Critical role for Gab2 in transformation by BCR/ABL.

The BCR/ABL oncogene causes chronic myelogenous leukemia (CML) in humans and a CML-like disease, as well as lymphoid leukemia, in mice. p210 BCR/ABL is an activated tyrosine kinase that phosphorylates itself and several cellular signaling proteins. The autophosphorylation site tyrosine 177 binds the adaptor Grb2 and helps determine the lineage and severity of BCR/ABL disease: Tyr177 mutation (BCR/ABL-Y177F) dramatically impairs myeloid leukemogenesis, while diminishing lymphoid leukemogenesis. The critical signal(s) from Tyr177 has remained unclear. We report that Tyr177 recruits the scaffolding adaptor Gab2 via a Grb2/Gab2 complex. Compared to BCR/ABL-expressing Ba/F3 cells, BCR/ABL-Y177F cells exhibit markedly reduced Gab2 tyrosine phosphorylation and association of phosphatidylinositol-3 kinase (PI3K) and Shp2 with Gab2 and BCR/ABL, and decreased PI3K/Akt and Ras/Erk activation, cell proliferation, and spontaneous migration. Remarkably, bone marrow myeloid progenitors from Gab2 (-/-) mice are resistant to transformation by BCR/ABL, whereas lymphoid transformation is diminished as a consequence of markedly increased apoptosis. BCR/ABL-evoked PI3K/Akt and Ras/Erk activation also are impaired in Gab2 (-/-) primary myeloid and lymphoid cells. Our results identify Gab2 and its associated proteins as key determinants of the lineage and severity of BCR/ABL transformation.

Association of initial thrombolysis in myocardial infarction flow grade with mortality among patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: a National Registry of Myocardial Infarction-5 (NRMI-5) analysis.

BACKGROUND: Initial epicardial coronary flow, as assessed by the Thrombolysis in Myocardial Infarction flow grade (TFG), prior to primary percutaneous coronary intervention (pPCI) for ST-segment elevation myocardial infarction (STEMI) has been associated with short- and long-term mortality in randomized clinical trials. This study was designed to determine the relationship between initial TFG and mortality in a large, heterogeneous, real-world population of STEMI patients undergoing pPCI. METHODS: The relationship between pre-pPCI TFG among patients undergoing pPCI and in-hospital mortality was evaluated among STEMI patients from 2004 to 2006 in the National Registry of Myocardial Infarction. RESULTS: Of 8,337 STEMI patients, 6,595 (79.1%) had pre-pPCI TFG 0/1, 1,126 (13.5%) had pre-pPCI TFG 2, and 616 (7.4%) had pre-pPCI TFG 3. TFG 0/1 prior to pPCI was associated with 3.4% in-hospital mortality, whereas TFG 2 (2.0%) and TFG 3 (1.8%) were associated with significantly lower mortality (TFG 0/1 vs TFG 2, P = .013; TFG 0/1 vs TFG 3, P = .035). TFG 0/1 prior to pPCI was also associated with a significant increase in the composite of death, recurrent myocardial infarction, heart failure, and shock (16.1%) when compared with patients presenting with TFG 2 (11.5%; P < .001) and TFG 3 (7.6%; P < .001). The difference in this composite was also significant between patients presenting with TFG 2 and TFG 3 (P = .01). CONCLUSIONS: In a large, heterogeneous group of real-world patients presenting with STEMI, pre-pPCI TFG 0/1 is associated with higher in-hospital mortality and other major adverse cardiovascular events. These results corroborate prior to post hoc analyses from randomized clinical trials and support continued efforts aimed at safely establishing early infarct-related artery patency among patients with STEMI.

Coronary flow reserve varies depending upon the location within the artery it is assessed and the TIMI myocardial perfusion grade: a PROTECT TIMI-30 analysis.

