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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.
Mindfulness-based stress reduction intervention during pregnancy changes maternal brain
(Nature Publishing Group, 2025-07-01) Gomez, Yvan; Nakaki, Ayako; Conti, Allegra; Castro-Barquero, Sara; Gambosi, Benedetta; Casas, Irene; Genero, Mariona; Youssef, Lina; Benítez, Leticia; Encabo, Noelia; Casas Rodríguez, Rosa M.; Martín Asuero, Andrés; Oller Guzmán, Teresa; Morilla, Ivette; Martínez-Arán, Anabel, 1971-; Bargalló Alabart, Núria; Toschi, Nicola; Estruch Riba, Ramon; Vieta i Pascual, Eduard, 1963-; Crispi Brillas, Fàtima; Gratacós Solsona, Eduard; Crovetto, Francesca
Our aim is to evaluate the effect of a structured stress reduction intervention based on mindfulness during pregnancy on the maternal brain. We report a secondary analysis of IMPACT BCN, a randomized clinical trial including pregnant women randomly allocated to 8-week Mindfulness-Based Stress Reduction (n = 41) or usual care (without any intervention, n = 35). Maternal magnetic resonance (MR) was performed in the third trimester, cluster-wise analysis was used to assess cortical morphometric differences, and proton magnetic resonance spectroscopy (1H-MRS) to evaluate the metabolic characteristics. Mindfulness status was evaluated using the Five Facet Mindfulness Questionnaire (FFMQ). Results showed that participants from Stress reduction group had significantly larger surface areas in the right superior frontal region as compared to the Usual care group (90%CI: 0.023-0.029, p = 0.03). The1H-MRS revealed that Stress reduction group participants, had higher concentrations of myo-inositol (adjusted mean difference D 0.37 mol/L, 95%CI 0.05-0.69) as compared to Usual care. Participants who had high mindfulness on FFMQ facets of non-judgmental (D 358.5 mm2, 95%CI 53.5-663.6) and non-reactivity (D 362.3 mm2, 95%CI 18.8-705.7) had larger right superior frontal area. In conclusion, Mindfulness-Based Stress Reduction program during pregnancy has a significant effect on maternal brain structure and is associated with metabolite concentration changes.
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.
IGLV3-21R110 mutation has prognostic value in patients with treatment-naive chronic lymphocytic leukemia
(American Society of Hematology, 2023-07-28) Syrykh, Charlotte; Pons-Brun, Berta; Russiñol, Núria; Playa-Albinyana, Heribert; Baumann, Tycho; Duran Ferrer, Martí; Kulis, Marta; Carbó-Meix, Anna; Mozas, Pablo; Alcoceba, Miguel; González, Marcos; Navarro-Bailón, Almudena; Colado, Enrique; Payer, Ángel R; Terol, María J; Lu, Junyan; Knisbacher, BBinyamin A; Hahn, Cynthia K; Ruiz-Gaspà, Silvia; Enjuanes, Anna; Wu, Catherine J; Getz, Gad; Zenz, Thorsten; López Guillermo, Armando; Martín-Subero, José Ignacio; Colomer Pujol, Dolors; Delgado González, Julio; Campo Güerri, Elias; Nadeu Prat, Ferran; Aymerich Gregorio, Marta
Chronic lymphocytic leukemia (CLL) has high biological and clinical heterogeneity. A few prognostic factors are used in clinical practice, including immunoglobulin heavy-chain variable (IGHV) gene somatic hypermutation (SHM) status, chromosome aberrations, and gene mutations, which remain insufficient for personalized patient management. Recent studies have shown that expression of the immunoglobulin lambda light chain IGLV3-21R110 gene carrying an SHM-derived G>C mutation changing the glycine at position 110 to an arginine (IGLV3-21 R110 ) defines a subset of CLL with an intermediate epigenetic profile and an aggressive clinical course. When occurring on the IGLV3-21*01 or *04 alleles, the R110 mutation allows homotypic B-cell receptor (BCR) interactions, triggering cell-autonomous BCR signaling and/or facilitating T-cell–independent engagement with superantigen. IGLV3-21 has been detected in up to 6.5% of patients with CLL at diagnosis and in up to 25% of patients enrolled in clinical trials. We and others have shown that all CLL cases belonging to aggressive stereotyped subset #2 carried the IGLV3-21 R110 . Nonetheless, approximately half of IGLV3-21 R110 CLL are not classified as stereotyped subset #2 but seem to have a similar clinical outcome, 5,6 suggesting that the conventional stereotyped subset #2 classification might not completely recognize this clinically aggressive subgroup of CLL. In addition, IGLV3-21 R110 seems to have a prognostic value independent of the IGHV gene SHM status and methylation–based epigenetic subtypes. However, further studies in independent cohorts are needed to support its application in clinical practice. The aim of this study was to assess the prognostic value of IGLV3-21 R110 in large and independent population-based cohorts of patients with CLL.
