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121.
Silvia Sevilla-Movilla Nohemí Arellano-Sánchez Mónica Martínez-Moreno Consuelo Gajate Anna Sánchez-Vencells Luis V Valcárcel Xabier Agirre Antonio Valeri Joaquin Martínez-López Felipe Prósper Faustino Mollinedo Joaquin Teixidó 《The Journal of pathology》2020,252(1):29-40
The interaction of multiple myeloma (MM) cells with the bone marrow (BM) microenvironment promotes MM cell retention, survival, and resistance to different anti-MM agents, including proteasome inhibitors (PIs) such as bortezomib (BTZ). The α4β1 integrin is a main adhesion receptor mediating MM cell–stroma interactions and MM cell survival, and its expression and function are downregulated by BTZ, leading to inhibition of cell adhesion-mediated drug resistance (CAM-DR) and MM cell apoptosis. Whether decreased α4β1 expression and activity are maintained or recovered upon development of resistance to BTZ represents an important question, as a potential rescue of α4β1 function could boost MM cell survival and disease progression. Using BTZ-resistant MM cells, we found that they not only rescue their α4β1 expression, but its levels were higher than in parental cells. Increased α4β1 expression in resistant cells correlated with enhanced α4β1-mediated cell lodging in the BM, and with disease progression. BTZ-resistant MM cells displayed enhanced NF-κB pathway activation relative to parental counterparts, which contributed to upregulated α4 expression and to α4β1-dependent MM cell adhesion. These data emphasize the upregulation of α4β1 expression and function as a key event during resistance to BTZ in MM, which might indirectly contribute to stabilize this resistance, as stronger MM cell attachment to BM stroma will regain CAM-DR and MM cell growth and survival. Finally, we found a strong correlation between high ITGB1 (integrin β1) expression in MM and poor progression-free survival (PFS) and overall survival (OS) during treatment of MM patients with BTZ and IMIDs, and combination of high ITGB1 levels and presence of the high-risk genetic factor amp1q causes low PFS and OS. These results unravel a novel prognostic value for ITGB1 in myeloma. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. 相似文献
122.
Yaroslau Compta Francesc Valldeoriola Xabier Urra Beatriz Gómez-Ansón Lorena Rami Eduardo Tolosa Francesc Graus 《Movement disorders》2007,22(5):736-738
Anti-Hu encephalomyelitis is one of the most frequent paraneoplastic syndromes, classically presenting with diffuse neurological involvement. We report a 69-year-old man presenting with a three-month isolated, progressive gait disorder with normal neurological examination, except for loss of balance and gait failure reminding frontal disequilibrium, only accompanied by a very mild rigidity of his right foot. MRI of the brain showed hyperintensities in both amygdale and left putamen. EMG study showed no abnormal continuous spontaneous fiber activity. Because of fast progression and MRI findings, anti-Hu antibodies were tested, resulting positive. Mediastinal biopsy of two adenopathies detected by body-PET, confirmed an oat-cell carcinoma. The patient received oral steroids and oncological therapy. One year later, the tumor is in remission. His gait and abnormal posture of right leg are normal. Only mild residual hyperintensities persist on follow-up MRI. A paraneoplastic syndrome should be considered in the differential diagnosis of subacute, fast progressive gait disorders. 相似文献
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124.
Marta Fernandez-Mercado Adam Burns Andrea Pellagatti Aristoteles Giagounidis Ulrich Germing Xabier Agirre Felipe Prosper Carlo Aul Sally Killick James S. Wainscoat Anna Schuh Jacqueline Boultwood 《Haematologica》2013,98(12):1856-1864
Interstitial deletion of chromosome 5q is the most common chromosomal abnormality in myelodysplastic syndromes. The catalogue of genes involved in the molecular pathogenesis of myelodysplastic syndromes is rapidly expanding and next-generation sequencing technology allows detection of these mutations at great depth. Here we describe the design, validation and application of a targeted next-generation sequencing approach to simultaneously screen 25 genes mutated in myeloid malignancies. We used this method alongside single nucleotide polymorphism-array technology to characterize the mutational and cytogenetic profile of 43 cases of early or advanced del(5q) myelodysplastic syndromes. A total of 29 mutations were detected in our cohort. Overall, 45% of early and 66.7% of advanced cases had at least one mutation. Genes with the highest mutation frequency among advanced cases were TP53 and ASXL1 (25% of patients each). These showed a lower mutation frequency in cases of 5q- syndrome (4.5% and 13.6%, respectively), suggesting a role in disease progression in del(5q) myelodysplastic syndromes. Fifty-two percent of mutations identified were in genes involved in epigenetic regulation (ASXL1, TET2, DNMT3A and JAK2). Six mutations had allele frequencies <20%, likely below the detection limit of traditional sequencing methods. Genomic array data showed that cases of advanced del(5q) myelodysplastic syndrome had a complex background of cytogenetic aberrations, often encompassing genes involved in myeloid disorders. Our study is the first to investigate the molecular pathogenesis of early and advanced del(5q) myelodysplastic syndromes using next-generation sequencing technology on a large panel of genes frequently mutated in myeloid malignancies, further illuminating the molecular landscape of del(5q) myelodysplastic syndromes. 相似文献
125.