Coronary flow reserve (CFR) is a measure of the capacity of the epicardial coronary artery and the microvasculature to achieve maximal blood flow in response to hyperemic stimulation. It is not known whether the CFR varies along the length of the artery. Likewise, the interaction between CFR and the thrombolysis in myocardial infarction (TIMI) myocardial perfusion grade (TMPG) is unknown. CFR was measured using the number of cineframes required for the contrast to traverse the same length of the coronary artery before and following the administration of intracoronary adenosine. Following percutaneous coronary intervention (PCI), CFR was assessed both proximal and distal to the lesion in 192 consecutive patients with non-ST-segment elevation acute coronary syndrome (NSTEACS) from the PROTECT TIMI-30 trial. TMPG was also assessed. The difference between the distal and proximal CFR for patients with TMPG 0/1 (n = 76) was 0.11 (95% CI 0.01-0.20, P = 0.026), while among those with TMPG 2/3 (n = 114) it was -0.02 (95% CI -0.09-0.06, P = 0.65). The difference in the CFR between the distal and proximal segments among patients with TMPG 0/1 and TMPG 2/3 was significant (P interaction = 0.044). Following PCI among patients with impaired TMPG (0/1) in the setting of NSTEACS, CFR varies significantly between the proximal and distal segment of coronary arteries and is associated with higher (greater) distal CFR.

Percutaneous coronary interventions in facilities without cardiac surgery on site.

Prior to the widespread adoption of intracoronary stent implantation, potential complications of percutaneous coronary intervention (PCI) necessitated the presence of backup cardiac surgery. However, as stent implantation has become the predominant form of PCI, the incidence of emergent cardiac surgery has declined exponentially. Despite this, current guidelines recommend against the performance of elective PCI at hospitals without on-site cardiac surgery and recommend that primary PCI for ST-segment elevation myocardial infarction (STEMI) might be considered at hospitals without backup cardiac surgery. These recommendations are based predominantly on two principles: (1) hospital volume for PCI is strongly associated with clinical outcomes, and (2) results from a large registry study, in which the authors reported a substantial increase in mortality among patients undergoing non-primary/rescue PCI at hospitals without backup cardiac surgery. Since that time, evidence from multiple studies has suggested that performance of PCI at hospitals without backup cardiac surgery is feasible, safe, and both clinically and cost effective. Among STEMI patients, in particular, performance of primary PCI at hospitals without on-site cardiac surgery reduces time to reperfusion and subsequent adverse cardiovascular events as well as likely reducing infarct size. In this review, we will examine the evidence surrounding the performance of PCI for stable and unstable coronary disease at hospitals without on-site backup cardiac surgery.

Precordial steering wheel: a fortunate accident.

BACKGROUND: Myocardial ischemia has been associated with motor vehicle collisions (MVCs). However, we were unable to find reported cases of ST-segment elevation myocardial infarction (STEMI) leading to ventricular tachyarrhythmia and subsequent MVC. In such patients, decisions regarding antiplatelet and antithrombotic therapy need to balance the risk of ongoing myocardial ischemia and hemorrhage. OBJECTIVES: To describe a case of STEMI and ventricular fibrillation (VF) associated with a head-on MVC, and to describe the management decisions involved in the care of such a patient. CASE REPORT: A 47-year-old man presented to the Emergency Department after a single-car head-on collision with a wall at high speed. He had a facial degloving injury as well as right-sided flail chest. An electrocardiogram demonstrated ST-segment elevation in the inferior and anterior leads. Due to the patient's significant traumatic injuries, he underwent a rapid trauma evaluation and was transferred for emergent cardiac catheterization, which demonstrated evidence of plaque rupture in the right coronary artery (RCA). Flow distal to the lesion was preserved, so stent implantation was initially deferred out of concern for hemorrhage secondary to the aggressive antiplatelet and antithrombotic regimen requisite with stent implantation. The patient then went into VF in the cardiac catheterization laboratory, and repeat angiography demonstrated an occluded RCA, and the patient underwent successful stent implantation. CONCLUSION: The management of STEMI in the setting of trauma is complex. Pharmacologic agents used in STEMI increase the risk of bleeding, and management must balance the risk of prolonged ischemia with the risk of hemorrhage.

Association of Thrombolysis in Myocardial Infarction Myocardial Perfusion Grade with cardiovascular magnetic resonance measures of infarct architecture after primary percutaneous coronary intervention for ST-segment elevation myocardial infarction.

