7-(4H-1,2,4-Triazol-3-yl)benzo[c][2,6]naphthyridines: a novel class of Pim kinase inhibitors with potent cell antiproliferative activity.

A novel class of pan-Pim kinase inhibitors was designed by modifying the CK2 inhibitor CX-4945. Introduction of a triazole or secondary amide functionality on the C-7 position and 2'-halogenoanilines on C-5 resulted in potent inhibitors of the Pim-1 and Pim-2 isoforms, with many analogs active at single digit nanomolar concentrations. The molecules inhibited the phosphorylation at Serine 112 of the apoptosis effector BAD, and had potent antiproliferative effects on the AML cell line MV-4-11 (IC(50) <30 nM).

Postoperative inotrope and vasopressor use following CABG: outcome data from the CAPS-care study.

Background/aim: Limited clinical data exist to guide practice patterns and evidence-based use of inotropes and vasopressors following coronary artery bypass grafting (CABG).

Methods: Contemporary Analysis of Perioperative Cardiovascular Surgical Care (CAPS-Care) collected detailed perioperative data from 2390 CABG patients between 2004 and 2005 at 55 U.S.

Complications after the Norwood operation: an analysis of The Society of Thoracic Surgeons Congenital Heart Surgery Database.

Background: Limited multicenter data exist regarding the prevalence of postoperative complications after the Norwood operation and their associated mortality risk.

Methods: We evaluated infants in The Society of Thoracic Surgeons Congenital Heart Surgery Database who underwent the Norwood operation from 2000 to 2009. The prevalence of postoperative complications after the Norwood operation and associated in-hospital mortality were described.

Relationship of the time interval between cardiac catheterization and elective coronary artery bypass surgery with postprocedural acute kidney injury.

Background: Some prior studies have suggested that the time to cardiac surgery after cardiac catheterization is inversely related to postoperative acute kidney injury (AKI). However, these studies, because of the small number of patients, were unable to adequately account for patient case-mix and included both those undergoing elective surgery and those undergoing urgent surgery.

Methods And Results: We examined data on 2441 consecutive patients undergoing elective coronary artery bypass surgery (CABG) after cardiac catheterization.

Public reporting of cardiac surgery performance: Part 1--history, rationale, consequences.

Cardiac surgical report cards have historically been mandatory. This paradigm changed when The Society of Thoracic Surgeons recently implemented a voluntary public reporting program based on benchmark analyses from its National Cardiac Database. The primary rationale is to provide transparency and accountability, thus affirming the fundamental ethical right of patient autonomy.

Public reporting of cardiac surgery performance: Part 2--implementation.

Appropriate implementation is essential to create a credible public reporting system. Ideally, data should be obtained from an audited clinical data registry, and structure, process, or outcomes metrics may be reported. Composite measures are increasingly used, as are measures of appropriateness, patient satisfaction, functional status, and health-related quality of life.

Unprecedented selectivity and structural determinants of a new class of protein kinase CK2 inhibitors in clinical trials for the treatment of cancer.

5-(3-Chlorophenylamino)benzo[c][2,6]naphthyridine-8-carboxylic acid (CX-4945), the first clinical stage inhibitor of protein kinase CK2 for the treatment of cancer, is representative of a new class of CK2 inhibitors with K(i) values in the low nanomolar range and unprecedented selectivity versus other kinases. Here we present the crystal structure of the complexes of CX-4945 and two analogues (CX-5011 and CX-5279) with the catalytic subunit of human CK2. Consistent with their ATP-competitive mode of inhibition, all three compounds bind in the active site of CK2 (type I inhibitors).

Regional variation in patient risk factors and mortality after coronary artery bypass grafting.

Background: Geographic variations in patient risk factors and operative mortality after coronary artery bypass graft surgery have not been well studied.