IGLV3-21R110 mutation has prognostic value in patients with treatment-naive chronic lymphocytic leukemia
(American Society of Hematology, 2023-07-28) Syrykh, Charlotte; Pons-Brun, Berta; Russiñol, Núria; Playa-Albinyana, Heribert; Baumann, Tycho; Duran Ferrer, Martí; Kulis, Marta; Carbó-Meix, Anna; Mozas, Pablo; Alcoceba, Miguel; González, Marcos; Navarro-Bailón, Almudena; Colado, Enrique; Payer, Ángel R; Aymerich Gregorio, Marta; Terol, María J; Lu, Junyan; Knisbacher, Binyamin A; Hahn, Cynthia K; Ruiz-Gaspà, Sílvia; Enjuanes, Anna; Wu, Catherine J; Getz, Gad; Zenz, Thorsten; López Guillermo, Armando; Martín-Subero, José Ignacio; Colomer Pujol, Dolors; Delgado González, Julio; Campo Güerri, Elias; Nadeu Prat, Ferran
Chronic lymphocytic leukemia (CLL) has high biological and clinical heterogeneity. 1,2 A few prognostic factors are used in clinical practice, including immunoglobulin heavy-chain variable (IGHV) gene somatic hypermutation (SHM) status, chromosome aberrations, and gene mutations, which remain insufficient for personalized patient management. 3,4 Recent studies have shown that expression of the immunoglobulin lambda light chain IGLV3-21 gene carrying an SHM-derived G>C mutation changing the glycine at position 110 to an arginine (IGLV3-21 R110 ) defines a subset of CLL with an intermediate epigenetic profile and an aggressive clinical course. 5,6 When occurring on the IGLV3-21*01 or *04 alleles, the R110 mutation allows homotypic B-cell receptor (BCR) interactions, triggering cell-autonomous BCR signaling 5,7 and/or facilitating T-cell–independent engagement with superantigen. 8 IGLV3-21 R110 has been detected in up to 6.5% of patients with CLL at diagnosis and in up to 25% of patients enrolled in clinical trials.5,6,9 We 6 and others 5 have shown that all CLL cases belonging to aggressive stereotyped subset #2 carried the IGLV3-21 R110 . Nonetheless, approximately half of IGLV3-21 R110 CLL are not classified as stereotyped subset #2 but seem to have a similar clinical outcome, 5,6 suggesting that the conventional stereotyped subset #2 classification might not completely recognize this clinically aggressive subgroup of CLL. In addition, IGLV3-21 R110 seems to have a prognostic value independent of the IGHV gene SHM status and methylation–based epigenetic subtypes.5,6 However, further studies in independent cohorts are needed to support its application in clinical practice. 1,2,10-12 The aim of this study was to assess the prognostic value of IGLV3-21 R110 in large and independentpopulation-based cohorts of patients with CLL.
Emotional intelligence and neurocognition profiles in first-episode psychosis: A two-year follow-up study
(Elsevier B.V., 2024-08-01) Clougher, Derek; Forte, Maria Florencia; Mezquida Mateos, Gisela; Sánchez Torres, Ana M.; Serra Navarro, Maria; Penadés Rubio, Rafael; Lobo, Antonio; González-Pinto, Ana; Panadero Gómez, Rocío; Roldán, Alexandra; Vieta i Pascual, Eduard, 1963-; Serna, Elena de la, 1978-; Trabsa, Amira; Martínez-Arán, Anabel, 1971-; Torrent Font, Carla; Tortorella, Alfonso; Menculini, Giulia; Ramos-Quiroga, Josep Antoni; Cuesta, Manuel J.; Bernardo Arroyo, Miquel; Amoretti Guadall, Silvia; PEPs Group
Emotional intelligence (EI) and neurocognition (NC) impairments are common in first-episode psychosis (FEP), yet their evolution over time remains unclear. This study identified patient profiles in EI and NC performance in FEP. 98 adult FEP patients and 128 healthy controls (HCs) were tested on clinical, functional, EI, and NC variables at baseline and two-year follow-up (FUP). A repeated-measures ANOVA compared the effects of group (patients and HCs) and time on EI. Significant EI improvements were observed in both groups. Four groups were created based on NC and EI performance at baseline and FUP in patients: impairment in NC and EI, impairment in NC only, impairment in EI only, and no impairment. At FUP, patients impaired in NC and EI showed less cognitive reserve (CR), greater negative and positive symptoms, and poorer functional outcomes. At FUP, three group trajectories were identified: (I) maintain dual impairment (II) maintain no impairment or improve, (III) maintain sole impairment or worsen. The maintain dual impairment group had the lowest levels of CR. EI and NC impairments progress differently in FEP. Greater CR may protect against comorbid EI/NC impairment. Identifying these patient characteristics could contribute to the development of personalised interventions.
