Publicació científica

S'han trobat 1424 publicacions amb els criteris indicats.
Crisà E, Kulasekararaj AG, Adema V, Such E, Schanz J, Haase D, Shirneshan K, Best S, Mian SA, Kizilors A, Cervera J, Lea N, Ferrero D, Germing U, Hildebrandt B, Martínez ABV, Santini V, Sanz GF, Solé F, Mufti GJ

Impact of somatic mutations in myelodysplastic patients with isolated partial or total loss of chromosome 7.

Leukemia 17 Feb 2020, . Epub 17 Feb 2020
Monosomy 7 [-7] and/or partial loss of chromosome 7 [del(7q)] are associated with poor and intermediate prognosis, respectively, in myelodysplastic syndromes (MDS), but somatic mutations may also play a key complementary role. We analyzed the impact on the outcomes of deep targeted mutational screening in 280 MDS patients with -7/del(7q) as isolated cytogenetic abnormality (86 with del(7q) and 194 with -7). Patients with del(7q) or -7 had similar demographic and disease-related characteristics. Somatic mutations were detected in 79% (93/117) of patients (82% in -7 and 73% in del(7q) group). Median number of mutations per patient was 2 (range 0-8). There was no difference in mutation frequency between the two groups. Patients harbouring ≥2 mutations had a worse outcome than patients with <2 or no mutations (leukaemic transformation at 24 months, 38% and 20%, respectively, p = 0.044). Untreated patients with del(7q) had better overall survival (OS) compared with -7 (median OS, 34 vs 17 months, p = 0.034). In multivariable analysis, blast count, TP53 mutations and number of mutations were independent predictors of OS, whereas the cytogenetic subgroups did not retain prognostic relevance. This study highlights the importance of mutational analysis in terms of prognosis in MDS patients with isolated -7 or del(7q).
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Capdevila J, Arqués O, Hernández Mora JR, Matito J, Caratù G, Mancuso FM, Landolfi S, Barriuso J, Jimenez-Fonseca P, Lopez Lopez C, Garcia-Carbonero R, Hernando J, Matos I, Paolo N, Hernández-Losa J, Esteller M, Martínez-Cardús A, Tabernero J, Vivancos A, Palmer HG

Epigenetic EGFR Gene Repression Confers Sensitivity to Therapeutic BRAFV600E Blockade in Colon Neuroendocrine Carcinomas

Clin. Cancer Res. 15 Feb 2020, 26 (4) 902-909. Epub 31 Oct 2019
The limited knowledge of the molecular alterations that characterize poorly differentiated neuroendocrine carcinomas has limited the clinical development of targeted agents directed to driver mutations. Here we aim to identify new molecular targets in colon neuroendocrine carcinomas (co-NEC) and proof the efficacy of matching drugs.
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Esteve-Puig R, Bueno-Costa A, Esteller M

Writers, Readers and Erasers of RNA Modifications in Cancer.

Cancer Lett. 25 Gen 2020, . Epub 25 Gen 2020
Although cancer was originally considered a disease driven only by genetic mutations, it has now been proven that it is also an epigenetic disease driven by DNA hypermethylation-associated silencing of tumor suppressor genes and aberrant histone modifications. Very recently, a third component has emerged: the so-called epitranscriptome understood as the chemical modifications of RNA that regulate and alter the activity of RNA molecules. In this regard, the study of genetic and epigenetic disruption of the RNA-modifying proteins is gaining momentum in advancing our understanding of cancer biology. Furthermore, the development of epitranscriptomic anticancer drugs could lead to new promising and unexpected therapeutic strategies for oncology in the coming years.
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Ikemori R, Gabasa M, Duch P, Vizoso M, Bragado P, Arshakyan M, Luis IC, Marín A, Morán S, Castro M, Fuster G, Gea-Sorli S, Jauset T, Soucek L, Montuenga LM, Esteller M, Monsó E, Peinado VI, Gascon P, Fillat C, Hilberg F, Reguart N, Alcaraz J

Epigenetic SMAD3 repression in tumor-associated fibroblasts impairs fibrosis and response to the antifibrotic drug nintedanib in lung squamous cell carcinoma

Cancer Res. 15 Gen 2020, 80 (2) 276-290. Epub 6 Nov 2019
The tumor-promoting fibrotic stroma rich in tumor-associated fibroblasts (TAF) is drawing increased therapeutic attention. Intriguingly, a trial with the antifibrotic drug nintedanib in non-small cell lung cancer reported clinical benefits in adenocarcinoma (ADC) but not squamous cell carcinoma (SCC), even though the stroma is fibrotic in both histotypes. Likewise, we reported that nintedanib inhibited the tumor-promoting fibrotic phenotype of TAFs selectively in ADC. Here we show that tumor fibrosis is actually higher in ADC-TAFs than SCC-TAFs
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Perez-Amill L, Suñe G, Antoñana-Vildosola A, Castella M, Najjar A, Bonet J, Fernández-Fuentes N, Inogés S, López A, Bueno C, Juan M, Urbano-Ispizua A, Martín-Antonio B

Preclinical development of a humanized chimeric antigen receptor against B cell maturation antigen for multiple myeloma.

