Citations

AbstractObjectiveTo determine whether disparities in access to invasive cardiac procedures still exist for Medicaid patients, given how old earlier studies are and given changes in the interim in appropriateness guidelines.Patients and MethodsA total of 5,022 Medicaid and private insurance patients in New York from January 1, 2008 through December 31, 2009 under age 65 with ST‐elevation myocardial infarction (STEMI) were compared with regard to their access to percutaneous coronary interventions (PCI) before and after controlling for numerous patient characteristics and other important factors.ResultsMedicaid patients were significantly less likely to be admitted initially to a hospital certified to perform PCI (90.4% vs. 94.3%, P < 0.001). Also, Medicaid patients were found to be significantly less likely to undergo PCI than other patients (adjusted odds ratio [AOR] = 0.81, 95% CI 0.66, 0.98, P = 0.03). When the probability of each hospital performing PCI for STEMI patients was controlled for, Medicaid patients were still less likely to undergo PCI after controlling for other risk factors (AOR = 0.80, 95% CI 0.65, 0.99, P = 0.04).ConclusionsMedicaid STEMI patients are significantly less likely to undergo PCI within the same day of admission as private pay patients even after adjusting for patient characteristics related to receiving PCI, and the strength of this relationship is not diminished when controlling for whether the admitting hospital has approval to perform PCI or controlling for the tendency of the admitting hospital to treat STEMI with PCI. (J Interven Cardiol 2013;26:470‐481)

ABSTRACTBACKGROUNDThe temporal evolution of white matter (WM) changes on MR examinations in hereditary diffuse leukoencephalopathy with spheroids (HDLS) is largely unknown. Our purpose was to investigate the evolution of these WM changes with diffusion weighted/tensor imaging (DWI/DTI) and MR Spectroscopy (MRS).METHODSA newly diagnosed patient with HDLS from the original Swedish family was followed prospectively with 5 MRI as well as DWI/DTI and MRS examinations during 16 months.RESULTSThe DTI eigenvalues demonstrated changes that suggested early myelin and axonal disturbances in the normal appearing WM (NAWM). DWI/DTI showed a rim of decreased diffusion progressively expanding through the WM from the initial frontal periventricular zones, and indicated complete destruction of axons and myelin in the area behind the front. MRS findings were suggestive of axonal destruction in the NAWM.CONCLUSIONWe describe HDLS changes in three temporal stages of development corresponding to lesions outside, in the vicinity of, and behind a characteristic rim centrifugally progressing from the ventricular horns. The axonal disturbances indicated by MRS changes in the NAWM support a primary axonal degeneration, as proposed in the original HDLS report, rather than axonal degeneration secondary to demyelination. These findings could help in differential diagnosis of HDLS.

Purpose To evaluate the impact of miR-155 on the outcome of adults with cytogenetically normal (CN) acute myeloid leukemia (AML) in the context of other clinical and molecular prognosticators and to gain insight into the leukemogenic role of this microRNA. Patients and Methods We evaluated 363 patients with primary CN-AML. miR-155 levels were measured in pretreatment marrow and blood by NanoString nCounter assays that quantified the expression of the encoding gene MIR155HG. All molecular prognosticators were assessed centrally. miR-155–associated gene and microRNA expression profiles were derived using microarrays. Results Considering all patients, high miR-155 expression was associated with a lower complete remission (CR) rate (P < .001) and shorter disease-free survival (P = .001) and overall survival (OS; P < .001) after adjusting for age. In multivariable analyses, high miR-155 expression remained an independent predictor for a lower CR rate (P = .007) and shorter OS (P < .001). High miR-155 expressers had approximately 50% reduction in the odds of achieving CR and 60% increase in the risk of death compared with low miR-155 expressers. Although high miR-155 expression was not associated with a distinct microRNA expression profile, it was associated with a gene expression profile enriched for genes involved in cellular mechanisms deregulated in AML (eg, apoptosis, nuclear factor-κB activation, and inflammation), thereby supporting a pivotal and unique role of this microRNA in myeloid leukemogenesis. Conclusion miR-155 expression levels are associated with clinical outcome independently of other strong clinical and molecular predictors. The availability of emerging compounds with antagonistic activity to microRNAs in the clinic provides the opportunity for future therapeutic targeting of miR-155 in AML.