Patient-derived follicular lymphoma spheroids recapitulate lymph node signaling and immune profile uncovering galectin-9 as a novel immunotherapeutic target
(Springer Nature, 2024-03-20) Dobaño-López, Cèlia; Garcia Valero, Juan; Araujo Ayala, Ferran; Nadeu Prat, Ferran; Gava, Fabien; Faria, Carla; Norlund, Marine; Morin, Renaud; Bernes-Lasserre, Pascale; Arenas Ríos, Fabián; Grau, Marta; López González, Cristina; López Oreja, Irene; Serrat Aymerich, Neus; Martínez-Farran, Ares; Hernández Pous, Lluís; Playa-Albinyana, Heribert; Giménez Martínez, Rubén; Beà Bobet, Sílvia M.; Campo Güerri, Elias; Lagarde, Jean-Michel; López Guillermo, Armando; Magnano, Laura; Colomer Pujol, Dolors; Bezombes, Christine; Pérez Galán, Patricia
Follicular lymphoma (FL), the most common indolent non-Hodgkin lymphoma, constitutes a paradigm of immune tumor microenvironment (TME) contribution to disease onset, progression, and heterogenous clinical outcome. Here we present the first FL-Patient Derived Lymphoma Spheroid (FL-PDLS), including fundamental immune actors and features of TME in FL lymph nodes (LNs). FL-PDLS is organized in disc-shaped 3D structures composed of proliferating B and T cells, together with macrophages with an intermediate M1/M2 phenotype. FL-PDLS recapitulates the most relevant B-cell transcriptional pathways present in FL-LN (proliferation, epigenetic regulation, mTOR, adaptive immune system, among others). The T cell compartment in the FL-PDLS preserves CD4 subsets (follicular helper, regulatory, and follicular regulatory), also encompassing the spectrum of activation/exhaustion phenotypes in CD4 and CD8 populations. Moreover, this system is suitable for chemo and immunotherapy testing, recapitulating results obtained in the clinic. FL-PDLS allowed uncovering that soluble galectin-9 limits rituximab, rituximab, plus nivolumab/TIM-3 antitumoral activities. Blocking galectin-9 improves rituximab efficacy, highlighting galectin-9 as a novel immunotherapeutic target in FL. In conclusion, FL-PDLS maintains the crosstalk between malignant B cells and the immune LN-TME and constitutes a robust and multiplexed pre-clinical tool to perform drug screening in a patient-derived system, advancing toward personalized therapeutic approaches.
Resonancia Magnetica funcional en la evaluacion de la actividad del cingulado anterior mediante el paradigma de Stroop
(IMR Press, 2002) Salgado-Pineda, Pilar; Vendrell i Gómez, Pere; Bargalló Alabart, Núria; Falcón Falcón, Carles Maria; Junqué i Plaja, Carme, 1955-
[spa] Introducción El paradigma de Stroop se ha utilizado para evaluar el ‘sistema atencional anterior’ que regula la capacidad inhibitoria de respuestas automáticas. Técnicas de neuroimagen funcional han evidenciado un papel preponderante del cingulado anterior en la ejecución de este paradigma. Objetivos Evaluar la activación del cingulado anterior, dado su interés clínico en el estudio de enfermedades neurológicas y psiquiátricas. Pacientes y métodos Participaron en el estudio 11 sujetos voluntarios sanos. Las imágenes funcionales se analizaron con el programa informático SPM99, mediante análisis individual y por grupos de segundo orden. Resultados Un primer análisis local evidenció activación en el cingulado anterior derecho (área 32 de Brodmann) y central izquierdo (áreas 31 y 23), núcleo caudado (cuerpo derecho y cola izquierda) y tálamo (bilateral). Globalmente, se halló activación significativa en el hemisferio izquierdo, en las áreas 44 (área de Broca), 7, 40 (giro supramarginal) y córtex insular, y en el hemisferio derecho, en al área 19. A pesar de ello, existen grandes diferencias individuales. Conclusiones Los resultados globales son acordes con el modelo de una compleja conectividad funcional para la atención y el control de automatismos. En nuestro estudio, el cingulado anterior no se activa de forma selectiva. La activación del tálamo y del núcleo caudado podría explicarse por su implicación en los circuitos frontoestriatales. La ausencia de consistencia individual puede deberse a diferentes estilos cognitivos personales en la resolución del conflicto. Según estos resultados, el paradigma de Stroop no serviría clínicamente para indicar el buen o mal funcionamiento del cingulado anterior.
