Lin R.-Z.,Harvard University |
Moreno-Luna R.,Institute Biomedicina Of Seville Ibis |
Moreno-Luna R.,Harvard University |
Zhou B.,Harvard University |
And 3 more authors.
Angiogenesis | Year: 2012
Mesenchymal stem cells (MSCs) can generate multiple end-stage mesenchymal cell types and constitute a promising population of cells for regenerative therapies. Additionally, there is increasing evidence supporting other trophic activities of MSCs, including the ability to enable formation of vasculature in vivo. Although MSCs were originally isolated from the bone marrow, the presence of these cells in the stromal vascular fraction of multiple adult tissues has been recently recognized. However, it is unknown whether the capacity to modulate vasculogenesis is ubiquitous to all MSCs regardless of their tissue of origin. Here, we demonstrated that tissue-resident MSCs isolated from four distinct tissues have equal capacity to modulate endothelial cell function, including formation of vascular networks in vivo. MSCs were isolated from four murine tissues, including bone marrow, white adipose tissue, skeletal muscle, and myocardium. In culture, all four MSC populations secreted a plethora of pro-angiogenic factors that unequivocally induced proliferation, migration, and tube formation of endothelial colony-forming cells (ECFCs). In vivo, co-implantation of MSCs with ECFCs into mice generated an extensive network of blood vessels with ECFCs specifically lining the lumens and MSCs occupying perivascular positions. Importantly, there were no differences among all four MSCs evaluated. Our studies suggest that the capacity to modulate the formation of vasculature is a ubiquitous property of all MSCs, irrespective of their original anatomical location. These results validate multiple tissues as potential sources of MSCs for future cell-based vascular therapies. © 2012 Springer Science+Business Media B.V. Source
Venero J.L.,University of Seville |
Venero J.L.,Institute Biomedicina Of Seville Ibis |
Burguillos M.A.,Karolinska Institutet |
Burguillos M.A.,Neuronal Survival Unit |
And 2 more authors.
Cell Death and Differentiation | Year: 2011
Activation of microglia and inflammation-mediated neurotoxicity are suggested to have key roles in the pathogenesis of several neurodegenerative disorders. We recently published an article in Nature revealing an unexpected role for executioner caspases in the microglia activation process. We showed that caspases 8 and 3/7, commonly known to have executioner roles for apoptosis, can promote microglia activation in the absence of death. We found these caspases to be activated in microglia of PD and AD subjects. Inhibition of this signaling pathway hindered microglia activation and importantly reduced neurotoxicity in cell and animal models of disease. Here we review evidence suggesting that microglia can have a key role in the pathology of neurodegenerative disorders. We discuss possible underlying mechanisms regulating their activation and neurotoxic effect. We focus on the provocative hypothesis that caspase inhibition can be neuroprotective by targeting the microglia rather than the neurons themselves. © 2011 Macmillan Publishers Limited All rights reserved. Source
Cabrera Serrano M.,Institute Biomedicina Of Seville Ibis
European Journal of Neurology | Year: 2012
Background and purpose: Define the usefulness of pulmonary function tests (PFT) and arterial blood gases (ABG) in patients admitted to the ICU with acute neuromuscular respiratory failure (NMRF). Methods: We reviewed 76 patients admitted to an ICU at Mayo Clinic (Rochester) between 2003 and 2009 with acute NMRF defined as need for mechanical ventilation (MV) because of primary impairment of the peripheral nervous system. Poor functional outcome was defined as a modified Rankin score >3. Results: Median age was 65years. The most frequent diagnosis was myasthenia gravis (25 patients); 54% of patients had no known neuromuscular diagnosis before admission, and 11% had no specific diagnosis at discharge. Median MV time was 16days; 14% of patients died during hospitalization, and 63% were severely disabled at discharge. Maximal expiratory pressure ≤30cm H 2O and maximal inspiratory pressure (MIP) worse than -28cm H 2O before MV were associated with need for invasive MV for longer than 7days (P=0.02). Indicators of chronic respiratory acidosis (low pH, high pCO 2, and high HCO 3) before MV were associated with in-hospital death and poor functional outcome, but mostly in patients with progressive, untreatable neuromuscular diagnoses. Conclusions: In patients with primary acute NMRF, bedside PFT and ABG before MV can be used to predict evolution and outcome. Lower MIP and MEP portend prolonged MV and are more useful than forced vital capacity. Presentation with chronic respiratory acidosis is associated with high risk of in-hospital mortality and severe disability, especially in patients without treatable diagnoses. © 2011 The Author(s). European Journal of Neurology © 2011 EFNS. Source
Romero O.A.,Genes and Cancer Group |
Torres-Diz M.,Genes and Cancer Group |
Pros E.,Genes and Cancer Group |
Savola S.,MRC Holland |
And 10 more authors.