BACKGROUND: Primary percutaneous coronary intervention (pPCI) routinely restores normal epicardial flow among patients with ST-segment elevation myocardial infarction (STEMI). However, impairment of myocardial perfusion frequently persists. The goal of this analysis was to determine whether impaired myocardial perfusion was associated with cardiovascular magnetic resonance-defined abnormalities in infarct architecture, including infarct size (IS), infarct surface area (ISA), infarct border zone (IBZ), and infarct complexity (IC). METHODS: Thirty-one patients with STEMI treated with pPCI were included in the analysis. Cardiovascular magnetic resonance was performed within 7 days of presentation and repeated at 3 months. Infarct complexity was defined as the ratio of actual ISA to an idealized smooth ISA and normalized to IS. RESULTS: Impaired Thrombolysis in Myocardial Infarction Myocardial Perfusion Grade (TMPG) (<3) was associated with larger ISA at baseline (78.2 +/- 25.3 cm(2) vs 40.3 +/- 30.3 cm(2), P = .02) and follow-up (58.8 +/- 27.5 cm(2) vs 26.3 +/- 20.2 cm(2), P = .03) and larger IBZ at follow-up (7.8% +/- 2.7% vs 4.1% +/- 3.3%, P = .02). At follow-up, ISA, when normalized to IS, was significantly higher among patients with impaired myocardial perfusion (TMPG <3) (6.9 +/- 2.5 vs 5.9 +/- 2.4 cm(2)/%, P = .03). Thrombolysis in MI myocardial perfusion grade <3 was also associated with increased IC at follow-up (52% +/- 12% vs 33% +/- 16%, P = .01). CONCLUSIONS: Impaired TMPG is associated with larger ISA, IBZ, and increased IC. At 3 months, TMPG remained associated with ISA and IC after adjusting for IS, suggesting that impaired TMPG after pPCI is associated with infarct architecture after healing, independent of IS.

Effect of prasugrel versus clopidogrel on outcomes among patients with acute coronary syndrome undergoing percutaneous coronary intervention without stent implantation: a TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel (TRITON)-Thrombolysis in Myocardial Infarction (TIMI) 38 substudy.

BACKGROUND: Prasugrel led to a significant reduction in ischemic cardiovascular events among patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) with stent implantation compared to clopidogrel. Whether this benefit extends to patients undergoing PCI without stent implantation is unknown. METHODS: In TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel (TRITON)-Thrombolysis in Myocardial Infarction (TIMI) 38, patients (n = 13 608) undergoing PCI for ACS were randomized to aspirin plus clopidogrel or prasugrel. This postrandomization analysis of a prespecified subgroup was restricted to patients who underwent PCI without stent implantation (n = 569). RESULTS: Patients who underwent PCI without stent implantation were older and had a higher incidence of hypertension, diabetes, prior myocardial infarction (MI), prior coronary artery bypass (CABG) surgery, and renal dysfunction than patients who underwent stent implantation. In the group that did not undergo stent implantation, baseline characteristics were similar between patients receiving clopidogrel and prasugrel. The composite of cardiovascular death, nonfatal MI, and nonfatal stroke occurred in 14.2% of patients receiving prasugrel and 17.1% of patients receiving clopidogrel (HR 0.82, P = .27). There were significant reductions favoring prasugrel in the rates of urgent target vessel revascularization (TVR; HR 0.46, P = .040) and any TVR (HR 0.40, P = .009) and a trend toward a reduction in the incidence of nonfatal MI (HR 0.65, P = .11). CABG-related TIMI major bleeding was more frequent among patients receiving prasugrel. There were no significant interactions between treatment and PCI type. CONCLUSION: Among ACS patients who underwent PCI without stent implantation, prasugrel therapy tended to reduce clinical ischemic events and to increase bleeding events to a similar magnitude as among patients who received stents.

Acute detection of ST-elevation myocardial infarction missed on standard 12-Lead ECG with a novel 80-lead real-time digital body surface map: primary results from the multicenter OCCULT MI trial.