Challenges with Approved Targeted Therapies against Recurrent Mutations in CLL: A Place for New Actionable Targets
(MDPI, 2021-06-24) López Oreja, Irene; Playa-Albinyana, Heribert; Arenas Ríos, Fabián; López Guerra, Mónica; Colomer Pujol, Dolors
Chronic lymphocytic leukemia (CLL) is characterized by a high degree of genetic variability and interpatient heterogeneity. In the last decade, novel alterations have been described. Some of them impact on the prognosis and evolution of patients. The approval of BTK inhibitors, PI3K inhibitors and Bcl-2 inhibitors has drastically changed the treatment of patients with CLL. The effect of these new targeted therapies has been widely analyzed in TP53-mutated cases, but few data exist about the response of patients carrying other recurrent mutations. In this review, we describe the biological pathways recurrently altered in CLL that might have an impact on the response to these new therapies together with the possibility to use new actionable targets to optimize treatment responses.
Imaging Efficacy of [18F]CTT1057 PET/CT in Patients with Biochemically Recurrent Prostate Cancer: Results from GuidePath-A Phase 3, Prospective Multicenter Study
(The Society of Nuclear Medicine and Molecular Imaging, 2025-08-01) Fanti, Stefano; Robles Barba, Javier Jesus; Behr, Spencer; Maurer, Tobias; Paredes Barranco, Pilar; Walz, Jochen; Duch, Joan; Simo Perdigo, Marc; Mainta, Ismini Charis; Bonnefoy, Pierre Benoit; Coulanges, Medge; Tang, Jun; Seigne, Christelle; Wilke, Celine; Catafau, Ana M.; Iagaru, Andrei; Aggarwal, Rahul
Improved diagnostic accuracy in patients with prostate cancer at first biochemical recurrence (BCR) with low prostate-specific antigen (PSA) levels is needed. This prospective study (GuidePath; NCT04838613) aimed to evaluate the imaging performance of the prostate-specific membrane antigen (PSMA)-targeted PET radiotracer [18F]CTT1057 to detect PSMA-positive lesions in patients diagnosed predominantly at first BCR. Methods: Eligible patients had a PSA of 0.2 ng/mL or greater after radical prostatectomy or an increase in PSA level of at least 2 ng/mL above nadir after radiation therapy. Patients received 370 MBq of [18F]CTT1057 and 150 MBq of [68Ga]Ga-PSMA-11 and underwent PET/CT 90 min (±30 min) and 50-100 after injection, respectively. [18F]CTT1057 images were assessed by 3 independent readers blinded to all clinical information. Coprimary endpoints were region-level correct localization rate (CLR) and patient-level positive predictive value (PPV) of [18F]CTT1057 to detect PSMA-positive lesions and were compared with a hierarchical composite truth standard (CTS). The CTS comprised 3 levels of standard-of-truth procedures (in order of priority): histopathology (CTS level 1); imaging, including at least 1 contrast-enhanced CT scan and 1 [68Ga]Ga-PSMA-11 PET/CT scan (CTS level 2); and a decrease in PSA level of 50% or greater 3 mo after radiation therapy (CTS level 3). For study success, the lower-bound 95% CI had to surpass 50% for region-level CLR and 20% for patient-level PPV for at least 2 of the 3 [18F]CTT1057 PET/CT readers. Results: Of 202 patients screened, 161 were evaluable for efficacy. Among these, 93.2% were experiencing their first BCR, 96.3% had received radical prostatectomy as initial definitive therapy, and baseline median PSA level was 0.4 ng/mL (interquartile range, 0.3-0.8 ng/mL). The imaging standard of truth was used for 159-160 patients (99%) across the 3 readers. Both coprimary endpoints were met. Region-level CLR ranged from 65.2% to 75.0% (lower-bound 95% CI, 53.4%-62.1%), and patient-level PPV ranged from 64.6% to 76.5% (lower-bound 95% CI, 51.8%-62.5%). Conclusion: [18F]CTT1057 met the predefined thresholds for region-level CLR and patient-level PPV in a clinically relevant patient cohort predominantly at first BCR with low PSA levels. [18F]CTT1057 is an accurate PSMA-targeted PET radiotracer for BCR detection.
