Ugarte-Berzal E.,CSIC - Biological Research Center |
Redondo-Munoz J.,CSIC - Biological Research Center |
Eroles P.,Hospital Clinico |
Del Cerro M.H.,CSIC - Biological Research Center |
And 3 more authors.
Blood | Year: 2010
B-cell chronic lymphocytic leukemia (BCLL) migration involves several molecules, including matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF). We have studied whether VEGF regulates MMP-9. VEGF significantly reduced MMP-9 protein expression in a dose-dependent manner, measured by gelatin zymography. Blocking the VEGFR2 receptor restored MMP-9 levels, implicating this receptor in the observed effect. Down-regulation of MMP-9 by VEGF resulted in significant inhibition of B-CLL cell migration through Matrigel or human umbilical vein endothelial cells, confirming the crucial role of MMP-9 in these processes. Reverse-transcription polymerase chain reaction analyses revealed that VEGF regulated MMP-9 at the transcriptional level. Indeed, VEGF induced STAT1 tyrosine phosphorylation, and this was blocked by inhibiting VEGFR2. STAT1 was responsible for MMP-9 down-regulation, as STAT1 gene silencing restored MMP-9 production and B-CLL cell migration in the presence of VEGF. Thus, the levels of VEGF and MMP-9 influence B-CLL cell expansion and both molecules could constitute therapeutic targets for this disease. © 2010 by The American Society of Hematology.
Induction of B-chronic lymphocytic leukemia cell apoptosis by arsenic trioxide involves suppression of the phosphoinositide 3-kinase/Akt survival pathway via c-jun-NH2 terminal kinase activation and PTEN upregulation
Redondo-Munoz J.,CSIC - Biological Research Center |
Escobar-Diaz E.,CSIC - Biological Research Center |
Del Cerro M.H.,CSIC - Biological Research Center |
Pandiella A.,University of Salamanca |
And 3 more authors.
Clinical Cancer Research | Year: 2010
Purpose: Arsenic trioxide (ATO) induces B-cell chronic lymphocytic leukemia (B-CLL) cell apoptosis in vitro. We sought to study the mechanism involved in this effect and whether ATO is suitable for combination therapies with protein kinase inhibitors. Experimental Design: B-CLL cells were isolated from the peripheral blood of 28 patients. Cell viability studies with ATO alone or in combination with kinase inhibitors were done by flow cytometry, Western blotting, and immunofluorescence analyses. Results: After 48 hours, 3 μmol/L ATO induced apoptosis (average 75%) in all B-CLL samples studied and with minimal effect on normal peripheral blood lymphocytes. Apoptosis entailed Akt and NF-κB inactivation, XIAP downregulation, and PTEN upregulation, thus implying inhibition of the phosphoinositide 3-kinase (PI3K) survival pathway. Indeed, the combination of ATO and PI3K inhibitors increased the apoptotic effect of either agent alone. ATO also induced c-jun-NH2 terminal kinase (JNK) activation, and this was crucial and required for subsequent apoptotic events, as inhibiting JNK activity by either gene silencing or specific inhibitors prevented Akt and NF-κB inactivation, caspase activation, and mitochondrial damage. Moreover, JNK activation was the earliest response to ATO, preceding and determining reactive oxygen species production. Conclusions: We identified the mechanism involved in ATO action on B-CLL cells and show that the combination of low doses of ATO and PI3K inhibitors efficiently induces B-CLL cell death. ATO may therefore constitute an efficient treatment for B-CLL, particularly in combined therapies. ©2010 AACR.
Gomez-Outes A.,Spanish Agency for Medicines and Medical Devices AEMPS |
Suarez-Gea M.L.,Spanish Agency for Medicines and Medical Devices AEMPS |
Lecumberri R.,University of Navarra |
Terleira-Fernandez A.I.,Hospital Clinico |
And 3 more authors.
