The Interplay between PP2A and microRNAs in Leukemia

Protein Phosphatase 2A (PP2A) is a serine/threonine phosphatase family whose members have been implicated in tumor suppression in many cancer models. In many cancers, loss of PP2A activity has been associated with tumorigenesis and drug resistance. Loss of PP2A results in failure to turn off survival signaling cascades that drive drug resistance such as those regulated by Protein Kinase B (AKT). PP2A is responsible for modulating function and controlling expression of tumor suppressors such as p53 and oncogenes such as BCL2 and MYC. Thus PP2A has diverse functions regulating cell survival. The importance of microRNAs (miRs) is emerging in cancer biology. A role for miR regulation of PP2A is not well understood however recent studies suggest a number of clinically significant miRs such as miR-155 and miR-19 may include PP2A targets. We have recently found that a PP2A B subunit (B55a) can regulate a number of miRs in acute myeloid leukemia (AML) cells. The identification of a miR/PP2A axis represents a novel regulatory pathway in cellular homeostasis. The ability of miRs to suppress specific PP2A targets and for PP2A to control such miRs can add an extra level of control in signaling that could be used as a rheostat for many signaling cascades that maintain cellular homeostasis. As such, loss of PP2A or expression of miRs relevant for PP2A function could promote tumorigenesis or at least result in drug resisatnce. In this review, we will cover the current state of miR regulation of PP2A with a focus on leukemia. We will also briefly discuss what si known of PP2A regulation of miR expression

Role for PKC δ in Fenretinide-Mediated Apoptosis in Lymphoid Leukemia Cells

The synthetic Vitamin A analog fenretinide is a promising chemotherapeutic agent. In the current paper, the role of PKC δ was examined in fenretinide-induced apoptosis in lymphoid leukemia cells. Levels of proapoptotic cleaved PKC δ positively correlated with drug sensitivity. Fenretinide promoted reactive oxygen species (ROS) generation. The antioxidant Vitamin C prevented fenretinide-induced PKC δ cleavage and protected cells from fenretinide. Suppression of PKC δ expression by shRNA sensitized cells to fenretinide-induced apoptosis possibly by a mechanism involving ROS production. A previous study demonstrated that fenretinide promotes degradation of antiapoptotic MCL-1 in ALL cells via JNK. Now we have found that fenretinide-induced MCL-1 degradation may involve PKC δ as cleavage of the kinase correlated with loss of MCL-1 even in cells when JNK was not activated. These results suggest that PKC δ may play a complex role in fenretinide-induced apoptosis and may be targeted in antileukemia strategies that utilize fenretinide

Stem cells and new intervention measures as emerging therapy in cardiac surgery

Cardiovascular disease (CVD) presents a great burden for elderly patients, their caregivers, and health systems. Structural and functional alterations of vessels accumulate throughout life, culminating in increased risk of developing CVD. Several inflammatory pathway are involved in vascular ageing. The growing elderly population worldwide highlights the need to understand how aging promotes CVD in order to develop new strategies to confront this challenge. In this review we analyzed the role of stem cells and new intervention measures as emerging drugs for vascular aging

Surgical "elephant trunk" arch replacement with a branched arch prosthesis: two alternative operative techniques

Introduction: Elephant trunk repair of the aortic arch cannot be performed with a branched prosthesis. Aim: We conceived two different modifications of the original technique to perform an arch replacement with a branched graft, while arranging an adequate landing zone for a subsequent thoracic endovascular aortic repair, without the need of dedicated material. Material and methods: Eight consecutive patients underwent arch replacement with one of our techniques. Five were emergency patients with acute aortic dissection, and 3 suffered chronic expansive disease. The "modified elephant trunk" includes a separate anastomosis of an endo-luminal prosthetic segment in the descending aorta. Subsequently, the branched arch prosthesis is anastomosed to the distal aortic stump with the attached trunk. In the "prophylactic debranching", a tail is left on the distal end of the arch prosthesis, so that the branches for the supra-aortic vessels will remain displaced proximally, allowing a "zone 1" available for landing. Results: Three patients experienced transient cerebral deficits (1 transient ischemic attack and post-operative delirium in 2 cases), 1 required re-operation for bleeding and 2 needed prolonged intubation. One died of multi-organ failure. Conclusions: Both techniques proved to be easily reproducible, and allow an adequate landing zone for a subsequent endovascular procedure, while retaining the advantages of using a tetra-furcated prosthesis. They are a viable alternative when a hybrid prosthesis cannot be implanted

Imaging and monitoring in minimally invasive valve surgery using an intra-aortic occlusion device: A single center experience