Imaging Efficacy of [18F]CTT1057 PET for the Detection of PSMA-Positive Tumors Using Histopathology as Standard of Truth: Results from the GuideView Phase 2/3 Prospective Multicenter Study
(The Society of Nuclear Medicine and Molecular Imaging, 2025-08-01) Iagaru, Andrei; Suárez-Novo, José Francisco; Behr, Spencer; Aggarwal, Rahul; Paredes Barranco, Pilar; Buffi, Nicolo; Penhoat, Thomas; Ceci, Francesco; Walz, Jochen; Doumerc, Nicolas; Coulanges, Medge; Xu, Zhongying; Seigne, Christelle; Wilke, Celine; Catafau, Ana M.; Fanti, Stefano; Maurer, Tobias
[18F]CTT1057 is a highly selective prostate-specific membrane antigen (PSMA)-targeted PET radiotracer for prostate cancer (PCa) detection. This prospective study (GuideView, NCT04838626) evaluates the imaging efficacy of [18F]CTT1057 PET to detect PSMA-positive lesions against histopathology in patients with newly diagnosed, untreated, high-risk PCa. Methods: Between September 7, 2021, and October 26, 2023, 201 patients planned for radical prostatectomy were screened and 195 patients were enrolled. Of these, 184 patients received a median of 355 MBq (range, 195-400 MBq) of [18F]CTT1057 and underwent PET/CT 90 min (±30 min) later. Three masked central independent readers evaluated the images. Coprimary endpoints were patient-level sensitivity (including primary tumor and pelvic lymph nodes) and region-level specificity (including pelvic lymph nodes only) for detection of PSMA-positive lesions, using histopathology as the standard of truth. The lower-bound 95% CI needed to surpass 50% for patient-level sensitivity and 70% for region-level specificity. Success was defined as at least 2 of 3 central readers meeting these criteria. Secondary endpoints included the patient-level and region-level positive predictive value and accuracy, region-level sensitivity, inter- and intrareader variability, detection rate of distant metastasis, pharmacokinetics, and safety and tolerability assessments. Results: Of the 184 patients who received [18F]CTT1057, 172 patients were evaluable for efficacy. Among these, a median of 19 lymph nodes (interquartile range, 13.0-28.5 lymph nodes) were dissected per patient. Both coprimary endpoints were met, with lower bounds of 95% CIs surpassing the success criteria for all 3 readers for both patient-level sensitivity (range, 86.8%-90.0%; lower-bound 95% CI, 80.7%-84.5%) and region-level specificity (97.1%; lower-bound 95% CI, 92.7%). Interreader variability Fleiss κ was 63.9%; intrareader reproducibility Cohen κ was 89.4%-100%. [18F]CTT1057 had a favorable safety profile. Conclusion: GuideView confirmed the imaging efficacy of [18F]CTT1057 for the detection of PSMA-positive lesions, with high patient-level sensitivity and region-level specificity. Substantial interreader variability and almost perfect intrareader reproducibility suggest that [18F]CTT1057 findings are robust and reliable. [18F]CTT1057 will contribute to expanding access to PSMA PET imaging to properly diagnose and treat patients with PCa.
Functional brain abnormalities in post COVID-19 condition and their relationship with cognition.
(Nature Publishing Group, 2025-07-01) Carreras Vidal, Lourdes; Pacheco Jaime, Laura; Ariza González, Mar; Cano, Neus; Garolera i Freixa, Maite; García Vicente, Carla; Roura, Ignacio; Capdevila Lacasa, Clara; Oltra González, Javier; Pardo, Jèssica; Martín Barceló, Cristina; Campabadal Delgado, Anna; Sala Llonch, Roser; Bargalló Alabart, Núria; Barrué, Cristian; Bejar, Javier; Cortés, Claudio Ulises; Junqué i Plaja, Carme, 1955-; NAUTILUS-Project Collaborative Group; Segura i Fàbregas, Bàrbara
After COVID-19 infection, some patients develop a post-COVID condition (PCC) that is popularly referred to as long COVID. Among its symptoms is persistent cognitive dysfunction that is potentially linked to altered brain functional connectivity (FC). While research has explored functional reorganization in patients with PCC, the intra- and inter- network connectivity and its relationship with cognitive status and clinical outcomes remain unclear. In this study, we recruited 121 individuals with PCC (67 with, and 54 without, cognitive impairment), 20 months after infection, along with 37 non-infected healthy controls from the NAUTILUS Project (ClinicalTrials.gov IDs: NCT05307549 and NCT05307575). Participants underwent resting-state functional magnetic resonance imaging and comprehensive neuropsychological assessment. Resting-state networks were characterized using independent component analyses, dual regression and network modelling for individual FC characterization. Group differences in intra- and inter-network FC, and their associations with clinical and neuropsychological data, were studied. Significance was set at a corrected p-value of < 0.05. Patients with PCC showed increased intra-network FC in 10 cognitively relevant networks, including the default mode, salience, executive control, auditory and basal ganglia networks, correlating positively with general cognition (Montreal Cognitive Assessment scores), time since infection, fatigue and subjective memory failures. Increased inter-network FC between default mode and sensorimotor networks was also observed. Increases in FC may reflect an inefficient compensatory mechanism in patients with PCC, associated with fatigue, subjective memory complaints and persistence of PCC.
