Lamo-de-Espinosa-Vázquez-de-Sola, J.M. (José María)
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- Preneoplastic somatic mutations including MYD88(L265P) in lymphoplasmacytic lymphoma(2022) Reinhardt, H.C. (Hans Christian); Vilas, A. (Amaia); Sanchez-Garcia, I. (Isidro); Perez, C. (Cristina); Paiva, A. (Artur); López-de-Arancibia, A. (Aitziber); Sacco, A. (Antonio); Santos, S. (S.); Celay, J. (Jon); Sarvide, S. (Sarai); García-Sanz, R. (Ramón); Goicoechea, I. (Ibai); García-Barchino, M.J. (María José); Martinez-Climent, J.A. (José Ángel); Gárate-Luzuriaga, S. (Sonia); Carrasco, Y.R. (Yolanda R.); Panizo, C. (Carlos); Larrayoz, M. (Marta); Vitoria, H. (Helena); Puig, N. (Noemí); Botta, C. (Cirino); Rodríguez-Díaz, S. (Saray); Garcés-Latre, J.J. (Juan José); Motta, M. (Marina); Geraldes, C. (Catarina); Lamo-de-Espinosa-Vázquez-de-Sola, J.M. (José María); Alignani, D. (Diego); Duarte, S. (Sara); Paiva, B. (Bruno); Larrayoz, M.J. (María J.); Prosper-Cardoso, F. (Felipe); Calasanz-Abinzano, M.J. (Maria Jose); Roccaro, A.M. (Aldo M.); Fuerte, G. (Gema); Tucci, A. (Alessandra); San-Miguel, J.F. (Jesús F.); Gentile, M. (Massimo); Jiménez, C. (Cristina)Normal cell counterparts of solid and myeloid tumors accumulate mutations years before disease onset; whether this occurs in B lymphocytes before lymphoma remains uncertain. We sequenced multiple stages of the B lineage in elderly individuals and patients with lymphoplasmacytic lymphoma, a singular disease for studying lymphomagenesis because of the high prevalence of mutated MYD88. We observed similar accumulation of random mutations in B lineages from both cohorts and unexpectedly found MYD88(L265P) in normal precursor and mature B lymphocytes from patients with lymphoma. We uncovered genetic and transcriptional pathways driving malignant transformation and leveraged these to model lymphoplasmacytic lymphoma in mice, based on mutated MYD88 in B cell precursors and BCL2 overexpression. Thus, MYD88(L265P) is a preneoplastic event, which challenges the current understanding of lymphomagenesis and may have implications for early detection of B cell lymphomas.
- An engineered periosteum for efficient delivery of rhBMP-2 and mesenchymal progenitor cells during bone regeneration(2023) Granero-Moltó, F. (Froilán); López-Martínez, T. (Tania); Riera-Alvarez, L. (Luis); Rodriguez-Florez, N. (Naiara); Elizalde, R. (Reyes); Ripalda-Cemboráin, P. (Purificación); Ruiz-de-Galarreta-Moriones, S.(Sergio); Juan-Pardo, E.M. (Elena M.) de; Childs, P. (Peter); Echanove-González De Anleo, M. (Miguel); Lamo-de-Espinosa-Vázquez-de-Sola, J.M. (José María); Valdés-Fernández, J. (José); Salmeron-Sanchez, M. (Manuel); Muiños-López, E. (Emma); Romero-Torrecilla, J.A. (Juan Antonio); Prosper-Cardoso, F. (Felipe); López-Barberena, A. (Asier); Abizanda-Sarasa, G. (Gloria); Jayawarna, V. (Vineetha)During bone regeneration, the periosteum acts as a carrier for key regenerative cues, delivering osteochondroprogenitor cells and crucial growth factors to the injured bone. We developed a biocompatible, 3D polycaprolactone (PCL) melt electro-written membrane to act as a mimetic periosteum. Poly (ethyl acrylate) coating of the PCL membrane allowed functionalization, mediated by fibronectin and low dose recombinant human BMP-2 (rhBMP-2) (10-25 mu g/ml), resulting in efficient, sustained osteoinduction in vitro. In vivo, rhBMP-2 functionalized mimetic periosteum demonstrated regenerative potential in the treatment of rat critical-size femoral defects with highly efficient healing and functional recovery (80%-93%). Mimetic periosteum has also proven to be efficient for cell delivery, as observed through the migration of transplanted periosteum-derived mesenchymal cells to the bone defect and their survival. Ultimately, mimetic periosteum demonstrated its ability to deliver key stem cells and morphogens to an injured site, exposing a therapeutic and translational potential in vivo when combined with unprecedentedly low rhBMP-2 doses.