Background: Minimally invasive approach through a right mini-thoracotomy is a world-wide used procedure for mitral valve surgery. We performed a retrospective analysis based on our center experience in order to propose an effective, safe and reproducible method using an intra-aortic occlusion device.Methods: This is a retrospective analysis on 48 consecutive patients undergoing mitral valve surgery through a right anterolateral mini-thoracotomy in our center. An intra-aortic occlusion device was used for aortic clamping and cardioplegia delivery. Simultaneous multi-plane three-dimensional echocardiography imaging was acquired to detect the venous cannulas position, the intra-aortic device location in the ascending aorta, the balloon inflation, the complete occlusion of the aorta, the cardioplegia delivery, the origin and the blood flow in the right coronary artery. Aortic root pressure was measured by the tip of the intra-aortic occlusion device. A bilateral upper extremity invasive arterial pressure monitoring was detected. Neuromonitoring was performed through bilateral cerebral oximetry.Results: The analysis has shown no aortic dissection, neurological damage type 1 and myocardial ischemia in the study population. In 3 cases a distal displacement of the intra-aortic occlusion device was promptly detected by the combined use of echocardiographic imaging and by a drop of the right cerebral oximetry saturation and of the right radial artery pressure.Conclusions: The combined use of transesophageal simultaneous multi- plane three- dimensional echocardiography imaging, bilateral upper extremity invasive arterial pressure monitoring, aortic root pressure and cerebral oximetry is an effective, safe and reproducible method in patients undergoing minimally invasive valve surgery using an intra-aortic occlusion device

Long-term follow-up of device-assisted clampless off-pump coronary artery bypass grafting compared with conventional on-pump technique

Study objective: To evaluate the long-term outcomes of clampless off-pump coronary artery bypass grafting (C-OPCAB) compared with conventional on-pump double clamping coronary artery bypass grafting (C-CABG). Methods: From October 2006 to December 2011, 366 patients underwent isolated coronary artery bypass grafting. After propensity score matching of preoperative variables, 143 pairs were selected who received C-OPCAB with the use of device-assisted PAS-Port proximal venous graft anastomoses or C-CABG, performed by the same surgeon experienced in both techniques. Data of the two groups of patients were retrospectively analyzed up to 14 years of follow-up. Results: As compared with C-OPCAB, in the C-CABG patients, the performed number of grafts per patient was higher (2.9 +/- 0.5 vs. 2.6 +/- 0.6, p-value 0.0001). At 14 years, overall survival, including in-hospital death, was 64 +/- 4.7% for the C-OPCAB vs. 55 +/- 5.5% for the C-CABG, freedom from overall MACCEs 51 +/- 6.2% vs. 41 +/- 7.7%, and from late cardiac death 94 +/- 2.4% vs. 96 +/- 2.2% (p-value not significant, for all comparisons). No significant statistical differences were observed in the actual rates of adverse events during follow-up. Independent predictors of survival were advanced age at operation (p-value 0.001) and a lower mean value of preoperative left ventricular ejection fraction (p-value 0.015). Conclusions: Our single-center study analysis suggests that clampless OPCAB using device-assisted proximal anastomoses proved to be not inferior to double-clamping CABG in the long-term follow-up, provided that involved surgeons are familiar with both techniques. These conclusions are supported by a large and long-term follow-up period, eliminating potential bias, i.e., by means of the propensity score matching and analyzing single-surgeon experience

Percutaneous transfemoral-transseptal implantation of a second-generation CardiAQ™ mitral valve bioprosthesis: first procedure description and 30-day follow-up

Transcatheter mitral valve implantation for mitral valve regurgitation is in the very early phase of development because of challenging anatomy and device dimensions. We describe the procedure of a transfemoral-transseptal implantation of the second-generation CardiAQ™ mitral valve bioprosthesis and 30-day follow-up

The effects of DeBakey type acute aortic dissection and preoperative peripheral and cardiac malperfusion on the outcomes after surgical repair

Introduction: Emergent surgical repair of DeBakey type I and II acute aortic dissection represents the standard of care to prevent lethal complications. Aim: Evaluation of the effect of extension of aortic dissection (AAD) according to DeBakey classification, type I and II AAD, and the relationship with preoperative peripheral and myocardial malperfusion on early outcome and the mid-term follow-up period. Material and methods: A total of 135 patients who underwent AAD surgery between January 2015 and October 2019 were analysed. Results: In total 103 patients were affected by DeBakey type I AAD and 32 by DeBakey type II; 56 patients preoperatively showed peripheral, cardiac malperfusion, or both. Intra-operative mortality was 11%. Postoperative peripheral, cardiac malperfusion, and intraoperative and postoperative mortality were lower for type II AAD. The protective factor for intra- and postoperative 60-day mortality was type II AAD (RR = 0.03, p = 0.001); independent predictors were hypertension, and preoperative cardiac and renal-visceral malperfusion. At 5 years the overall survival was 74 ±6.9%. Independent predictors of reduced survival were major extension of type I AAD (RR = 5.37, p < 0.05) and preoperative cardiac malperfusion (RR = 5.78, p < 0.05). Five-year freedom from cardiac death, redo surgical operation, and new vascular procedures on the thoracic and abdominal aorta was 92 ±5.7%, 99 ±1.2%, and 81 ±7.2%, respectively. Extension of DeBakey type I AAD into the thoracic-abdominal aorta segment was also a predictor of the need for new vascular procedures (RR = 1.66, p = 0.05). Conclusions: A more favourable anatomy of DeBakey type II AAD is associated with better early and late outcomes after aortic repair. This is due to a lower incidence of peripheral and cardiac malperfusion