New models for MPNST: establishment and comprehensive characterization of two tumor cell lines
(BioMed Central, 2025-07-18) Ortega Bertran, Sara; Creus Bachiller, Edgar; Magallón Lorenz, Miriam; Carrió, Meritxell; Gel Moreno, Bernat; Villanueva Garatachea, Alberto; Lopez-Gutierrez, Juan Carlos; Estival, Anna; Serra, Eduard; Fernández Rodríguez, Juana; Lázaro García, Conxi
Background: Malignant peripheral nerve sheath tumors (MPNSTs) are rare, invasive, and aggressive soft tissue sarcomas arising from peripheral nerves. They may occur sporadically or in association with Neurofibromatosis type 1 (NF1), in which they are the leading cause of mortality. Currently, there are no effective therapies other than surgery. Therefore, tumor-derived cell lines are essential for testing new therapeutic strategies, especially when used in parallel with in vivo models. In this study, we present two new MPNST cell lines and two patient-derived orthotopic xenograft (PDOX) models from a sporadic (SP-10) and an NF1-related (NF1-18B) MPNST patient to increase the number of available preclinical models for in vitro and in vivo drug testing. Methods: The cell lines were isolated and extensively characterized genetically (tumor suppressor gene mutation status, DNA content), phenotypically (cell morphology, marker expression), and functionally (proliferation rate, colony formation capacity, migration rate, tumorigenic ability). We validated the models by comparing the genomic (copy number variation profile) and histological characteristics of the cell lines and PDOX tumors with their corresponding patient tumors. Results: The new cell lines and PDOXs tumors exhibited similar genomic copy number variation profiles, histological patterns, and marker expressions as the patient tumors, validating them as faithful models. Interestingly, the NF1-18B cell model presented two cell subpopulations with different ploidy states (one < 3n and the other 4n) and functional features in vitro. NF1-18B 4n, along with SP-10 cell lines, exhibited in vitro functional hallmarks of MPNSTs, including high proliferation and migration rates and colony forming ability. However, only the SP-10 model exhibited aggressive tumorigenicity in athymic mice. In contrast, the NF1-18B < 3n showed a low migration rate and did not form colonies or aggregates in vitro. Conclusions: The newly established MPNST cell lines, along with their corresponding PDOX models, serve as valuable tools for both in vitro and in vivo testing of novel therapeutic agents. Notably, the SP-10 cell line model represents one of the few documented cases isolated from a genuine "classic" MPNST.
Gene expression imputation provides clinical and biological insights into treatment-resistant schizophrenia polygenic risk
(Elsevier B.V., 2024-01-05) Prohens Coll, Llucia; Rodríguez Ferret, Natalia; Gonzàlez Segura, Àlex; Martínez Pinteño, Albert; Olivares Berjaga, David; Martínez-Serrano, Irene; González, Aitor; Mezquida Mateos, Gisela; Parellada, Mara; Cuesta, Manuel J.; Bernardo Arroyo, Miquel; Gassó Astorga, Patricia; Mas Herrero, Sergi
Genome-wide association studies (GWAS) have revealed the polygenic nature of treatment-resistant schizophrenia TRS. Gene expression imputation allowed the translation of GWAS results into regulatory mechanisms and the construction of gene expression (GReX) risk scores (GReX-RS). In the present study we computed GReX-RS from the largest GWAS of TRS to assess its association with clinical features. We perform transcriptome imputation in the largest GWAS of TRS to find GReX associated with TRS using brain tissues. Then, for each tissue, we constructed a GReX-RS of the identified genes in a sample of 254 genotyped first episode of psychosis (FEP) patients to test its association with clinical phenotypes, including clinical symptomatology, global functioning and cognitive performance. Our analysis provides evidence that the polygenic basis of TRS includes genetic variants that modulate the expression of certain genes in certain brain areas (substantia nigra, hippocampus, amygdala and frontal cortex), which at the same time are related to clinical features in FEP patients, mainly persistence of negative symptoms and cognitive alterations in sustained attention, which have also been suggested as clinical predictors of TRS. Our results provide a clinical explanation of the polygenic architecture of TRS and give more insight into the biological mechanisms underlying TRS.