Rationale: Mutagenesis screening is a powerful genetic tool for probing biological mechanisms underlying vertebrate development and human diseases. However, the increased colony management efforts in vertebrates impose a significant challenge for identifying genes affecting a particular organ, such as the heart, especially those exhibiting adult phenotypes on depletion. Objective: We aim to develop a facile approach that streamlines colony management efforts via enriching cardiac mutants, which enables us to screen for adult phenotypes. Methods and Results: The transparency of the zebrafish embryos enabled us to score 67 stable transgenic lines generated from an insertional mutagenesis screen using a transposon-based protein trapping vector. Fifteen lines with cardiac monomeric red fluorescent protein reporter expression were identified. We defined the molecular nature for 10 lines and bred them to homozygosity, which led to the identification of 1 embryonic lethal, 1 larval lethal, and 1 adult recessive mutant exhibiting cardiac hypertrophy at 1 year of age. Further characterization of these mutants uncovered an essential function of methionine adenosyltransferase II, α a (mat2aa) in cardiogenesis, an essential function of mitochondrial ribosomal protein S18B (mrps18b) in cardiac mitochondrial homeostasis, as well as a function of DnaJ (Hsp40) homolog, subfamily B, member 6b (dnajb6b) in adult cardiac hypertrophy. Conclusions: We demonstrate that transposon-based gene trapping is an efficient approach for identifying both embryonic and adult recessive mutants with cardiac expression. The generation of a zebrafish insertional cardiac mutant collection shall facilitate the annotation of a vertebrate cardiac genome, as well as enable heart-based adult screens.

Abstract The inv(16)(p13q22)/t(16;16)(p13;q22) in acute myeloid leukemia results in multiple CBFB-MYH11 fusion transcripts, with type A being most frequent. The biologic and prognostic implications of different fusions are unclear. We analyzed CBFB-MYH11 fusion types in 208 inv(16)/t(16;16) patients with de novo disease, and compared clinical and cytogenetic features and the KIT mutation status between type A (n = 182; 87%) and non–type A (n = 26; 13%) patients. At diagnosis, non–type A patients had lower white blood counts (P = .007), and more often trisomies of chromosomes 8 (P = .01) and 21 (P < .001) and less often trisomy 22 (P = .02). No patient with non–type A fusion carried a KIT mutation, whereas 27% of type A patients did (P = .002). Among the latter, KIT mutations conferred adverse prognosis; clinical outcomes of non–type A and type A patients with wild-type KIT were similar. We also derived a fusion-type–associated global gene-expression profile. Gene Ontology analysis of the differentially expressed genes revealed—among others—an enrichment of up-regulated genes involved in activation of caspase activity, cell differentiation and cell cycle control in non–type A patients. We conclude that non–type A fusions associate with distinctclinical and genetic features, including lack of KIT mutations, and a unique gene-expression profile.

AbstractRecently, we showed that increased miR-181a expression was associated with improved outcomes in cytogenetically normal acute myeloid leukemia (CN-AML). Interestingly, miR-181a expression was increased in CN-AML patients harboring CEBPA mutations, which are usually biallelic and associate with better prognosis. CEBPA encodes the C/EBPα transcription factor. We demonstrate here that the presence of N-terminal CEBPA mutations and miR-181a expression are linked. Indeed, the truncated C/EBPα-p30 isoform, which is produced from the N-terminal mutant CEBPA gene or from the differential translation of wild-type CEBPA mRNA and is commonly believed to have no transactivation activity, binds to the miR-181a-1 promoter and up-regulates the microRNA expression. Furthermore, we show that lenalidomide, a drug approved for myelodysplastic syndromes and multiple myeloma, enhances translation of the C/EBPα-p30 isoform, resulting in higher miR-181a levels. In xenograft mouse models, ectopic miR-181a expression inhibits tumor growth. Similarly, lenalidomide exhibits antitumorigenic activity paralleled by increased miR-181a expression. This regulatory pathway may explain an increased sensitivity to apoptosis-inducing chemotherapy in subsets of AML patients. Altogether, our data provide a potential explanation for the improved clinical outcomes observed in CEBPA-mutated CN-AML patients, and suggest that lenalidomide treatment enhancing the C/EBPα-p30 protein levels and in turn miR-181a may sensitize AML blasts to chemotherapy.

Objective— Endothelial cell (EC) inflammatory status is critical to many vascular diseases. Emerging data demonstrate that mutations of Krüppel-like factor-11 (KLF11), a gene coding maturity-onset diabetes mellitus of the young type 7 ( MODY7 ), contribute to the development of neonatal diabetes mellitus. However, the function of KLF11 in the cardiovascular system still remains to be uncovered. In this study, we aimed to investigate the role of KLF11 in vascular endothelial inflammation. Methods and Results— KLF11 is highly expressed in vascular ECs and induced by proinflammatory stimuli. Adenovirus-mediated KLF11 overexpression inhibits expression of tumor necrosis factors-α–induced adhesion molecules. Moreover, small interfering RNA–mediated KLF11 knockdown augments the proinflammatory status in ECs. KLF11 inhibits promoter activity of adhesion molecules induced by tumor necrosis factor-α and nuclear factor-κB p65 overexpression. Mechanistically, KLF11 potently inhibits nuclear factor-κB signaling pathway via physical interaction with p65. Furthermore, KLF11 knockdown results in increased binding of p65 to vascular cell adhesion molecule-1 and E-selectin promoters. At the whole organism level, KLF11 −/− mice exhibit a significant increase in leukocyte recruitment to ECs after lipopolysaccharide administration. Conclusion— Taken together, our data demonstrate for the first time that KLF11 is a suppressor of EC inflammatory activation, suggesting that KLF11 constitutes a novel potential molecular target for inhibition of vascular inflammatory diseases.