Methods: Using The Society of Thoracic Surgeons National Cardiac Database, a retrospective cohort study was performed of patients undergoing isolated coronary artery bypass graft surgery from 2004 to 2007 (n = 504,608). Records were sorted into four major geographic regions (Northeast, Midwest, South, and West) and compared with respect to patient risk profiles and outcomes.

Pre-clinical characterization of CX-4945, a potent and selective small molecule inhibitor of CK2 for the treatment of cancer.

In this article we describe the preclinical characterization of 5-(3-chlorophenylamino) benzo[c][2,6]naphthyridine-8-carboxylic acid (CX-4945), the first orally available small molecule inhibitor of protein CK2 in clinical trials for cancer. CX-4945 was optimized as an ATP-competitive inhibitor of the CK2 holoenzyme (Ki = 0.38 nM).

Successful linking of the Society of Thoracic Surgeons database to social security data to examine survival after cardiac operations.

Background: Long-term evaluation of cardiothoracic surgical outcomes is a major goal of The Society of Thoracic Surgeons (STS). Linking the STS Database to the Social Security Death Master File (SSDMF) allows for the verification of "life status." This study demonstrates the feasibility of linking the STS Database to the SSDMF and examines longitudinal survival after cardiac operations.

Care processes associated with quicker door-in-door-out times for patients with ST-elevation-myocardial infarction requiring transfer: results from a statewide regionalization program.

Background: The ability to rapidly identify patients with ST-segment elevation-myocardial infarction (STEMI) at hospitals without percutaneous coronary intervention (PCI) and transfer them to hospitals with PCI capability is critical to STEMI regionalization efforts. Our objective was to assess the association of prehospital, emergency department (ED), and hospital processes of care implemented as part of a statewide STEMI regionalization program with door-in-door-out times at non-PCI hospitals.

Methods And Results: Door-in-door-out times for 436 STEMI patients at 55 non-PCI hospitals were determined before (July 2005 to September 2005) and after (January 2007 to March 2007) a year-long implementation of standardized protocols as part of a statewide regionalization program (Reperfusion of Acute Myocardial Infarction in North Carolina Emergency Departments, RACE).

Transition from open to robotic-assisted pediatric pyeloplasty: a feasibility and outcome study.

Purpose: Laparoscopic reconstructive procedures in the pediatric patient are associated with a steep learning curve. Outcomes from robotic-assisted pediatric urology have been reported by surgeons with known facility in laparoscopic surgery. We describe the experience of a single surgeon in transitioning from open to robotic-assisted laparoscopic pyeloplasty (RALP) without previous training in traditional laparoscopic pyeloplasty or intracorporeal suturing.

Care models and associated outcomes in congenital heart surgery.

Objective: Recently, there has been a shift toward care of children undergoing heart surgery in dedicated pediatric cardiac intensive care units (CICU). The impact of this trend on patient outcomes is unclear. We evaluated postoperative outcomes associated with a CICU versus other ICU models.

Risk factors for mortality and morbidity after the neonatal Blalock-Taussig shunt procedure.

Background: Perioperative advances have led to significant improvements in outcomes after many complex neonatal open heart procedures. Whether similar improvements have been realized for the modified Blalock-Taussig shunt, the most common palliative neonatal closed-heart procedure, is not known.

Methods: Data were abstracted from The Society of Thoracic Surgeons Congenital Heart Surgery Database (2002 to 2009).

Center variation in patient age and weight at Fontan operation and impact on postoperative outcomes.

Background: The impact of age and weight on outcomes after the Fontan operation is unclear. Previous analyses have suggested that lower weight-for-age z-score is an important predictor of poor outcome in patients undergoing bidirectional Glenn. We evaluated variation in age, weight, and weight-for-age z-score at Fontan across institutions, and the impact of these variables on postoperative morbidity and mortality.

Lessons learned from 119 consecutive cardiac transplants for pediatric and congenital heart disease.

Background: This manuscript reviews all patients who underwent orthotopic heart transplantations (OHT) at our program (116 patients underwent 119 OHT) to describe their diagnostic characteristics and to assess risk factors for mortality.