STUDY OBJECTIVE: Although 80-lead ECG body surface mapping is more sensitive for ST-elevation myocardial infarction (STEMI) than the 12-lead ECG, its clinical utility in chest pain in the emergency department (ED) has not been studied. We sought to determine the prevalence, clinical care patterns, and clinical outcomes of patients with STEMI identified on 80-lead but not on 12-lead (80-lead-only STEMI). METHODS: The Optimal Cardiovascular Diagnostic Evaluation Enabling Faster Treatment of Myocardial Infarction trial was a multicenter prospective observational study of moderate- to high-risk chest pain patients presenting to the ED. Patients received simultaneous 12-lead and 80-lead ECGs as part of their initial evaluation and were treated according to the standard of care, with clinicians blinded to the 80-lead results. The primary outcome of the trial was door-to-sheath time in patients with 80-lead-only STEMI versus patients with STEMI identified by 12-lead alone (12-lead STEMI). Secondary outcomes included angiographic and clinical outcomes at 30 days. RESULTS: One thousand eight hundred thirty patients were evaluated, 91 had a discharge diagnosis of 12-lead STEMI, and 25 patients met criteria for 80-lead-only STEMI. Eighty-four of the 91 12-lead STEMI patients underwent cardiac catheterization, with a median door-to-sheath time of 54 minutes, versus 14 of the 25 80-lead-only STEMI patients, with a door-to-sheath time of 1,002 minutes (estimated treatment difference in median=881; 95% confidence interval 181 to 1,079 minutes). Clinical outcomes and revascularization rates, however, were similar between 80-lead-only STEMI and 12-lead STEMI patients. CONCLUSION: The 80-lead ECG provides an incremental 27.5% increase in STEMI detection versus the 12-lead. Patients with 80-lead-only STEMI have adverse outcomes similar to those of 12-lead STEMI patients but are treated with delayed or conservative invasive strategies.

Association of TIMI myocardial perfusion grade and ST-segment resolution with cardiovascular magnetic resonance measures of microvascular obstruction and infarct size following ST-segment elevation myocardial infarction.

BACKGROUND: Impairment of coronary microvascular perfusion is common among patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI). Cardiovascular magnetic resonance imaging (CMR) can identify microvascular obstruction (MO) following reperfusion of STEMI. We hypothesized that myocardial perfusion, as assessed by the Thrombolysis in Myocardial Infarction (TIMI) Myocardial Perfusion Grade (TMPG), would be associated with a CMR metric of MO in this population. METHODS: Twenty-one STEMI patients who underwent successful primary PCI were evaluated. Contrast-enhanced CMR was performed within 7 days of presentation and repeated at three months. TIMI Flow Grade (TFG), corrected TIMI Frame Count (cTFC), TMPG, MO, infarct size, and left ventricular ejection fraction (EF) were assessed. RESULTS: The median peak creatine phosphokinase (CPK) was 1,775 IU/l (interquartile range 838-3,321). TFG 3 was present following PCI in 19 (90%) patients. CMR evidence of MO was present in 52% following PCI. Abnormal post-PCI TMPG (0/1/2) was present in 48% of subjects and was associated with MO on CMR (90% MO with TMPG 0/1/2 vs. 18% MO with TMPG 3, P < 0.01). Abnormal post-PCI TMPG was also associated with a greater peak CK (median 3,623 IU/l vs. 838 IU/l, P < 0.001) and greater relative infarct size (17.3% vs. 5.2%, P < 0.01). CONCLUSION: Among STEMI patients undergoing primary PCI, post-PCI TMPG correlates with CMR measures of MO and infarct size. The combined use of both metrics in a comprehensive assessment of microvascular integrity and infarct size following STEMI may aid in the evaluation of future therapeutic strategies.

Trends in reperfusion strategies, door-to-needle and door-to-balloon times, and in-hospital mortality among patients with ST-segment elevation myocardial infarction enrolled in the National Registry of Myocardial Infarction from 1990 to 2006.

BACKGROUND: Among patients with ST-segment elevation myocardial infarction (STEMI), rapid reperfusion is associated with improved mortality. As such, door-to-needle (D2N) and door-to-balloon (D2B) times have become metrics of quality of care and targets for intense quality improvement. METHODS: The National Registry of Myocardial Infarction (NRMI) collected data regarding reperfusion therapy, its timing and in-hospital mortality among STEMI patients from 1990 through 2006. RESULTS: Since 1990, NRMI has enrolled 1,374,232 STEMI patients at 2,157 hospitals. Among those, 774,279 (56.3%) were eligible for reperfusion upon arrival. The proportion receiving fibrinolytic therapy fell from 52.5% in 1990 to 27.6% in 2006 (P < .001), while the proportion undergoing primary percutaneous coronary intervention (pPCI) increased from 2.6% to 43.2%. Among reperfusion-eligible patients who received fibrinolytic therapy, there was a nearly linear decline in median D2N time from 59 minutes in 1990 to 29 minutes in 2006 (P < .001 for trend) as well as a decrease in mortality from 7.0% in 1994 to 6.0% in 2006 (P < .001). Among those undergoing pPCI, D2B time among nontransfer patients declined linearly from 111 minutes in 1994 to 79 minutes in 2006 (P < .001) with a decline in mortality from 8.6% to 3.1% (P < .001). The relative improvement in mortality attributable to improvements in D2N time was 16.3% and to D2B time was 7.5%. CONCLUSIONS: Since 1990, there has been a progressive decline in D2N and D2B time among reperfusion-eligible STEMI patients. These improvements have contributed, at least in part, to a progressive decline in mortality.

