miR-130a targets MET and induces TRAIL-sensitivity in NSCLC by downregulating miR-221 and 222

Non-small cell lung cancer (NSCLC) accounts for ～80% of all lung cancers. Although some advances in lung cancer therapy have been made, patient survival is still quite poor. Two microRNAs, miR-221 and miR-222, upregulated by the MET proto-oncogene, have been already described to enhance cell survival and to induce TNF-related apoptosis-inducing ligand (TRAIL) resistance in NSCLC cell lines, through the downregulation of p27(kip1), PTEN and TIMP3. Here, we further investigated this pathway and showed that miR-130a, expressed at low level in lung cancer cell lines, by targeting MET was able to reduce TRAIL resistance in NSCLC cells through the c-Jun-mediated downregulation of miR-221 and miR-222. Moreover, we found that miR-130a reduced migratory capacity of NSCLC. A better understanding of MET-miR-221 and 222 axis regulation in drug resistance is the key in developing new strategies in NSCLC therapy.     

Congenital and Developmental Cataracts: Focus on Strabismus Outcomes at Long-Term Follow-Up

Purpose: To evaluate the incidence of strabismus in congenital and developmental cataract surgery in patients with a follow-up longer than five years. Methods: All patients with congenital and developmental cataracts observed from 1996 to 2013 with a follow-up longer than five years were retrospectively included. Results: We included 117 patients (58 females and 59 males, mean age 0.62±0.3 years, 160 eyes) with congenital cataracts and 73 patients (32 females and 41 males, mean age 6.63±0.7 years, 121 eyes) with developmental cataracts. Before cataract surgery, strabismus was present in 88 patients with congenital cataracts (75.2%) and in 30 patients with developmental cataracts (41.1%) (p=0.01). After a follow-up of 9.26±1.3 years (range, 5–14 years), a significantly greater incidence of strabismus was observed after surgery only in patients with unilateral congenital cataracts who underwent cataract removal and primary IOL implantation (p=0.02). Distance BCVA and near BCVA were better after surgery for developmental cataracts (p<0.05). Presence of binocular vision was more frequent after surgery for developmental cataracts (p=0.001). Conclusion: Incidence of strabismus and postsurgical onset of strabismus at long-term follow-up was greater in patients with congenital cataracts.     

Aptamer targeting EGFRvIII mutant hampers its constitutive autophosphorylation and affects migration,invasion and proliferation of glioblastoma cells

Glioblastoma Multiforme (GBM) is the most common and aggressive human brain tumor, associated with very poor survival despite surgery, radiotherapy and chemotherapy.The epidermal growth factor receptor (EGFR) and the platelet-derived growth factor receptor β (PDGFRβ) are hallmarks in GBM with driving roles in tumor progression. In approximately half of the tumors with amplified EGFR, the EGFRvIII truncated extracellular mutant is detected. EGFRvIII does not bind ligands, is highly oncogenic and its expression confers resistance to EGFR tyrosine kinase inhibitors (TKIs). It has been demonstrated that EGFRvIII-dependent cancers may escape targeted therapy by developing dependence on PDGFRβ signaling, thus providing a strong rationale for combination therapy aimed at blocking both EGFRvIII and PDGFRβ signaling.We have recently generated two nuclease resistant RNA aptamers, CL4 and Gint4.T, as high affinity ligands and inhibitors of the human wild-type EGFR (EGFRwt) and PDGFRβ, respectively.Herein, by different approaches, we demonstrate that CL4 aptamer binds to the EGFRvIII mutant even though it lacks most of the extracellular domain. As a consequence of binding, the aptamer inhibits EGFRvIII autophosphorylation and downstream signaling pathways, thus affecting migration, invasion and proliferation of EGFRvIII-expressing GBM cell lines.Further, we show that targeting EGFRvIII by CL4, as well as by EGFR-TKIs, erlotinib and gefitinib, causes upregulation of PDGFRβ. Importantly, CL4 and gefitinib cooperate with the anti-PDGFRβ Gint4.T aptamer in inhibiting cell proliferation.The proposed aptamer-based strategy could have impact on targeted molecular cancer therapies and may result in progresses against GBMs.     

Minor myocardial damage and inflammatory response after three different procedures of left anterior descending artery revascularization.

BACKGROUND: Intracoronary stenting, conventional coronary artery bypass with cardiopulmonary bypass and minimally invasive direct coronary artery bypass without extracorporeal circulation are the three accepted options for revascularizing the left anterior descending coronary artery. We compare the effects of these three procedures in terms of minor myocardial damage and systemic inflammatory response. METHODS: Ninety patients undergoing left anterior descending coronary artery revascularization with these three different techniques (thirty patients per group) were considered. Blood samples were collected preoperatively and immediately postoperatively, and then 24, 48 and 72 hours after the procedures to measure troponin I, creatine kinase, its MB fraction and C-reactive protein levels. RESULTS: Postoperative levels of troponin I and MB-creatine kinase were significantly higher in conventional coronary grafting group than in PTCA-stent and in the minimally invasive surgery groups (p < 0.0003), while in both surgery groups there were higher post-operative levels of total creatine kinase and C-reactive protein (p = 0.0001). CONCLUSIONS: Minimally invasive direct coronary artery bypass surgery and PTCA-stent are similar in terms of virtual absence of minor myocardial damage. Skeletal muscle damage and inflammatory reaction are comparable in surgical patients, but they do not appear to have any clinical relevance.     