Haematologica 9 Gen 2020, . Epub 9 Gen 2020
Multiple myeloma is a prevalent and incurable disease, despite the development of new and effective drugs. The recent development of chimeric antigen receptor (CAR)-T cell therapy has shown impressive results in the treatment of patients with relapsed or refractory hematological B cell malignancies. In the recent years, B-cell maturation antigen (BCMA) has appeared as a promising antigen to target using a variety of immuno-therapy treatments including CART cells, for MM patients. To this end, we generated clinical-grade murine CART cells directed against BCMA, named ARI2m cells. Having demonstrated its efficacy, and in an at-tempt to avoid the immune rejection of CART cells by the patient, the single chain variable fragment was humanized, creating ARI2h cells. ARI2h cells demonstrated comparable in vitro and in vivo efficacy to ARI2m cells, and superiority in cases of high tumor burden disease. In terms of inflammatory response, ARI2h cells showed a lower TNFα production and lower in vivo toxicity profile. Large-scale expansion of both ARI2m and ARI2h cells was efficiently conducted following Good Manufacturing Practice guidelines, obtaining the target CART cell dose required for treatment of multiple myeloma patients. Moreover, we demonstrate that soluble BCMA and BCMA released in vesicles impacts on CAR-BCMA activity. In sum-mary, this study sets the bases for the implementation of a clinical trial (EudraCT code: 2019-001472-11) to study the efficacy of ARI2h cell treatment for multiple myeloma patients.
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Xiu Y, Dong Q, Fu L, Bossler A, Tang X, Boyce B, Borcherding N, Leidinger M, Sardina JL, Xue HH, Li Q, Feldman A, Aifantis I, Boccalatte F, Wang L, Jin M, Khoury J, Wang W, Hu S, Yuan Y, Wang E, Yuan J, Janz S, Colgan J, Habelhah H, Waldschmidt T, Müschen M, Bagg A, Darbro B, Zhao C

Coactivation of NF-κB and Notch signaling is sufficient to induce B-cell transformation and enables B-myeloid conversion.

Blood 9 Gen 2020, 135 (2) 108-120.
NF-κB and Notch signaling can be simultaneously activated in a variety of B-cell lymphomas. Patients with B-cell lymphoma occasionally develop clonally related myeloid tumors with poor prognosis. Whether concurrent activation of both pathways is sufficient to induce B-cell transformation and whether the signaling initiates B-myeloid conversion in a pathological context are largely unknown. Here, we provide genetic evidence that concurrent activation of NF-κB and Notch signaling in committed B cells is sufficient to induce B-cell lymphomatous transformation and primes common progenitor cells to convert to myeloid lineage through dedifferentiation, not transdifferentiation. Intriguingly, the converted myeloid cells can further transform, albeit at low frequency, into myeloid leukemia. Mechanistically, coactivation of NF-κB and Notch signaling endows committed B cells with the ability to self renew. Downregulation of BACH2, a lymphoma and myeloid gene suppressor, but not upregulation of CEBPα and/or downregulation of B-cell transcription factors, is an early event in both B-cell transformation and myeloid conversion. Interestingly, a DNA hypomethylating drug not only effectively eliminated the converted myeloid leukemia cells, but also restored the expression of green fluorescent protein, which had been lost in converted myeloid leukemia cells. Collectively, our results suggest that targeting NF-κB and Notch signaling will not only improve lymphoma treatment, but also prevent the lymphoma-to-myeloid tumor conversion. Importantly, DNA hypomethylating drugs might efficiently treat these converted myeloid neoplasms.
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Li ST, Wang J, Wei R, Shi R, Adema V, Nagata Y, Kerr CM, Kuzmanovic T, Przychodzen B, Sole F, Maciejewski JP, LaFramboise T

Rare germline variant contributions to myeloid malignancy susceptibility.

Leukemia 7 Gen 2020, . Epub 7 Gen 2020Més informació
Gonzalez-Santamarta M, Quinet G, Reyes-Garau D, Sola B, Roué G, Rodriguez MS

Resistance to the Proteasome Inhibitors: Lessons from Multiple Myeloma and Mantle Cell Lymphoma.

Adv. Exp. Med. Biol. 2020, 1233 153-174. Epub 18 Feb 2020
Since its introduction in the clinics in early 2000s, the proteasome inhibitor bortezomib (BTZ) significantly improved the prognosis of patients with multiple myeloma (MM) and mantle cell lymphoma (MCL), two of the most challenging B cell malignancies in western countries. However, relapses following BTZ therapy are frequent, while primary resistance to this agent remains a major limitation for further development of its therapeutic potential. In the present chapter, we recapitulate the molecular mechanisms associated with intrinsic and acquired resistance to BTZ learning from MM and MCL experience, including mutations of crucial genes and activation of prosurvival signalling pathways inherent to malignant B cells. We also outline the preclinical and clinical evaluations of some potential druggable targets associated to BTZ resistance, considering the most meaningful findings of the past 10 years. Although our understanding of BTZ resistance is far from being completed, recent discoveries are contributing to develop new approaches to treat relapsed MM and MCL patients.
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Falgàs A, Pallarès V, Serna N, Sánchez-García L, Sierra J, Gallardo A, Alba-Castellón L, Álamo P, Unzueta U, Villaverde A, Vázquez E, Mangues R, Casanova I

Selective delivery of T22-PE24-H6 to CXCR4

Theranostics 2020, 10 (12) 5169-5180. Epub 6 Abr 2020Més informació
Wössner N, Alhalabi Z, González J, Swyter S, Gan J, Schmidtkunz K, Zhang L, Vaquero A, Ovaa H, Einsle O, Sippl W, Jung M

Sirtuin 1 Inhibiting Thiocyanates (S1th)-A New Class of Isotype Selective Inhibitors of NAD

Front Oncol 2020, 10 657. Epub 30 Abr 2020
Sirtuin 1 (Sirt1) is a NAD
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