Effects of pretreatment with clopidogrel on nonemergent percutaneous coronary intervention after fibrinolytic administration for ST-segment elevation myocardial infarction: a Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis in Myocardial Infarction (CLARITY-TIMI) 28 study.

BACKGROUND: The use of routine nonemergent percutaneous coronary intervention (PCI) among patients with ST-segment elevation myocardial infarction (STEMI) after fibrinolytic therapy is unknown. We sought to evaluate the effect of nonemergent PCI on mortality among patients with STEMI treated with fibrinolytic administration and the consequence of clopidogrel pretreatment on this effect. METHODS: CLARITY-TIMI 28 randomized 3491 patients with STEMI treated with fibrinolytic administration and aspirin to clopidogrel or placebo. All patients were to undergo angiography 48 to 192 hours after randomization. Percutaneous coronary intervention was performed at the discretion of the treating physician. Nonemergent PCI, which was defined as PCI that was not precipitated by recurrent myocardial infarction, was performed in 1781 patients (55.7%). RESULTS: Nonemergent PCI did not affect 30-day mortality (2.0% vs 2.3% among patients who did not undergo PCI). However, nonemergent PCI was associated with lower mortality among patients randomized to clopidogrel (1.3% vs 2.8%, P = .04) but not among those randomized to placebo (2.6% vs 1.7%, P = .25; interaction P = .025). In multivariate modeling, PCI remained associated with lower mortality among patients randomized to clopidogrel (OR 0.34, 95% CI 0.13-0.92, P = .034) but not placebo (OR 1.41, 95% CI 0.63-3.19, P = .40, interaction P = .028). CONCLUSION: Among patients with STEMI treated with fibrinolytic administration and aspirin, nonemergent PCI was associated with lower mortality among patients pretreated with clopidogrel. These results suggest that routine nonemergent PCI is beneficial among such patients, although further confirmatory randomized studies are needed.

Association of blood glucose with angiographic and clinical outcomes among patients with ST-segment elevation myocardial infarction (from the CLARITY-TIMI-28 study).

Overt hyperglycemia has been associated with adverse clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI). The association of hypoglycemia and mild hyperglycemia with angiographic outcomes and the effect of clopidogrel on these outcomes have not been extensively evaluated. Patients with STEMI enrolled in the CLARITY-TIMI 28 trial (n=3,491) were divided into 6 groups based on admission blood glucose level (<81, 81 to 99, 100 to 125, 126 to 149, 150 to 199, and >199 mg/dl). Angiographic and clinical outcomes were analyzed. Thirty-day mortality was increased (p<0.001) in patients with hypoglycemia (glucose<81 mg/dl, 6.3%) and severe hyperglycemia (glucose>199 mg/dl, 10.4%) compared with the euglycemic group (glucose 81 to 99 mg/dl, 2.6%). Occlusion of the infarct-related artery (IRA; Thrombolysis In Myocardial Infarction flow grade 0/1) at scheduled angiography was more common with increased glucose (9.3% for glucose 81 to 99 mg/dl, 15.6% for glucose>199 mg/dl, p=0.004). Multivariable analysis demonstrated that hyperglycemia was associated with a twofold increase in the composite of an occluded IRA, death, or recurrent MI before angiography (glucose>199 mg/dl, odds ratio 1.93, 95% confidence interval 1.17 to 3.18, p=0.01; glucose 150 to 199 mg/dl, odds ratio 2.04, 95% confidence interval 1.30 to 3.22, p=0.002). There was no significant interaction between clopidogrel administration and the association of glucose and IRA patency (p interaction=NS). In conclusion, in patients with STEMI, hypoglycemia and severe hyperglycemia are associated with increased 30-day mortality. IRA patency after fibrinolytic administration is related to admission glucose independent of clopidogrel administration.

