Targeting the phosphoinositide 3-kinase pathway in hematologic malignancies

The phosphoinositide 3-kinase pathway represents an important anticancer target because it has been implicated in cancer cell growth, survival, and motility. Recent studies show that PI3K may also play a role in the development of resistance to currently available therapies. In a broad range of cancers, various components of the phosphoinositide 3-kinase signaling axis are genetically modified, and the pathway can be activated through many different mechanisms. The frequency of genetic alterations in the phosphoinositide 3-kinase pathway, coupled with the impact in oncogenesis and disease progression, make this signaling axis an attractive target in anticancer therapy. A better understanding of the critical function of the phosphoinositide 3-kinase pathway in leukemias and lymphomas has led to the clinical evaluation of novel rationally designed inhibitors in this setting. Three main categories of phosphoinositide 3-kinase inhibitors have been developed so far: agents that target phosphoinositide 3-kinase and mammalian target of rapamycin (dual inhibitors), pan-phosphoinositide 3-kinase inhibitors that target all class I isoforms, and isoform-specific inhibitors that selectively target the α, -β, -γ, or -δ isoforms. Emerging data highlight the promise of phosphoinositide 3-kinase inhibitors in combination with other therapies for the treatment of patients with hematologic malignancies. Further evaluation of phosphoinositide 3-kinase inhibitors in first-line or subsequent regimens may improve clinical outcomes. This article reviews the role of phosphoinositide 3-kinase signaling in hematologic malignancies and the potential clinical utility of inhibitors that target this pathway

Development and targeted use of nilotinib in chronic myeloid leukemia

The development of imatinib has resulted in sustained hematologic and cytogenetic remissions in all phases of chronic myeloid leukemia (CML). Despite the high efficacy, relapses have been observed and are much more prevalent in patients with advanced disease. The most common mechanism of acquired resistance has been traced to Bcr-Abl kinase domain mutations. Several strategies have been developed to overcome the problem of imatinib resistance, including imatinib dose escalation, novel targeted agents and combination treatments. A second generation of tyrosine kinase inhibitors was developed, which displays increased potency towards Bcr-Abl and is able to target the majority of CML mutant clones. Nilotinib (Tasigna®, AMN107, Novartis) is a close analog of imatinib with approximately 20-fold higher potency for BCR-ABL kinase inhibition. Preclinical and clinical investigations demonstrate that nilotinib effectively overcomes imatinib resistance, and has induced high rates of hematologic and cytogenetic responses in CML post imatinib failure, with a good tolerance. Nilotinib has been approved for CML patients in chronic and accelerated phases, post imatinib failure

Brazil: considerations on recent political dynamics

This article attempts to forge a synthesis of political dynamics started in 2003. The analyses core lies in the political parties and social class dynamics which resulted in an attempt both to transition acceleration to a New National Development Project as a growing and organized resistance of the ruling classes. Resistance who gained great strenght since the "siege to monetary" promoted by Dilma Rousseff government in 2012, becomes a real political force during 2013 and in mass movement since the Dilma´s second term

On The Chinese Socialist Market Economy And The “New Projectment Economy”

This article aims to show that the Chinese development process over the past four decades is not a self-explanatory fact. It is a process that may have revealed the ultimate limitation of the current capacities for interpretation represented by both orthodox and heterodox approaches. This limitation is due to two objective facts: 1) the transformation of the “socialist market economy” into a new socioeconomic formation (NSEF), a process that has accelerated since the financial crisis of 2008—the emergence of this NSEF results from a series of institutional innovations designed to accommodate a myriad of modes of production, all of them under the leadership of the public (socialist) sector; and 2) the continuous technical progress achieved by the state-owned enterprises (SOEs). Following the successful implementation of proactive industrial policies, the above-mentioned developments led to the appearance in China of new and superior forms of economic planning. This process can be understood as the re-emergence of Ignacio Rangel’s “project economy,” now under the title of the “new projectment economy.” In our view, perceiving and understanding this change in the mode of production in China, and the theoretical resources involved in it, represents the greatest challenge before today’s social science

Managerial dominance over the board and audit committee independence in financial institutions

International audienceThe purpose of this paper is to analyze whether the degree of control exercised by management affects the independence of the audit committee over the board of directors. Four characteristics of the bo ard are being examined; size, composition, CEO duality and manage ment ownership. Results from a samp le of 54 Lebanese banks operating in various Lebanese territories during the period 2009-2011 show that all of these banks created an audit committee between 2009-2011 and comply with Lebanese central ba nk regulations (BDL) to guara ntee their independence from management which requires the audit committee in Lebanese ba nks to be including independent members. Empirical results suggest that in Lebanese banks, managers can impair the effectiveness of audit committees by the presence of inside directors on the board and CEO duality

Assessing a 600-mg Loading Dose of Clopidogrel 24 Hours Prior to Pipeline Embolization Device Treatment

Background: Clopidogrel/aspirin antiplatelet therapy routinely is administered 7-10 days before pipeline aneurysm treatment. Our study assessed the safety and efficacy of a 600-mg loading dose of clopidogrel 24 hours before Pipeline Embolization Device (PED) treatment. Methods: In this retrospective cohort study, we included patients treated with PED from October 2010 to May 2016. A total of 39.7% (n = 158) of patients were dispensed a loading dose of 650 mg of aspirin plus at least 600 mg of clopidogrel 24 hours preceding PED deployment, compared to 60.3% (n = 240) of patients who received 81-325 mg of aspirin daily for 10 days with 75 mg of clopidogrel daily preprocedurally. The mean follow-up was 15.8 months (standard deviation [SD] 12.4 months). modified Rankin Scale (mRS) was registered before the discharge and at each follow-up visit. To control confounding, we used multivariable logistic regression and propensity score conditioning. Results: Of 398 patients, the proportion of female patients was ~16.5% (41/240) in both groups and shared the same mean of age ~56.46 years. ~12.2% (mean = 0.09; SD = 0.30) had a subarachnoid hemorrhage. 92% (mean = 0.29; SD = 0.70) from the pretreatment group and 85.7% (mean = 0.44; SD = 0.91) of the bolus group had a mRS ≤2. In multivariate analysis, bolus did not affect the mRS score, P = 0.24. Seven patients had a long-term recurrence, 2 (0.83%; mean = 0.01; SD = 0.10) of which from the pretreatment group. In a multivariable logistic regression, bolus was not associated with a long-term recurrence rate (odds ratio [OR] 1.91; 95% confidence interval [CI] 0.27-13.50; P = 0.52) or with thromboembolic accidents (OR 0.99; 95% CI 0.96-1.03; P = 0.83) nor with hemorrhagic events (OR 1.00; 95% CI 0.97-1.03; P = 0.99). Three patients died: one who received a bolus had an acute subarachnoid hemorrhage. The mean mortality rate was parallel in both groups ~0.25 (SD = 0.16). Bolus was not associated with mortality (OR 1.11; 95% CI 0.26-4.65; P = 0.89). The same associations were present in propensity score-adjusted models. Conclusions: In a cohort receiving PED, a 600-mg loading dose of clopidogrel should be safe and efficacious in those off the standard protocol or showing \u3c30% platelet inhibition before treatment