- Uncovering perturbations in human hematopoiesis associated with healthy aging and myeloid malignancies at single-cell resolution(2023) Gomez-Cabrero, D. (David); Lasaga, M. (Miren); Diez-Campelo, M. (M.); Molero, A. (Antonieta); San-Martín-Uriz, P. (Patxi); Romero-Riojas, J.P. (Juan Pablo); Alfonso-Piérola, A. (Ana); San-Julian, M. (Mikel); Jimenez-Solas, T. (Tamara); Ezponda, T. (Teresa); Valcarcel, D. (David); Lopez, F. (Félix); Dupéré-Richer, D. (Daphné); Lamo-de-Espinosa-Vázquez-de-Sola, J.M. (José María); Alignani, D. (Diego); Montoro, J. (Julia); Mution, S. (Sandra); Hernaez, M. (Mikel); Serrano-Sanz, G. (Guillermo); Ainciburu-Fernández, M. (Marina); Prosper-Cardoso, F. (Felipe); Berastegui-Zufiaurre, N. (Nerea); Diaz-Mazquiaran, A. (Aintzane); Sanchez-Guijo, F.M. (Fermín M.)Early hematopoiesis is a continuous process in which hematopoietic stem and progenitor cells (HSPCs) gradually differentiate toward specific lineages. Aging and myeloid malignant transformation are characterized by changes in the composition and regulation of HSPCs. In this study, we used single-cell RNA sequencing (scRNA-seq) to characterize an enriched population of human HSPCs obtained from young and elderly healthy individuals. Based on their transcriptional profile, we identified changes in the proportions of progenitor compartments during aging, and differences in their functionality, as evidenced by gene set enrichment analysis. Trajectory inference revealed that altered gene expression dynamics accompanied cell differentiation, which could explain aging-associated changes in hematopoiesis. Next, we focused on key regulators of transcription by constructing gene regulatory networks (GRNs) and detected regulons that were specifically active in elderly individuals. Using previous findings in healthy cells as a reference, we analyzed scRNA-seq data obtained from patients with myelodysplastic syndrome (MDS) and detected specific alterations of the expression dynamics of genes involved in erythroid differentiation in all patients with MDS such as TRIB2. In addition, the comparison between transcriptional programs and GRNs regulating normal HSPCs and MDS HSPCs allowed identification of regulons that were specifically active in MDS cases such as SMAD1, HOXA6, POU2F2, and RUNX1 suggesting a role of these transcription factors (TFs) in the pathogenesis of the disease. In summary, we demonstrate that the combination of single-cell technologies with computational analysis tools enable the study of a variety of cellular mechanisms involved in complex biological systems such as early hematopoiesis and can be used to dissect perturbed differentiation trajectories associated with perturbations such as aging and malignant transformation. Furthermore, the identification of abnormal regulatory mechanisms associated with myeloid malignancies could be exploited for personalized therapeutic approaches in individual patients
- Do we really improve life quality after total knee arthroplasty in patients with Parkinson’s disease?(Springer Nature, 2020) Montiel-Terrón, V. (Verónica); Vitoria-Sola, M. (María); Lamo-de-Espinosa-Vázquez-de-Sola, J.M. (José María); Valentí-Nin, J.R. (Juan Ramón); Valentí-Azcárate, A. (Andrés)Introduction The knee in Parkinson’s disease (PD) patients is a problematic joint due to pain, stifness and gait instability. The aim of this study is to evaluate the functional outcome and degree of pain relief achieved after total knee arthroplasty (TKA) in PD patients. Materials and methods This is a retrospective review of 26 PD patients (32 knees) with osteoarthritis who underwent a TKA between 1994 and 2013. Comorbidities, anesthetic procedures and complications were recorded. Patient functional status was assessed with the Knee Society Function Score (KFS) and the Knee Society Score (KSS). PD stage was classifed with the Hoehn and Yahr Scale. Results The mean follow-up was 3.5 years (range 2–9). The mean age was 71 years (range 61–83) with a mean time since PD diagnosis of 11.8 years (range 4–24). PD severity on the Hoehn and Yahr Scale was 1.5 points before surgery and 2 points postoperatively. Pain on the visual analogic scale improved from 8 points preoperatively to 5 points at 1-year follow-up; function improved from 32 (range 20–45) to 71 (range 50–81) and from 34 (range 28–52) to 59 (range 25–76) on the KSS and KFS, respectively. The mean postoperative hospital stay was 9.8 days (range 5–21). Confusion and fexion contracture were the most frequent perioperative complications. Conclusion TKA successfully provided pain relief in PD patients. However, the functional outcome is related to disease progression and, therefore, variable. Perioperative complications are difcult to avoid and manage.