Relation of hyperemic epicardial flow to outcomes among patients with ST-segment elevation myocardial infarction receiving fibrinolytic therapy.

In patients with ST-segment elevation myocardial infarction (STEMI), the restoration of normal epicardial flow following fibrinolytic administration is associated with improved clinical outcomes. The goal of this analysis was to examine the relation between hyperemic flow and outcomes following fibrinolytic administration for STEMI. In Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis In Myocardial Infarction 28 (CLARITY-TIMI 28), patients with STEMI (n=3,491) treated with fibrinolytic therapy were scheduled to undergo angiography 48 to 192 hours after randomization. Corrected TIMI frame count (CTFC) and TIMI myocardial perfusion grade (TMPG) were assessed, and their associations with outcomes at 30 days were evaluated. When evaluating initial angiography of the infarct-related artery, there was a nearly linear relation between CTFC and 30-day mortality, with faster flow (lower CTFC) associated with improved outcomes. Conversely, in patients who underwent percutaneous coronary intervention (PCI), very fast flow (CTFC<14) after intervention was associated with worse outcomes. Post-PCI hyperemic flow (CTFC<14) was associated with a higher incidence of mortality (p=0.056), recurrent myocardial infarction (p=0.011), and a composite of death or myocardial infarction (p<0.001) compared with normal flow (CTFC 14 to 28). When post-PCI CTFC was further stratified by TMPG, there was a U-shaped relation between mortality and CTFC in patients with poor myocardial perfusion (TMPG 0 or 1). This relation appeared to be linear in patients with TMPG 2 or 3. In conclusion, in patients who undergo PCI after fibrinolytic therapy for STEMI, hyperemic flow on coronary angiography is associated with an increased incidence of adverse outcomes. Hyperemic flow with associated impaired myocardial perfusion may be a marker of more extensive downstream microembolization.

Lyme carditis.

Cardiovascular manifestations of Lyme disease were first reported nearly 30 years ago. This article describes Lyme carditis, its epidemiology, pathophysiology, methods of diagnosis, and treatment options.

A novel small molecule met inhibitor induces apoptosis in cells transformed by the oncogenic TPR-MET tyrosine kinase.

The Met receptor tyrosine kinase has been shown to be overexpressed or mutated in a variety of solid tumors and has, therefore, been identified as a good candidate for molecularly targeted therapy. Activation of the Met tyrosine kinase by the TPR gene was originally described in vitro through carcinogen-induced rearrangement. The TPR-MET fusion protein contains constitutively elevated Met tyrosine kinase activity and constitutes an ideal model to study the transforming activity of the Met kinase. We found, when introduced into an interleukin 3-dependent cell line, TPR-MET induces factor independence and constitutive tyrosine phosphorylation of several cellular proteins. One major tyrosine phosphorylated protein was identified as the TPR-MET oncoprotein itself. Inhibition of the Met kinase activity by the novel small molecule drug SU11274 [(3Z)-N-(3-chlorophenyl)-3-([3,5-dimethyl-4-[(4-methylpiperazin-1-yl)carbonyl]-1H-pyrrol-2-yl]methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide] led to time- and dose-dependent reduced cell growth. The inhibitor did not affect other tyrosine kinase oncoproteins, including BCR-ABL, TEL-JAK2, TEL-PDGFbetaR, or TEL-ABL. The Met inhibitor induced G(1) cell cycle arrest and apoptosis with increased Annexin V staining and caspase 3 activity. The autophosphorylation of the Met kinase was reduced on sites that have been shown previously to be important for activation of pathways involved in cell growth and survival, especially the phosphatidylinositol-3'-kinase and the Ras pathway. In particular, we found that the inhibitor blocked phosphorylation of AKT, GSK-3beta, and the pro-apoptotic transcription factor FKHR. The characterization of SU11274 as an effective inhibitor of Met tyrosine kinase activity illustrates the potential of targeting for Met therapeutic use in cancers associated with activated forms of this kinase.

Differential expression and signaling of CBL and CBL-B in BCR/ABL transformed cells.