Cancer Discovery | Year: 2014
Our knowledge of small cell lung cancer (SCLC) genetics is still very limited, ampli-fication of L-MYC, N-MYC, and C-MYC being some of the well-established gene alterations. Here, we report our discovery of tumor-specific inactivation of the MYC-associated factor X gene, MAX, in SCLC. MAX inactivation is mutually exclusive with alterations of MYC and BRG1, the latter coding for an ATPase of the switch/sucrose nonfermentable (SWI/SNF) complex. We demonstrate that BRG1 regulates the expression of MAX through direct recruitment to the MAX promoter, and that depletion of BRG1 strongly hinders cell growth, specifically in MAX-deficient cells, heralding a synthetic lethal interaction. Furthermore, MAX requires BRG1 to activate neuroendocrine transcriptional programs and to upregulate MYC targets, such as glycolysis-related genes. Finally, inactivation of the MAX dimerization protein, MGA, was also observed in both non-small cell lung cancer and SCLC. Our results provide evidence that an aberrant SWI/SNF-MYC network is essential for lung cancer development. SIGNIFICANCE: We discovered that the MYC-associated factor X gene, MAX, is inactivated in SCLCs. Furthermore, we revealed a preferential toxicity of the inactivation of the chromatin remodeler BRG1 in MAX-deficient lung cancer cells, which opens novel therapeutic possibilities for the treatment of patients with SCLC with MAX-deficient tumors. © 2013 American Association for Cancer Research. Source
Demetri G.D.,Dana-Farber Cancer Institute |
Garrett C.R.,H. Lee Moffitt Cancer Center and Research Institute |
Schoffski P.,Catholic University of Leuven |
Shah M.H.,Ohio State University |
And 16 more authors.
Clinical Cancer Research | Year: 2012
Purpose: To analyze final long-term survival and clinical outcomes from the randomized phase III study of sunitinib in gastrointestinal stromal tumor patients after imatinib failure; to assess correlative angiogenesis biomarkers with patient outcomes. Experimental Design: Blinded sunitinib or placebo was given daily on a 4-week-on/2-week-off treatment schedule. Placebo-assigned patients could cross over to sunitinib at disease progression/study unblinding. Overall survival (OS) was analyzed using conventional statistical methods and the rank-preserving structural failure time (RPSFT) method to explore cross-over impact. Circulating levels of angiogenesis biomarkers were analyzed. Results: In total, 243 patients were randomized to receive sunitinib and 118 to placebo, 103 of whom crossed over to open-label sunitinib. Conventional statistical analysis showed that OS converged in the sunitinib and placebo arms (median 72.7 vs. 64.9 weeks; HR, 0.876; P=0.306) as expected, given the cross-over design. RPSFT analysis estimated median OS for placebo of 39.0 weeks (HR, 0.505, 95% CI, 0.262-1.134; P = 0.306). No new safety concerns emerged with extended sunitinib treatment. No consistent associations were found between the pharmacodynamics of angiogenesis-related plasma proteins during sunitinib treatment and clinical outcome. Conclusions: The cross-over design provided evidence of sunitinib clinical benefit based on prolonged time to tumor progression during the double-blind phase of this trial. As expected, following cross-over, there was no statistical difference in OS. RPSFT analysis modeled the absence of cross-over, estimating a substantial sunitinib OS benefit relative to placebo. Long-term sunitinib treatment was tolerated without new adverse events. ©2012 AACR. Source