European Journal of Haematology | Year: 2015
In recent years, several direct-acting oral anticoagulants (DOAC) have become available for use in Europe and other regions in indications related to prophylaxis and treatment of venous and arterial thromboembolism. They include the oral direct thrombin inhibitor dabigatran etexilate (Pradaxa®, Boehringer Ingelheim) and the oral direct FXa inhibitors rivaroxaban (Xarelto®, Bayer HealthCare), apixaban (Eliquis®, Bristol-Myers Squibb), and edoxaban (Lixiana®/Savaysa®, Daiichi-Sankyo). The new compounds have a predictable dose response and few drug-drug interactions (unlike vitamin k antagonists), and they do not require parenteral administration (unlike heparins). However, they accumulate in patients with renal impairment, lack widely available monitoring tests for measuring its anticoagulant activity, and no specific antidotes for neutralization in case of overdose and/or severe bleeding are currently available. In this review, we describe the pharmacology of the DOAC, the efficacy, and safety data from pivotal studies that support their currently approved indications and discuss the postmarketing experience available. We also summarize practical recommendations to ensure an appropriate use of the DOAC according to existing data. Finally, we discuss relevant ongoing studies and future perspectives. © 2015 John Wiley & Sons A/S.
Ruiz P.J.G.,Fundacion Jimenez Diaz |
Catalan M.J.,Hospital Clinico |
Carril J.M.F.,Hospital Of Guadalajara
Neurologist | Year: 2011
Parkinson disease (PD) is characterized by a wide variety of motor and nonmotor symptoms. Although recently nonmotor symptoms have gained considerable relevance and interest, especially in advanced stages, motor symptoms define the main core of PD and are essential for clinical diagnosis. In this article, we review the characteristics, presentation, and evolution of motor symptoms in early PD. © 2011 by Lippincott Williams & Wilkins ISSN.
Turpie A.G.G.,McMaster University |
Kreutz R.,Charité - Medical University of Berlin |
Llau J.,Hospital Clinico |
Norrving B.,Lund University |
Haas S.,TU Munich
Thrombosis and Haemostasis | Year: 2012
A number of novel oral anticoagulants that directly target factor Xa or thrombin have been developed in recent years. Rivaroxaban and apixa-ban (direct factor Xa inhibitors) and dabigatran etexilate (a direct throm-bin inhibitor) have shown considerable promise in large-scale, random -ised clinical studies for the management of thromboembolic disorders, and have been approved for clinical use in specific indications. Rivar-oxaban is licensed for the prevention of venous thromboembolism in patients undergoing elective hip or knee replacement surgery, the treatment of deep-vein thrombosis and prevention of recurrent venous thromboem-bolism, and for stroke prevention in patients with non-valvular atrial fibrillation. Based on the clinical trial data for rivaroxaban, feedback on its use in clinical practice and the authors' experience with the use of riva -roxaban, practical guidance for the use of rivaroxaban in special patient populations and specific clinical situations is provided. Although most recommendations are in line with the European summary of product characteristics for the approved indications, additional and, in several areas, different recommendations are given based on review of the literature and the authors' clinical experience. © Schattauer 2012.
Moize V.,Hospital Clinico
Avances en Diabetologia | Year: 2014
A description is presented on the different areas of therapeutic intervention and the role of the dietitian in each of these. The increasing prevalence of obesity has led to a parallel increase in the number of patients seeking and receiving treatment, which represents a new and challenging opportunity for dietitians to develop innovative programs. Interpersonal skills of dietitians play an important role in the treatment outcomes, and deserve periodic review and training. A full understanding of the pathology and how this can affect people's lives, increase dietitian skills to empathize, and thereby, facilitate patient management in the short and long term to ensure a comprehensive multidisciplinary approach. © 2014 Sociedad Española de Diabetes.
