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Balsas P.,Institute Dinvestigacions Biomediques August Pi Isunyer Idibaps | Esteve-Arenys A.,Institute Dinvestigacions Biomediques August Pi Isunyer Idibaps | Roldan J.,Institute Dinvestigacions Biomediques August Pi Isunyer Idibaps | Jimenez L.,Institute Dinvestigacions Biomediques August Pi Isunyer Idibaps | And 16 more authors.
Journal of Hematology and Oncology | Year: 2017

Background: Pharmacological inhibition of B cell receptor (BCR) signaling has recently emerged as an effective approach in a wide range of B lymphoid neoplasms. However, despite promising clinical activity of the first Bruton’s kinase (Btk) and spleen tyrosine kinase (Syk) inhibitors, a small fraction of patients tend to develop progressive disease after initial response to these agents. Methods: We evaluated the antitumor activity of IQS019, a new BCR kinase inhibitor with increased affinity for Btk, Syk, and Lck/Yes novel tyrosine kinase (Lyn), in a set of 34 B lymphoid cell lines and primary cultures, including samples with acquired resistance to the first-in-class Btk inhibitor ibrutinib. Safety and efficacy of the compound were then evaluated in two xenograft mouse models of B cell lymphoma. Results: IQS019 simultaneously engaged a rapid and dose-dependent de-phosphorylation of both constitutive and IgM-activated Syk, Lyn, and Btk, leading to impaired cell proliferation, reduced CXCL12-dependent cell migration, and induction of caspase-dependent apoptosis. Accordingly, B cell lymphoma-bearing mice receiving IQS019 presented a reduced tumor outgrowth characterized by a decreased mitotic index and a lower infiltration of malignant cells in the spleen, in tight correlation with downregulation of phospho-Syk, phospho-Lyn, and phospho-Btk. More interestingly, IQS019 showed improved efficacy in vitro and in vivo when compared to the first-in-class Btk inhibitor ibrutinib, and was active in cells with acquired resistance to this latest. Conclusions: These results define IQS019 as a potential drug candidate for a variety of B lymphoid neoplasms, including cases with acquired resistance to current BCR-targeting therapies. © 2017 The Author(s).


Marin-Aguilera M.,Hospital Clinic Of Barcelona | Codony-Servat J.,Hospital Clinic Of Barcelona | Reig O.,Hospital Clinic Of Barcelona | Fernandez P.L.,Institute DInvestigacions Biomediques August Pi ISunyer IDIBAPS | And 11 more authors.
Molecular Cancer Therapeutics | Year: 2014

Molecular characterization of radical prostatectomy specimens after systemic therapy may identify a gene expression profile for resistance to therapy. This study assessed tumor cells from patients with prostate cancer participating in a phase II neoadjuvant docetaxel and androgen deprivation trial to identify mediators of resistance. Transcriptional level of 93 genes from a docetaxel-resistant prostate cancer cell lines microarray study was analyzed by TaqMan low-density arrays in tumors from patients with high-risk localized prostate cancer (36 surgically treated, 28 with neoadjuvant docetaxel androgen deprivation). Gene expression was compared between groups and correlated with clinical outcome. VIM, AR and RELA were validated by immunohistochemistry. CD44 and ZEB1 expression was tested by immunofluorescence in cells and tumor samples. Parental and docetaxel-resistant castration-resistant prostate cancer cell lines were tested for epithelial-to-mesenchymal transition (EMT) markers before and after docetaxel exposure. Reversion of EMT phenotype was investigated as a docetaxel resistance reversion strategy. Expression of 63 (67.7%) genes differed between groups (P < 0.05), including genes related to androgen receptor, NF-kB transcription factor, and EMT. Increased expression of EMT markers correlated with radiologic relapse. Docetaxel-resistant cells had increased EMT and stem-like cell markers expression. ZEB1 siRNA transfection reverted docetaxel resistance and reduced CD44 expression in DU-145R and PC-3R. Before docetaxel exposure, a selected CD44+ subpopulation of PC-3 cells exhibited EMT phenotype and intrinsic docetaxel resistance; ZEB1/CD44 + subpopulations were found in tumor cell lines and primary tumors; this correlated with aggressive clinical behavior. This study identifies genes potentially related to chemotherapy resistance and supports evidence of the EMT role in docetaxel resistance and adverse clinical behavior in early prostate cancer. © 2014 American Association for Cancer Research.


Fernandez-Cabello S.,University of Salzburg | Fernandez-Cabello S.,University of Barcelona | Valls-Pedret C.,Institute dInvestigacions Biomediques August Pi iSunyer IDIBAPS | Valls-Pedret C.,CIBER ISCIII | And 9 more authors.
Neurobiology of Aging | Year: 2016

Cognitive reserve (CR) models posit that lifestyle factors such as education modulate the relationship between brain damage and cognition. However, the functional correlates of CR in healthy aging are still under investigation. White matter hyperintensities (WMHs) are a common age-associated finding that impacts cognition. In this study, we used functional magnetic resonance imaging to characterize the patterns of brain activation during a working memory task in older participants with high and low levels of education (as a proxy of CR) and high and low WMH volumes. Ninety older volunteers (aged 63–76 years) and 16 young adults (aged 21–27) completed the study. We found that older adults with higher education had better working memory performance than their less educated peers. Among the highly educated participants, those with WMH over-recruited areas engaged by young volunteers and showed activation in additional cortical and subcortical structures. However, those with low WMH differed little with respect to their younger counterparts. Our findings demonstrate that the functional mechanisms subtending the effects of education, as a proxy of CR, are modulated according to the WMH burden. © 2016 Elsevier Inc.