Purpose To evaluate the prognostic significance of the international European LeukemiaNet (ELN) guidelines for reporting genetic alterations in acute myeloid leukemia (AML). Patients and Methods We analyzed 1,550 adults with primary AML, treated on Cancer and Leukemia Group B first-line trials, who had pretreatment cytogenetics and, for cytogenetically normal patients, mutational status of NPM1, CEBPA, and FLT3 available. We compared complete remission (CR) rates, disease-free survival (DFS), and overall survival (OS) among patients classified into the four ELN genetic groups (favorable, intermediate-I, intermediate-II, adverse) separately for 818 younger (age < 60 years) and 732 older (age ≥ 60 years) patients. Results The percentages of younger versus older patients in the favorable (41% v 20%; P < .001), intermediate-II (19% v 30%; P < .001), and adverse (22% v 31%; P < .001) genetic groups differed. The favorable group had the best and the adverse group the worst CR rates, DFS, and OS in both age groups. Both intermediate groups had significantly worse outcomes than the favorable but better than the adverse group. Intermediate-I and intermediate-II groups in older patients had similar outcomes, whereas the intermediate-II group in younger patients had better OS but not better CR rates or DFS than the intermediate-I group. The prognostic significance of ELN classification was confirmed by multivariable analyses. For each ELN group, older patients had worse outcomes than younger patients. Conclusion The ELN classification clearly separates the genetic groups by outcome, supporting its use for risk stratification in clinical trials. Because they have different proportions of genetic alterations and outcomes, younger and older patients should be reported separately when using the ELN classification.

Neural cells derived from induced pluripotent stem cells from patients with genetic forms of Parkinson’s disease provide insights into disease pathogenesis.

Abstract Phospholipase C epsilon (PLCε or PLC∈ 1) is a phosphoinositide-specific enzyme phospholipase C that converts phosphatidylinositol 4,5-biphosphate to two intracellular second messengers, diacylglycerol and inositol 1,4,5-trisphosphate, which regulate protein kinase C activity and calcium mobilization, respectively. These responses are involved in the regulation of cell growth, differentiation and oncogenesis. However, the involvement of PLCε in human carcinogenesis, particularly in esophageal cancer, was not been recognized until a susceptible SNP (rs2274223: A5780G:His1927Arg) was recently identified in a large genome-wide association study (GWAS). This SNP, located within exon 26 and C2 domain of the PLCε gene at chromosome 10q23, leads to a nonsynonymous alteration from CAC (A allele, encoding histidine) to CGC (G allele, encoding arginine), which was associated with an increased risk of both squamous cell carcinoma and esophagus-cardia gastric adenocarcinoma. In the current report, we demonstrate that the presence of the G allele (AG or GG) at this locus leads to increased PLCε mRNA and protein expression in human esophageal cancer tissues and in human esophageal cancer cell lines. The present of G allele also leads o a higher enzyme activity in esophageal cancer cells in vitro. Quantitative analysis of the C2 domain sequences revealed that A:G allelic imbalance is strongly associated with esophageal malignancy. Moreover, the analysis of 10,614 non-cancer subjects from high- and low-risk areas of China demonstrated that the presence of the G allele is strongly associated with moderate to severe esophagitis in the subjects from the high-risk areas of China: 77% of the severe esophagitis individuals in high-risk areas had AG/GG genotypes vs. only 37% of these subjects in low-risk areas (OR 6.03 with 95% CI 1.59-22.9 vs. OR 0.74 with 95% CI 0.33-1.64; p=0.008). These data suggest that the interaction of potential environmental factors with PLCε, particularly in individuals with AG or GG allele, not only exists in high-risk areas for esophageal cancer development in China, but also correlates with the severity of esophagitis. In conclusion, PLCε is likely to play a pivotal role in esophageal carcinogenesis: the presence of the 5780G allele may not only predict a high risk of future esophageal cancer development, but may also participate in esophageal cancer growth and progression by upregulating levels of PLCε mRNA, protein, and enzyme activity, ultimately leading to augmentation of the inflammatory process in esophageal epithelium. Thus, the 5780G allele in PLCε may constitute a promising biomarker for esophageal squamous carcinoma risk stratification, early detection, and progression prediction. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4704. doi:10.1158/1538-7445.AM2011-4704