Carlos Manterola Galo Duque Luis Grande Xabier de Aretxabala Roque Conejeros Tamara Otzen Nayely García 《HPB : the official journal of the International Hepato Pancreato Biliary Association》2019,21(11):1427-1435
BackgroundEquipoise exists regarding the benefit of adjuvant therapy (AT) in patients with gallbladder cancer (GBC). The aim of this study was to critically review the available evidence for the effectiveness of AT in patients with GBC following surgery with curative intent.MethodsA systematic review was performed. Relevant studies were identified from Trip Database, BIREME-BVS, SciELO, Cochrane Central Register, WoS, MEDLINE, EMBASE and SCOPUS. Adjuvant therapies considered included chemotherapy, chemoradiotherapy, and radiotherapy. The primary outcome was overall survival (OS). Subgorup analysis of patients with positive lymph node disease (PLND), positive surgical margin (PSM), or advanced stage (AS) were performed.Results748 related articles were identified; 27 met the selection criteria (3 systematic reviews and 24 observational studies). Evidence provided was moderate, poor and very poor for chemotherapy, chemoradiotherapy, and radiotherapy. Existing evidence is not robust, but suggests certain benefits with AT in improving OS, especially in patients with PLND, PSM and AS.ConclusionResults do not provide strong evidence that AT is effective in patients who undergo resection for GBC. Subgroups of PLND and PSM may have a survival advantage. Future studies with appropriate internal validity and adequate number of patients are required to better answer this question. 相似文献
126.
127.
Vanesa Martín Ana Valencia Xabier Agirre Jose Cervera Edurne San Jose‐Eneriz Amaia Vilas‐Zornoza Paula Rodriguez‐Otero Miguel A. Sanz Concepción Herrera Antonio Torres Felipe Prosper Jose Román‐Gómez 《Cancer science》2010,101(2):425-432
Wnt5a is a member of the Wnt family of proteins that signals through the non‐canonical Wnt/Ca2+pathway to suppress cyclin D1. Deregulation of this pathway has been found in animal models suggesting that it acts as tumour suppressor in acute myeloid leukemia (AML). Although DNA methylation is the main mechanism of regulation of the canonical Wnt pathway in AML, the role of WNT5A abnormalities has never been evaluated in this clinical setting. The methylation status of WNT5A promoter–exon 1 was analyzed by methylation‐specific PCR and sequencing in eleven AML‐derived cell lines and 252 AML patients. We observed WNT5A hypermethylation in seven cell lines and in 43% (107/252) of AML patients. WNT5A methylation was associated with decreased WNT5A expression (P < 0.001) that was restored after exposure to 5‐Aza‐2’‐deoxycytidine. Moreover, WNT5A hypermethylation correlated with upregulation of CYCLIN D1 expression (P < 0.001). Relapse (15%vs 37%, P < 0.001) and mortality (61%vs 79%, P = 0.004) rates were lower for patients in the non‐methylated group. Disease‐free survival and overall survival at 6 and 7 years, respectively, were 60% and 27% for unmethylated patients and 20% and 0% for hypermethylated patients (P = 0.0001 and P = 0.04, respectively). Interestingly, significant differences were also observed when the analysis was carried out according to cytogenetic risk groups. We demonstrate that WNT5A, a putative tumor suppressor gene in AML, is silenced by methylation in this disease and that this epigenetic event is associated with upregulation of CYCLIN D1 expression and confers poor prognosis in patients with AML. (Cancer Sci 2009) 相似文献
128.
Aranguren XL Verfaillie CM Luttun A 《Journal of molecular medicine (Berlin, Germany)》2009,87(1):3-16
Peripheral vascular disease (PVD) is a growing medical problem in Western societies and presents itself mainly in two different
clinical forms. Intermittent claudication is an early moderate manifestation, while patients with critical limb ischemia suffer
from severe muscle tissue loss or ulcers and are at high risk for limb amputation. Unfortunately, many patients cannot be
helped with currently available surgical or endovascular revascularization procedures because of the complex anatomy of the
vascular occlusion and/or the presence of other risk factors. Noninvasive stem cell therapy has been proposed as an alternative
for such patients. Although pioneering clinical experience with stem cell-related therapy seems promising, it is too early
for general clinical use of this technique, since many questions remain unanswered. Indeed, while questions about safety,
dose, and administration route/timing/frequency are the first ones to be addressed when designing a stem cell-based clinical
approach, there is accumulating evidence from recent (pre-)clinical studies that other issues may also be at stake. For instance,
the choice of stem cells to be used and its precise mechanism of action, the need/possibility for concurrent tissue regeneration
in case of irreversible tissue loss, the differentiation degree and specific vascular identity of the transplanted cells,
and the long-term survival of engrafted cells in the absence of a normal supportive tissue environment should be well considered.
Here, rather than presenting a comprehensive and extensive overview on the current literature on stem/progenitor cells and
revascularization, we highlight some of the outstanding issues emerging from the recent (pre-)clinical literature that may
codetermine the successful application of stem cells in a wide range of PVD patients in the future. 相似文献
129.
Vázquez I Maicas M Marcotegui N Conchillo A Guruceaga E Roman-Gomez J Calasanz MJ Agirre X Prosper F Odero MD 《Proceedings of the National Academy of Sciences of the United States of America》2010,107(44):E167-8; author reply E169-70