Jose A.,Institute dInvestigacions Biomediques August Pi ISunyer IDIBAPS | Jose A.,Research Center Biomedica En Red Of Enfermedades Raras Ciberer | Rovira-Rigau M.,Institute dInvestigacions Biomediques August Pi ISunyer IDIBAPS | Rovira-Rigau M.,Research Center Biomedica En Red Of Enfermedades Raras Ciberer | And 10 more authors.
Journal of Controlled Release | Year: 2014

Selective tumor targeting of oncolytic adenovirus at the level of cell entry remains a major challenge to improve efficacy and safety. Matrix metalloproteases (MMPs) are overexpressed in a variety of tumors and in particular in pancreatic cancer. In the current work, we have exploited the expression of MMPs together with the penetration capabilities of a TAT-like peptide to engineer tumor selective adenoviruses. We have generated adenoviruses containing CAR-binding ablated fibers further modified with a C-terminus TAT-like peptide linked to a blocking domain by an MMP-cleavable sequence. This linker resulted in a MMP-dependent cell transduction of the reporter MMP-activatable virus AdTATMMP and in efficient transduction of neoplastic cells and cancer-associated fibroblasts. Intravenous and intraductal administration of AdTATMMP into mice showed very low AdTATMMP activity in the normal pancreas, whereas increased transduction was observed in pancreatic tumors of transgenic Ela-myc mice. Intraductal administration of AdTATMMP into mice bearing orthotopic tumors led to a 25-fold increase in tumor targeting compared to the wild type fiber control. A replication competent adenovirus, AdRCMMP, with the MMP-activatable fiber showed oncolytic efficacy and increased antitumor activity compared to Adwt in a pancreatic orthotopic model. Reduced local and distant metastases were observed in AdRCMMP treated-mice. Moreover, no signs of pancreatic toxicity were detected. We conclude that MMP-activatable adenovirus may be beneficial for pancreatic cancer treatment. © 2014 Elsevier B.V.


De Cosmo S.,Scientific Institute | Rossi M.C.,Consorzio Mario Negri Sud | Pellegrini F.,Consorzio Mario Negri Sud | Lucisano G.,Consorzio Mario Negri Sud | And 8 more authors.
Nephrology Dialysis Transplantation | Year: 2014

BackgroundKidney dysfunction is a strong predictor of end-stage renal disease and cardiovascular (CV) events. The main goal was to study the clinical correlates of diabetic kidney disease in a large cohort of patients with type 2 diabetes mellitus (T2DM) attending 236 Diabetes Clinics in Italy.MethodsClinical data of 120 903 patients were extracted from electronic medical records by means of an ad hoc-developed software. Estimated glomerular filtration rate (GFR) and increased urinary albumin excretion were considered. Factors associated with the presence of albuminuria only, GFR < 60 mL/min/1.73 m 2 only or both conditions were evaluated through multivariate analysis.ResultsMean age of the patients was 66.6 ± 11.0 years, 58.1% were male and mean duration of diabetes was 11.1 ± 9.4 years. The frequency of albuminuria, low GFR and both albuminuria and low GFR was 36.0, 23.5 and 12.2%, respectively. Glycaemic control was related to albuminuria more than to low GFR, while systolic and pulse pressure showed a trend towards higher values in patients with normal kidney function compared with those with both albuminuria and low GFR. Multivariate logistic analysis showed that age and duration of disease influenced both features of kidney dysfunction. Male gender was associated with an increased risk of albuminuria. Higher systolic blood pressure levels were associated with albuminuria, with a 4% increased risk of simultaneously having albuminuria and low GFR for each 5 mmHg increase.ConclusionsIn this large cohort of patients with T2DM, reduced GFR and increased albuminuria showed, at least in part, different clinical correlates. A worse CV risk profile is associated with albuminuria more than with isolated low GFR. © 2014 © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.


Bassi G.L.,Institute dInvestigacions Biomediques August Pi iSunyer IDIBAPS | Bassi G.L.,Research Center Biomedica En Red Enfermedades Respiratorias
Current Respiratory Medicine Reviews | Year: 2014

Retention of airway secretions is highly common in critically ill patients, on mechanical ventilation (MV). The endotracheal tube (ETT) plays a critical role in this context; indeed, upon inflation of the ETT cuff, mucociliary transport drastically impairs. Additionally, patients with neurological impairments or underlying diseases, i.e. asthma, chronic obstructive pulmonary disease, cystic fibrosis and non-cystic fibrosis bronchiectasis are at the greatest risk. Indeed, in these patients, MV rapidly disrupts the balance between overproduction of mucus and impaired clearance capabilities. Importantly, during MV, mechanically ventilated patients are positioned in the semi recumbent position and several laboratory studies suggested that in this position retained mucus might move toward the distal airways, driven by gravity. Additionally, airflow promotes clearance or retention of retained mucus, via a two-phase gas-liquid flow mechanism. In sedated, invasively ventilated patients, the inspiratory flow can be modulated through the ventilatory settings, and theoretically, mucus clearance could be promoted or hindered through adjustments of the ventilatory settings. Yet, these assumptions should be corroborated in large translational clinical trials. Importantly, humidification of respiratory gases plays an essential role in maintaining mucus clearance rate within the physiologic range. Thus, the most appropriate humidifier should be chosen on a case-by-case basis, and given the reported poor performance of heat-moisture exchanger during ventilation at high minute volumes, heated humidifiers should be a primary choice for patients requiring high ventilatory support. Finally, numerous drugs, commonly used in ventilated patients, i.e. oxygen, inhaled anesthetics, narcotics profoundly affect mucociliary clearance and increase mucus retention. © 2014 Bentham Science Publishers.

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