Effects of naloxone on myocardial ischemic preconditioning in humans

OBJECTIVES

We attempted to establish whether naloxone, an opioid receptor antagonist, abolishes the adaptation to ischemia observed in humans during coronary angioplasty after repeated balloon inflations.

BACKGROUND

Experimental studies indicate that myocardial opioid receptors are involved in ischemic preconditioning.

METHODS

Twenty patients undergoing angioplasty for an isolated stenosis of a major epicardial coronary artery were randomized to receive intravenous infusion of naloxone or placebo during the procedure. Intracoronary electrocardiogram and cardiac pain (using a 100-mm visual analog scale) were determined at the end of the first two balloon inflations. Average peak velocity in the contralateral coronary artery during balloon occlusion, an index of collateral recruitment, was also assessed by using a Doppler guide wire in the six patients of each group with a stenosis on the left anterior descending coronary artery.

RESULTS

In naloxone-treated patients, ST-segment changes and cardiac pain severity during the second inflation were similar to those observed during the first inflation (12 ± 6 vs. 11 ± 7 mm, p = 0.3, and 58 ± 13 vs. 56 ± 12 mm, p = 0.3, respectively), whereas in placebo-treated patients, they were significantly less (6 ± 3 vs. 13 ± 6 mm, p = 0.002 and 31 ± 21 vs. 55 ± 22 mm, p = 0.008, respectively). In both naloxone- and placebo-treated patients, average peak velocity significantly increased from baseline to the end of the first inflation (p = 0.04 and p = 0.02, respectively), but it did not show any further increase during the second inflation.

CONCLUSIONS

The adaptation to ischemia observed in humans after two sequential coronary balloon inflations is abolished by naloxone and is independent of collateral recruitment. Thus, it is due to ischemic preconditioning and is, at least partially, mediated by opioid receptors, suggesting their presence in the human heart.     

Valve Replacement with a Sutureless Aortic Prosthesis in a Patient with Concomitant Mitral Valve Disease and Severe Aortic Root Calcification

Aortic valve replacement with concomitant mitral valve surgery in the presence of severe aortic root calcification is technically difficult, with long cardiopulmonary bypass and aortic cross-clamp times.We performed sutureless aortic valve replacement and mitral valve annuloplasty in a 68-year-old man who had severe aortic stenosis and moderate-to-severe mitral regurgitation. Intraoperatively, we found severe calcification of the aortic root. We approached the aortic valve through a transverse aortotomy, performed in a higher position than usual, and we replaced the valve with a Sorin Perceval S sutureless prosthesis. In addition, we performed mitral annuloplasty with use of an open rigid ring.The aortic cross-clamp time was 63 minutes, and the cardiopulmonary bypass time was 83 minutes. No paravalvular leakage of the aortic prosthesis was detected 30 days postoperatively.Our case shows that the Perceval S sutureless bioprosthesis can be safely implanted in patients with aortic root calcification, even when mitral valve disease needs surgical correction.     

Rheolytic thrombectomy during percutaneous coronary intervention improves long-term outcome in high-risk patients with acute myocardial infarction

OBJECTIVES: Aim of the present study was to compare the immediate and long-term effects of AngioJet rheolytic thrombectomy performed in the setting of a percutaneous coronary angioplasty (PTCA) with those of conventional PTCA in patients with acute myocardial infarction (AMI) and angiographic evidence of high intracoronary thrombus burden. BACKGROUND: Plaque rupture, with subsequent exposure to the flowing bloodstream of high thrombotic materials often leads to intravascular thrombosis, representing the main pathophysiological event of acute coronary syndromes. PTCA is the first-choice treatment for these patients in hospitals with cardiac catheterization facilities. However, distal embolization of thrombotic material, fibrin, and other fragments from atherosclerotic plaques might lead to procedural failure. METHODS: Immediate and 1-year follow-up results of a group of 30 consecutive patients, presenting with AMI and angiographic evidence of high thrombus burden, who underwent rheolytic thrombectomy and PTCA were compared with those of 30 consecutive patients with similar clinical presentation, risk profile, and angiographic picture, and treated with standard PTCA procedure. RESULTS: After the procedure, angiographic analysis showed a higher incidence of final thrombolysis in myocardial infarction (TIMI) flow grade 3 in the AngioJet group (93.3% vs 83.3%, P = 0.034). In addition, mean corrected TIMI frame count (cTFC) was significantly lower in the AngioJet group (22.4 vs 32.4, P = 0,0004). At 1-year follow-up, patients treated with AngioJet showed a significantly lower incidence of death (3.33% vs 13.33%,P < 0.001), major adverse cardiac events (MACE: 10% vs 30%, P = 0.026), and need of revascularization (6.67% vs 20%, P = 0.013). CONCLUSIONS: Data of the present study highlight that AngioJet thrombectomy in selected AMI patients at high risk for distal thrombotic embolization results not only in immediately improved angiographic results as compared to conventional PTCA but, indeed, seems to be associated with a significantly better long-term clinical outcome.     

Percutaneous transvenous biopsy for the diagnosis of a right atrial myxoma

Intracardiac tumors are generally diagnosed by transthoracic echocardiography, transesophageal echocardiography and, more recently, magnetic resonance imaging. However, these techniques do not permit a histopathologic diagnosis. When surgery is not indicated because of limited hemodynamic changes but the benign nature of the tumoral mass is questionable, percutaneous transvenous biopsy, when technically feasible, may represent an alternative approach. In this case report, we utilized percutaneous transvenous biopsy to obtain specimens from a right atrial mass in a 39-year-old woman.