Mid-term results of mitral valve replacement and repair: current clinical experience, technical aspects, and risk factor analysis

Aim: we evaluated the short- and mid-term results of mitral valve replacement (MVR) and mitral valve repair (MV-repair). Methods: in total, 168 patients (mean age 67 ± 11 years) underwent MVR (n = 104) and MV-repair (n = 64). To treat posterior leaflet disease, MV-repair techniques included triangular or quadrangular resection (n = 38), P1-P2 plication (n = 4), side-to side P1-P2 (n = 1), posterior-medial commissure-plasty (n = 1), and annuloplasty (n = 20). A prosthetic ring was implanted in all patients. In the presence of degenerative disease involving the anterior leaflet, extensive myxomatous and/or prolapsing pathology of the entire valve, and/or rheumatic and endocarditis degeneration, surgical orientation was to perform MVR directly. When possible, the sub-valvular apparatus with its papillary muscle was partially preserved. The mean follow-up was 38 ± 22 months. Results: operative mortality (0.96% vs. 1.56%) and six-year survival (94% vs. 100%) were similar in MVR and MV-repair. The only independent predictor of late survival was advanced age at the operation (79.2 years vs. 66.4 years; P = 0.012). Freedom from redo-operation was 100%. Partial preservation of the sub-valvular apparatus with its papillary muscle during MVR allowed postoperatively a better left ventricular function with similar values achieved with MV-repair (P = 0.05), and it was a protective factor against the development of left ventricular dysfunction during follow-up (P = 0.01). Conclusion: MVR and MV-repair are associated with satisfactory results in the short and medium term. MV-repair to treat posterior leaflet disease is associated with a stable and long-lasting result; MVR allows equally satisfactory results in the presence of more extensive and more complex mitral valve disease. Partial preservation of the subvalvular apparatus favors a better left ventricular systolic function

The impact of dual antiplatelet therapy administration on the risk of bleeding complications during coronary artery bypass surgery

Introduction: Dual antiplatelet therapy reduces the risk of cardiovascular death, myocardial infarction and recurrence of adverse ischemic events in patients affected by acute coronary syndromes, but in patients urgently needing coronary artery surgery it can increase the risk of severe perioperative bleeding complications. Aim: We evaluated the impact of dual antiplatelet therapy (DAPT) based on acetylsalicylic acid plus clopidogrel or ticagrelor in patients undergoing coronary artery bypass grafting (CABG). Material and methods: Three hundred and thirty-three patients underwent coronary artery bypass grafting with DAPT discontinuation > 72 hours or 3-4 days (group A, n = 159), 48-72 hours or 2-3 days (group B, n = 126), < 24 hours or 0-1 day (group C, n = 24) prior to CABG. Results: Operative mortality was 1.87% (group A), 0.79% (group B), absent (group C). The incidence of mediastinal re-exploration was 1.25% or 2 patients (group A), 1.59% or 2 patients (group B), 8.33% or 4 patients (group C) (p = 0.01). Group C showed postoperatively a greater incidence of a blood loss greater than 500 ml at 6 hours and a blood loss from chest tube drainages significantly higher at 6 and 24 hours (p < 0.01). Multivariate analysis showed that ongoing ticagrelor intake in group C (HR = 42.4; p = 0.02) and group C (HR = 6.9; p = 0.04) were the only independent predictors of surgical re-exploration. In group C, surgical re-exploration was 2.56% or 1/39 patients taking clopidogrel, 33.3% or 3/9 patients taking ticagrelor (p = 0.002). Conclusions: Dual antiplatelet therapy ongoing until 1 day or 24 hours before CABG showed a significantly increased risk of bleeding complications in comparison with its discontinuation at 2-3 and > 3-4 days before, respectively. Major blood loss and surgical re-exploration were not associated with increased risk of operative all-cause or bleeding-related mortality. As expected, taking ticagrelor compared with clopidogrel in the short interval confers a higher risk of bleeding complications