Methods: Median age at OHT was 179 days (mean, 1,446.6 ± 188.

Fifteen-year outcome trends for valve surgery in North America.

Background: Although results in valvular heart surgery may be improving, too few cases are available in most centers to quantify changes, especially for uncommon procedural categories. This study examined comprehensively national trends in valve surgery outcomes over the past 15 years.

Methods: From 1993 through 2007, 623,039 valve procedures were grouped into single aortic (A), mitral (M), and tricuspid (T) operations, along with AM, MT, AT, and AMT multiple valves ± coronary artery bypass graft surgery.

Novel potent pyrimido[4,5-c]quinoline inhibitors of protein kinase CK2: SAR and preliminary assessment of their analgesic and anti-viral properties.

We describe the discovery of novel potent substituted pyrimido[4,5-c]quinoline ATP-competitive inhibitors of protein kinase CK2. A binding model of the inhibitors with the protein was elaborated on the basis of SAR and revealed various modes of interaction with the hinge region. Representative analog 14k (CK2 IC(50)=9 nM) showed anti-viral activity at nanomolar concentrations against HIV-1.

Do physicians' attitudes toward implantable cardioverter defibrillator therapy vary by patient age, gender, or race?

Background: Implantable cardioverter defibrillator (ICD) therapy improves survival of patients with systolic heart failure. We assessed whether physicians' recommendation for ICD therapy varies as a function of patient age, gender, race, and physician's specialty.

Methods: We surveyed a random sample (n = 9969) of U.

Discovery and SAR of 5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-8-carboxylic acid (CX-4945), the first clinical stage inhibitor of protein kinase CK2 for the treatment of cancer.

Herein we chronicle the discovery of CX-4945 (25n), a first-in-class, orally bioavailable ATP-competitive inhibitor of protein kinase CK2 in clinical trials for cancer. CK2 has long been considered a prime cancer drug target because of the roles of deregulated and overexpressed CK2 in cancer-promoting prosurvival and antiapoptotic pathways. These biological properties as well as the suitability of CK2's small ATP binding site for the design of selective inhibitors, led us to fashion novel therapeutic agents for cancer.

Outcomes for endocarditis surgery in North America: a simplified risk scoring system.

Objective: Operation for infective endocarditis is associated with the highest mortality of any valve disease, with overall rates of in-hospital mortality exceeding 20%. The Society of Thoracic Surgeons Adult Cardiac Surgery Database was examined to develop a simple risk scoring system and identify areas for quality improvement.

Methods: From 2002 through 2008, 19,543 operations were performed for infective endocarditis.

Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth.

Deregulated ribosomal RNA synthesis is associated with uncontrolled cancer cell proliferation. RNA polymerase (Pol) I, the multiprotein complex that synthesizes rRNA, is activated widely in cancer. Thus, selective inhibitors of Pol I may offer a general therapeutic strategy to block cancer cell proliferation.

CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy.

Malignant transformation and maintenance of the malignant phenotype depends on oncogenic and non-oncogenic proteins that are essential to mediate oncogene signaling and to support the altered physiologic demands induced by transformation. Protein kinase CK2 supports key prosurvival signaling pathways and represents a prototypical non-oncogene. In this study, we describe CX-4945, a potent and selective orally bioavailable small molecule inhibitor of CK2.

Linking clinical registry data with administrative data using indirect identifiers: implementation and validation in the congenital heart surgery population.

Background: The use of clinical registries and administrative data sets in pediatric cardiovascular research has become increasingly common. However, this approach is limited by relatively few existing datasets, each of which contain limited data, and do not communicate with one another. We describe the implementation and validation of methodology using indirect patient identifiers to link The Society of Thoracic Surgeons Congenital Heart Surgery (STS-CHS) Database to The Pediatric Health Information Systems (PHIS) Database (a pediatric administrative database).