Triple Combination of MEK, BET, and CDK Inhibitors Significantly Reduces Human Malignant Peripheral Nerve Sheath Tumors in Mouse Models
(American Association for Cancer Research (AACR), 2025-03-03) Ortega Bertran, Sara; Fernández Rodríguez, Juana; Magallón Lorenz, Miriam; Zhang, Xiaohu; Creus Bachiller, Edgar; Diazgranados, Adriana Paola; Uriarte Arrazola, Itziar; Mazuelas, Helena; Blanco, Ignacio; Valverde Morales, Claudia; Carrió, Meritxell; Villanueva Garatachea, Alberto; Raedt, Thomas de; Romagosa Pérez-Portabella, Cleofé; Gel Moreno, Bernat; Salvador, Héctor; Ferrer, Marc; Lázaro García, Conxi; Serra Arenas, Eduard
Purpose: Malignant peripheral nerve sheath tumor (MPNST) is an aggressive soft-tissue sarcoma that develops sporadically or in patients with neurofibromatosis type 1 (NF1). Its development is marked by the inactivation of specific tumor suppressor genes (TSG): NF1, CDKN2A, and SUZ12/EED (polycomb repressor complex 2). Each TSG loss can be targeted by particular drug inhibitors, and we aimed to systematically combine these inhibitors, guided by TSG inactivation status, to test their precision medicine potential for MPNSTs.Experimental Design: We performed a high-throughput screening in 3 MPNST cell lines testing 14 MEK inhibitors (MEKi), 11 cyclin-dependent kinase 4/6 inhibitors (CDKi), and 3 bromodomain inhibitors (BETi) as single agents and 147 pairwise co-treatments. Best combinations were validated in nine MPNST cell lines, and three were tested in one sporadic and one NF1-associated patient-derived orthotopic xenograft (PDOX) MPNST mouse model. A final combination of the three inhibitor classes was tested in the same PDOX models.Results: A high degree of redundancy was observed in the effect of compounds of the same inhibitory class, individually or in combination, and responses matched with TSG inactivation status. The MEKi-BETi (ARRY-162 + I-BET151) co-treatment triggered a reduction in half of the NF1-related MPNST PDOXs and all the sporadic tumors, reaching 65% reduction in tumor volume in the latter. Remarkably, this reduction was further increased in both models combining the three inhibitor classes, reaching 85% shrinkage on average in the sporadic MPNST.Conclusions: Our results strongly support precision therapies for MPNSTs guided by TSG inactivation status. MEKi-BETi CDKi triple treatment elicits a significant reduction of human MPNST PDOXs.
Braquiterapia en el cáncer de labio
(Medicina Oral SL, 2006-01-22) Rovirosa Casino, Angeles; Planas Toledano, Isabel; Ferre Jorge, J.; Oliva Díez, José María; Conill Llobet, Carlos; Arenas Prat, Meritxell
El cáncer de labio es de los más prevalentes entre los tumores cutáneos de cabeza y cuello. Las características del tumor, por su crecimiento exofítico en una zona de fácil acceso visual, permite un diagnóstico en estadios incipientes y, por tanto, un mejor pronóstico con los actuales tratamientos. En estadios iniciales se puede realizar tratamiento con cirugía o braquiterapia, siendo los resultados similares en cuanto al control local; sin embargo la braquiterapia ofrece mejores resultados estéticos y funcionales. Presentamos un trabajo de revisión bibliográfica al respecto de de las indicaciones, técnicas y resultados de la braquiterapia en el cáncer de labio.
SOX11 expression is restricted to EBV-negative Burkitt lymphoma and associates with molecular genetic features
(American Society of Hematology, 2024-07-11) Sureda Gómez, Marta; Iaccarino, Ingram; Bolòs, Anna de; Meyer, Mieke; Balsas, Patricia; Richter, Julia; Rodríguez, Marta-Leonor; López González, Cristina; Carreras-Caballé, Maria; Glaser, Selina; Nadeu Prat, Ferran; Jares Gerboles, Pedro; Clot Razquin, Guillem; Siciliano, Maria Chiara; Bellan, Cristina; Tornambè, Salvatore; Boccacci, Roberto; Leoncini, Lorenzo; Campo Güerri, Elias; Siebert, Reiner; Amador Espinosa, Virginia; Klapper, Wolfram
SRY-related HMG-box gene 11 (SOX11) is a transcription factor overexpressed in mantle cell lymphoma (MCL), a subset of Burkitt lymphomas (BL) and precursor lymphoid cell neoplasms but is absent in normal B cells and other B-cell lymphomas. SOX11 has an oncogenic role in MCL but its contribution to BL pathogenesis remains uncertain. Here, we observed that the presence of Epstein-Barr virus (EBV) and SOX11 expression were mutually exclusive in BL. SOX11 expression in EBV-negative (EVB-) BL was associated with an IG∷MYC translocation generated by aberrant class switch recombination, whereas in EBV-negative (EBV-)/SOX11-negative (SOX11-) tumors the IG∷MYC translocation was mediated by mistaken somatic hypermutations. Interestingly, EBV- SOX11-expressing BL showed higher frequency of SMARCA4 and ID3 mutations than EBV-/SOX11- cases. By RNA sequencing, we identified a SOX11-associated gene expression profile, with functional annotations showing partial overlap with the SOX11 transcriptional program of MCL. Contrary to MCL, no differences on cell migration or B-cell receptor signaling were found between SOX11- and SOX11-positive (SOX11+) BL cells. However, SOX11+ BL showed higher adhesion to vascular cell adhesion molecule 1 (VCAM-1) than SOX11- BL cell lines. Here, we demonstrate that EBV- BL comprises 2 subsets of cases based on SOX11 expression. The mutual exclusion of SOX11 and EBV, and the association of SOX11 with a specific genetic landscape suggest a role of SOX11 in the early pathogenesis of BL.