Which molecular biology techniques must conform to the armamentarium for basic research in uro-oncology? [Quétécnicas de biología molecular deben conformar el armamentario para la investigación básica en uro-oncología]
Oriola J.,Hospital Clinico
Archivos Espanoles de Urologia | Year: 2013
Molecular biology has been one of the scientific disciplines in which there has been more advances in the last years. The first impulse in the study of genetic alterations came from the discovery of DNA structure, followed by elucidation of the genetic code, the discovery of restriction enzymes and subsequently the invention of PCR, not forgetting the exponential development of computer science. All of them have allowed us to know much more about our genome and its regulation than we could imagine. The impulse in proteomics has been especially in tune up of soft methods of ionization coupled with mass spectrometry. Nevertheless, this seems to be only the beginning since today there are continuous methodological advances that will increase more, without doubt, the knowledge and applications in this discipline.
Sostres C.,Hospital Clinico |
Lanas A.,Hospital Clinico
Nature Reviews Gastroenterology and Hepatology | Year: 2011
Aspirin is being used as an effective analgesic and anti-inflammatory agent at doses >325 mg daily. At low doses (75-325 mg daily), aspirin is the key antiplatelet drug in the pharmacological prevention of cardiovascular diseases. Topical and systemic effects of aspirin in the gastrointestinal mucosa are associated with mucosal damage in the upper and lower gastrointestinal tract. The risk of upper gastrointestinal bleeding with aspirin is increased with old age, male sex, ulcer history and concomitant medication with NSAIDs, cyclooxygenase 2 selective inhibitors, corticosteroids or other antithrombotic agents. In some patients, the cardiovascular benefits of low-dose aspirin might be overcome by the risk of gastrointestinal complications, but withdrawal of aspirin therapy can precipitate a cardiovascular event. These patients will need concomitant therapy with antisecretory agents, especially PPIs, to reduce the gastrointestinal risk. Eradication of Helicobacter pylori infection might be an additional option in patients with a history of ulcer. Furthermore, there is growing evidence that long-term use of aspirin decreases the risk of colorectal cancer, even at low doses. As aspirin is one of the most prescribed drugs worldwide and its clinical impact is huge, physicians need to consider the benefits and harms for each individual patient in order to maximize the benefits of aspirin.
News Article | October 6, 2016
Parkinson’s disease is the second most common neurodegenerative disorder in the developed world, with around 60,000 people diagnosed in the U.S. each year. Although there is no cure for the disease, there are treatments that can reduce the severity of a patient’s symptoms. But for these treatments to be effective, clinicians need a method to regularly monitor the patient’s symptoms in the home. In a paper published in the journal Scientific Reports, researchers at MIT and elsewhere describe a technique they have developed to monitor Parkinson’s disease progression as patients interact with a computer keyboard. In this way the technique, which is based on technology originally developed to replace computer passwords, allows Parkinson’s signs to be monitored as people perform ordinary tasks such as typing emails or updating their Facebook status, according to Luca Giancardo, a former Catalyst Fellow in the Madrid-MIT M+Vision Consortium in the Research Laboratory of Electronics at MIT, and one of the paper’s lead authors. “This approach uses something we do normally — interacting with a digital device — so it does not add any additional burden or take time away from daily activities,” he said. Parkinson’s disease, which is caused by a loss of nerve cells in the brain leading to a reduction in levels of the chemical dopamine, is a progressive disorder with signs including tremors and motor difficulties, and ultimately severe disability and dementia. Medication to replace dopamine levels or mimic dopamine’s activity can help to lessen the severity of its signs. If Parkinson’s could be diagnosed earlier, researchers may even be able to develop drugs that could potentially stall the progression of the disease, according to Álvaro Sánchez-Ferro, joint lead author and a former Catalyst Fellow in the Madrid-MIT M+Vision Consortium. “The problem is that so far there has not been an easy method to provide this early detection, and one reason is that the progression of the disease is very slow,” he said. Existing methods to evaluate the severity of Parkinson’s signs are based on trained medical personnel assessing the patient’s ability to perform a number of movement activities. However, these assessments tend to be carried out in a clinical