San Martín, P. (Patxi)

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    Characterization of complete lncRNAs transcriptome reveals the functional and clinical impact of lncRNAs in multiple myeloma.
    (Springer Nature, 2021) Carrasco-León, A. (Arantxa); Ezponda, T. (Teresa); Meydan, C. (Cem); Valcárcel-García, L.V. (Luis Vitores); Ordoñez, R. (Raquel); Kulis, M. (Marta); Garate, L. (Leire); Miranda, E. (Estibaliz); Segura, V. (Víctor); Guruceaga, E. (Elizabeth); Vilas-Zornoza, A. (Amaia); Alignani, D. (Diego); Pascual, M. (Marien); Amundarain, A. (Ane); Castro-Labrador, L. (Laura); San Martín, P. (Patxi); El-Omri, H. (Halima); Taha, R.Y. (Ruba Y.); Calasanz-Abinzano, M.J. (Maria Jose); Planes-Pedreño, F.J. (Francisco Javier); Paiva, B. (Bruno); Mason, C. E. (Christopher, E.); San-Miguel, J.F. (Jesús F.); Martin-Subero, J.I. (Jose Ignacio); Melnick, A. (Ari); Prosper-Cardoso, F. (Felipe); Aguirre-Ena, X. (Xabier)
    Multiple myeloma (MM) is an incurable disease, whose clinical heterogeneity makes its management challenging, highlighting the need for biological features to guide improved therapies. Deregulation of specific long non-coding RNAs (lncRNAs) has been shown in MM, nevertheless, the complete lncRNA transcriptome has not yet been elucidated. In this work, we identified 40,511 novel lncRNAs in MM samples. lncRNAs accounted for 82% of the MM transcriptome and were more heterogeneously expressed than coding genes. A total of 10,351 overexpressed and 9,535 downregulated lncRNAs were identified in MM patients when compared with normal bone-marrow plasma cells. Transcriptional dynamics study of lncRNAs in the context of normal B-cell maturation revealed 989 lncRNAs with exclusive expression in MM, among which 89 showed de novo epigenomic activation. Knockdown studies on one of these lncRNAs, SMILO (specific myeloma intergenic long non-coding RNA), resulted in reduced proliferation and induction of apoptosis of MM cells, and activation of the interferon pathway. We also showed that the expression of lncRNAs, together with clinical and genetic risk alterations, stratified MM patients into several progression-free survival and overall survival groups. In summary, our global analysis of the lncRNAs transcriptome reveals the presence of specific lncRNAs associated with the biological and clinical behavior of the disease.
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    Functional and transcriptomic analysis of extracellular vesicles identifies calprotectin as a new prognostic marker in peripheral arterial disease (PAD)
    (2020) Gomez-Cabrero, D. (David); Paramo, J.A. (José Antonio); Saenz-Pipaón, G. (Goren); Ravassa, S. (Susana); Orbe, J. (Josune); Rodriguez, J.A. (José Antonio); Lara-Astiaso, D. (David); Planell, N. (Núria); Dupéré-Richer, D. (Daphné); Maillo, A. (Alberto); Alameda, D. (Daniel); Martínez-Aguilar, E. (Esther); Roncal, C. (Carmen); Prosper-Cardoso, F. (Felipe); San Martín, P. (Patxi)
    Peripheral arterial disease (PAD) is associated with a high risk of cardiovascular events and death and is postulated to be a critical socioeconomic cost in the future. Extracellular vesicles (EVs) have emerged as potential candidates for new biomarker discovery related to their protein and nucleic acid cargo. In search of new prognostic and therapeutic targets in PAD, we determined the prothrombotic activity, the cellular origin and the transcriptomic profile of circulating EVs. This prospective study included control and PAD patients. Coagulation time (Procoag-PPL kit), EVs cellular origin and phosphatidylserine exposure were determined by flow cytometry in plateletfree plasma (n = 45 PAD). Transcriptomic profiles of medium/large EVs were generated using the MARS-Seq RNA-Seq protocol (n = 12/group). The serum concentration of the differentially expressed gene S100A9, in serum calprotectin (S100A8/A9), was validated by ELISA in control (n = 100) and PAD patients (n = 317). S100A9 was also determined in EVs and tissues of human atherosclerotic plaques (n = 3). Circulating EVs of PAD patients were mainly of platelet origin, predominantly Annexin V positive and were associated with the procoagulant activity of plateletfree plasma. Transcriptomic analysis of EVs identified 15 differentially expressed genes. Among them, serum calprotectin was elevated in PAD patients (p < 0.05) and associated with increased amputation risk before and after covariate adjustment (mean follow-up 3.6 years, p < 0.01). The combination of calprotectin with hs-CRP in the multivariate analysis further improved risk stratification (p < 0.01). Furthermore, S100A9 was also expressed in femoral plaque derived EVs and tissues. In summary, we found that PAD patients release EVs, mainly of platelet origin, highly positive for AnnexinV and rich in transcripts related to platelet biology and immune responses. Amputation risk prediction improved with calprotectin and was significantly higher when combined with hs-CRP. Our results suggest that EVs can be a promising component of liquid biopsy to identify the molecular signature of PAD patients.