Sentinel lymph node detection in early-stage ovarian cancer: a systematic review and meta-analysis
(Lippincott, Williams & Wilkins. Wolters Kluwer Health, 2023-10-01) Agustí, Núria; Viveros Carreño, David; Grillo Ardila, Carlos; Izquierdo, Nora; Paredes Barranco, Pilar; Vidal i Sicart, Sergi; Torné Bladé, Aureli; Díaz Feijoo, Berta
Background: A systematic pelvic and para-aortic lymphadenectomy remains the surgical standard management of early-stage epithelial ovarian cancer. Sentinel lymph node mapping is being investigated as an alternative procedure; however, data reporting sentinel lymph node performance are heterogeneous and limited. Objective: This study aimed to evaluate the detection rate and diagnostic accuracy of sentinel lymph node mapping in patients with early-stage ovarian cancer. Methods: A systematic search was conducted in Medline (through PubMed), Embase, Scopus, and the Cochrane Library. We included patients with clinical stage I-II ovarian cancer undergoing a sentinel lymph node biopsy and a pelvic and para-aortic lymphadenectomy as a reference standard. We conducted a meta-analysis for the detection rates and measures of diagnostic accuracy and assessed the risk of bias using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) with identifying number CRD42022351497. Results: After duplicate removal, we identified 540 studies, 18 were assessed for eligibility, and nine studies including 113 patients were analyzed. The pooled detection rates were 93.3% per patient (95% CI 77.8% to 100%; I2=74.3%, p<0.0001), and the sentinel lymph node technique correctly identified 11 of 12 patients with lymph node metastases, with a negative predictive value per patient of 100% (95% CI 97.6% to 100%; I2=0%). The combination of indocyanine green and 99mTc-albumin nanocolloid had the best detection rate (100% (95% CI 94% to 100%; I2=0%)) when injected into the utero-ovarian and infundibulo-pelvic ligaments. Conclusion: Sentinel lymph node biopsy in early-stage ovarian cancer showed a high detection rate and negative predictive value. The utero-ovarian and infundibulo-pelvic injection using the indocyanine green and technetium-99 combination could increase sentinel lymph node detection rates. However, given the limited quality of evidence and the small number of reports, results from ongoing trials are awaited before its implementation in routine clinical practice.
Combining OPM and lesion mapping data for epilepsy surgery planning: a simulation study
(Nature Publishing Group, 2024-02-04) The MELD Project Consortium; Bargalló Alabart, Núria; Pascual-Diaz, Saül; González Ortiz, Sofía; Conde Blanco, Estefanía; Pariente, Jose Carlos
When planning for epilepsy surgery, multiple potential sites for resection may be identified through anatomical imaging. Magnetoencephalography (MEG) using optically pumped sensors (OP-MEG) is a non-invasive functional neuroimaging technique which could be used to help identify the epileptogenic zone from these candidate regions. Here we test the utility of a-priori information from anatomical imaging for differentiating potential lesion sites with OP-MEG. We investigate a number of scenarios: whether to use rigid or flexible sensor arrays, with or without a-priori source information and with or without source modelling errors. We simulated OP-MEG recordings for 1309 potential lesion sites identified from anatomical images in the Multi-centre Epilepsy Lesion Detection (MELD) project. To localise the simulated data, we used three source inversion schemes: unconstrained, prior source locations at centre of the candidate sites, and prior source locations within a volume around the lesion location. We found that prior knowledge of the candidate lesion zones made the inversion robust to errors in sensor gain, orientation and even location. When the reconstruction was too highly restricted and the source assumptions were inaccurate, the utility of this a-priori information was undermined. Overall, we found that constraining the reconstruction to the region including and around the participant's potential lesion sites provided the best compromise of robustness against modelling or measurement error.
La dimensión temporal de la enfermedad crónica: duración, diagnóstico y edad
(Associação Nacional de Pós-Graduação e Pesquisa em Ciências Sociais - ANPOCS, 2015-06) Masana, Lina
Las enfermedades y malestares crónicos se experimentan cronológicamente y biográficamente, a lo largodel tiempo y de la vida de la persona. Por tratarse de problemas de salud de larga duración, presentanciertas particularidades que las diferencian de los problemas de salud agudos o de corta duración, conimplicaciones para la esfera individual y social. El diagnóstico de una enfermedad crónica y la edad enla que se reciba, condicionarán la vida de la persona y de los que están a su alrededor. El objetivo de esteartículo, basado en material etnográfico recogido durante mi investigación doctoral sobre la experiencia yla gestión de la cronicidad en adultos en Cataluña (España), es el de reflexionar y mostrar algunas de lascaracterísticas principales de la dimensión temporal de la cronicidad y de cómo ésta afecta la biografía deaquellos que sufren enfermedades o malestares de larga duración.

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