CBL and the related CBL-B protein are two members of a family of RING finger type ubiquitin E3 ligases that are believed to function as negative regulators of signal transduction in hematopoietic and immune cells. In mice, expression of v-Cbl causes lymphomas, and targeted disruption of either the CBL gene or the CBL-B gene can result in a lymphoproliferative disorder or hypersensitivity of lymphocytes. CBL is one of the most prominent targets of the BCR/ABL tyrosine kinase oncogene. We compared the role of CBL and CBL-B in signal transduction of BCR/ABL using pairs of cell lines before and after expression of BCR/ABL. In contrast to CBL, BCR/ABL was found to rapidly downregulate the expression of CBL-B protein. The decrease in CBL-B protein induced by BCR/ABL was associated with downregulation of CBL-B mRNA. Downregulation and tyrosine phosphorylation of CBL-B required BCR/ABL kinase activity. However, despite their known similarities in structure and function, we found CBL and CBL-B proteins to be involved in distinct signaling complexes. CBL was predominantly in a complex with phosphatidylinositol 3'-kinase and CRKL, while CBL-B was not associated with any significant phosphatidylinositol 3'-kinase activity. A major CBL-B associated protein was identified as mono-ubiquitinated Vav, a nucleotide exchange factor for Rac1. These results demonstrate that BCR/ABL signals differentially through CBL and CBL-B, with downregulation of the CBL-B protein potentially contributing to BCR/ABL-mediated transformation.

Prevalence, consequences, and implications for clinical trials of unrecognized myocardial infarction.

Patients with myocardial infarction (MI) generally present with chest pain or pressure at rest or minimal exertion and have associated electrocardiographic changes and/or elevation of the biomarkers of myocardial necrosis. A subset of patients, however, experience little chest discomfort or do not present to medical attention despite experiencing symptoms. Unrecognized MI might be detected using electrocardiographic or imaging techniques, such as echocardiography, nuclear imaging, or cardiovascular magnetic resonance imaging. Unrecognized MI is a common clinical entity, with an incidence as great as 35% in high-risk populations. Moreover, the risk of a subsequent major adverse cardiovascular event might be similar to the risk after a clinically apparent MI. In the present review, we examined the incidence of unrecognized MI across broad groups of subjects and the subsequent risk of adverse cardiovascular events. Finally, we explored the potential role of including unrecognized MI as a major adverse outcome in randomized clinical trials of agents aimed at reducing cardiovascular morbidity.

Association between angiographic complications and clinical outcomes among patients with acute coronary syndrome undergoing percutaneous coronary intervention: an EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome) angiographic substudy.

OBJECTIVES: The goal of this analysis was to determine the association between intraprocedural complications and clinical outcomes among patients with high-risk non-ST-segment elevation acute coronary syndrome (NSTEACS) undergoing percutaneous coronary intervention (PCI). BACKGROUND: Among patients undergoing PCI for NSTEACS, the relationship between intraprocedural complications and clinical outcomes, independent of epicardial and myocardial perfusion, has not been well characterized. METHODS: The EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome) trial enrolled 9,406 patients with high-risk NSTEACS undergoing an early invasive strategy. Of these, 1,452 underwent angiographic assessment in an independent core laboratory and did not have a myocardial infarction (MI) between enrollment and angiography. We assessed the relationship between abrupt closure, loss of side branch(es), distal embolization, and no-reflow phenomenon and 30-day clinical outcomes in these patients. RESULTS: Of the patients, 166 (11.4%) experienced an intraprocedural complication. Baseline clinical characteristics were similar between patients who did and did not have complications. The 30-day composite of death or MI was significantly higher among patients with an intraprocedural complication (28.3% vs. 7.8%, odds ratio [OR]: 4.68, 95% confidence interval [CI]: 3.2 to 7.0, p < 0.001). Individually, both mortality (3.0% vs. 0.9%, OR: 3.60, 95% CI: 1.2 to 10.5, p = 0.019) and MI (27.1% vs. 7.4%, OR: 4.66, 95% CI: 3.1 to 7.0, p < 0.001) were significantly increased. After adjusting for differences in post-PCI epicardial and myocardial perfusion, the association with 30-day death or MI remained significant. CONCLUSIONS: Among high-risk NSTEACS patients undergoing an invasive strategy, the incidence of intraprocedural complications is high, and the occurrence of these complications is associated with worse clinical outcomes independent of epicardial and myocardial perfusion. (Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-segment Elevation Acute Coronary Syndrome [EARLY ACS]; NCT00089895).