setting, limiting how often they can be undertaken. So the researchers set out to investigate whether keystroke dynamics, a technique used to identify a computer user by the time they take to press down and release each key — typically around 100 milliseconds — could be used to monitor the motor effects of Parkinson’s disease in the home. In previous work the researchers had demonstrated that the technique can be used to spot signs of sleep inertia, or the decline in motor dexterity caused by grogginess on being suddenly woken. In the new experiments, at Spanish medical clinics 12 de Octubre, Hospital Clinico, and HM CINAC, coordinated by Sánchez Ferro and co-author José Obeso at HM CINAC, the researchers asked 42 patients with early stage Parkinson’s disease and 43 healthy subjects to type out a text of their choosing for 10-15 minutes on a computer keyboard. The computer was installed with software designed to measure the timing of each press and release. When they analyzed the typing data, they found a significant variation in the timing of each press and release in patients with early stage Parkinson’s disease, while in the healthy control group this was much more uniform, Giancardo said. “By looking at the variation of this press and release, we were able to find a signature that allows us to detect Parkinson’s disease in our cohort.” To ensure the privacy of patients taking part in the test, the software does not monitor the words people type, he said. The system can be installed as software on a standard computer, or added to the hardware of a device, or even deployed on a webpage. “We envisage that this could be used to fill in the gaps between visits to the neurologist, for example, or between other tests that cannot be carried out continuously,” said Giancardo. Monitoring patients’ signs as they go about their daily activities could help doctors determine the most effective dosage of medication to prescribe at that time, and could ultimately help researchers to develop treatments to halt the disease, said Sanchez-Ferro. It could also help patients to monitor the effectiveness of activities that can reduce the effects of Parkinson’s disease, he said. “There are activities such as sports and yoga that can significantly help with the symptoms, and so the Parkinson’s community has been looking for a way to measure Parkinson’s signs quantitatively, which has so far proven very difficult to do,” said Giancardo. This is a very important piece of work, according to Bryan Strange, director of the Laboratory for Clinical Neuroscience within the Technical University of Madrid’s Center for Biomedical Technology, in Spain. “At present the ability to monitor the motor signs of those with Parkinson’s or those who are starting to develop the disease is limited to a clinical setting,” he said. This restricts the frequency with which such tests can be carried out. “This [test] is not something that requires the patient to do something out of the ordinary,” he added. The researchers hope the technique could ultimately be used to create algorithms that can detect signs of other neurological or motor-based disorders. They have already received interest from technology startup companies interested in helping the team translate the technology.
Alvarez-Larran A.,Hospital del Mar |
Hernandez-Boluda J..-C.,Hospital Clinico |
Cervantes F.,University of Barcelona |
Besses C.,Hospital del Mar
British Journal of Haematology | Year: 2013
The effectiveness of low-dose aspirin in the primary prevention of thrombosis in patients with high-risk essential thrombocythaemia (ET) treated with cytoreductive drugs is not well established. The risk-benefit balance of low-dose aspirin plus cytoreductive therapy compared with cytoreduction alone was retrospectively analysed in 247 patients with high-risk ET without prior thrombosis. Follow-up was 763 and 685 person-years for cytoreduction plus low-dose aspirin and cytoreduction alone, respectively. The rate of thrombosis was not significantly reduced in patients on cytoreduction plus aspirin (14·4 events per 1000 person-years) when compared with those on cytoreduction alone (24·8 events per 1000 person-years; P = 0·2). However, in the subgroup of patients older than 60 years, the addition of low-dose aspirin was associated with a significantly lower rate of thrombosis (8·6 vs. 29·2 thrombosis per 1000 person-years for combined treatment and cytoreduction alone, respectively, P = 0·02). The rate of major bleeding was significantly higher with combined therapy than with cytoreduction alone both in the whole series (14·4 vs. 1·4 haemorrhagic events per 1000 person-years, respectively, P = 0·006) and in the subgroup of patients older than 60 years. In conclusion, low-dose aspirin benefits high-risk ET patients older than 60 years receiving cytoreductive therapy as primary prophylaxis of thrombosis. © 2013 John Wiley & Sons Ltd.