancy. A multivariate analysis was conducted to assess factors related to higher maternal stress and anxiety and worse well-being and sleep quality. Results: High levels of maternal stress were reported in 23.1% of participants at the end of pregnancy, with maternal age <40 years (OR 2.02; 95% CI 1.08–3.81, p = 0.03), non-white ethnicity (OR 2.09; 95% CI 1.19–4.02, p = 0.01), and non-university studies (OR 1.86; 95% CI 1.08–3.19, p = 0.02) being the parameters mostly associated with it. A total of 20.7% of women had high levels of anxiety in the third trimester and the presence of psychiatric disorders (OR 3.62; 95% CI 1.34–9.78, p = 0.01) and non-university studies (OR 1.70; 95% CI 1.11–2.59, p = 0.01) provided a significant contribution to high anxiety at multivariate analysis. Poor maternal well-being was observed in 26.5% of women and a significant contribution was provided by the presence of psychiatric disorders (OR 2.96; 95% CI 1.07–8.25, p = 0.04) and non-university studies (OR 1.74; 95% CI 1.10–2.74, p = 0.02). Finally, less sleep quality was observed at the end of pregnancy (p < 0.001), with 81.1% of women reporting poor sleep quality. Conclusion: Maternal stress and anxiety, compromised maternal well-being, and sleep quality disturbances are prevalent throughout pregnancy. Anxiety and compromised sleep quality may increase over gestation. The screening of these conditions at different stages of pregnancy and awareness of the associated risk factors can help to identify women at potential risk.

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