Rationale: Mechanisms of coronary occlusion in ST-elevation acute coronary syndrome are poorly understood. We have previously reported that neutrophil (polymorphonuclear cells [PMNs]) accumulation in culprit lesion site (CLS) thrombus is a predictor of cardiovascular outcomes. Objective: The goal of this study was to characterize PMN activation at the CLS. We examined the relationships between CLS neutrophil extracellular traps (NETs), bacterial components as triggers of NETosis, activity of endogenous deoxyribonuclease, ST-segment resolution, and infarct size. Methods and Results: We analyzed coronary thrombectomies from 111 patients with ST-elevation acute coronary syndrome undergoing primary percutaneous coronary intervention. Thrombi were characterized by immunostaining, flow cytometry, bacterial profiling, and immunometric and enzymatic assays. Compared with femoral PMNs, CLS PMNs were highly activated and formed aggregates with platelets. Nucleosomes, double-stranded DNA, neutrophil elastase, myeloperoxidase, and myeloid-related protein 8/14 were increased in CLS plasma, and NETs contributed to the scaffolds of particulate coronary thrombi. Copy numbers of Streptococcus species correlated positively with dsDNA. Thrombus NET burden correlated positively with infarct size and negatively with ST-segment resolution, whereas CLS deoxyribonuclease activity correlated negatively with infarct size and positively with ST-segment resolution. Recombinant deoxyribonuclease accelerated the lysis of coronary thrombi ex vivo. Conclusions: PMNs are highly activated in ST-elevation acute coronary syndrome and undergo NETosis at the CLS. Coronary NET burden and deoxyribonuclease activity are predictors of ST-segment resolution and myocardial infarct size.
Aberrant anaplastic lymphoma kinase (ALK) expression is a defining feature of many human cancers and was identified first in anaplastic large-cell lymphoma (ALCL), an aggressive non-Hodgkin T-cell lymphoma. Since that time, many studies have set out to identify the mechanisms used by aberrant ALK toward tumorigenesis. We have identified a distinct profile of micro-RNAs (miRNAs) that characterize ALCL; furthermore, this profile distinguishes ALK + from ALK − subtypes, and thus points toward potential mechanisms of tumorigenesis induced by aberrant ALK. Using a nucleophosmin-ALK transgenic mouse model as well as human primary ALCL tumor tissues and human ALCL-derived cell lines, we reveal a set of overlapping deregulated miRNAs that might be implicated in the development and progression of ALCL. Importantly, ALK + and ALK − ALCL could be distinguished by a distinct profile of "oncomirs": Five members of the miR-17-92 cluster were expressed more highly in ALK + ALCL, whereas miR-155 was expressed more than 10-fold higher in ALK − ALCL. Moreover, miR-101 was down-regulated in all ALCL model systems, but its forced expression attenuated cell proliferation only in ALK + and not in ALK − cell lines, perhaps suggesting different modes of ALK-dependent regulation of its target proteins. Furthermore, inhibition of mTOR, which is targeted by miR-101, led to reduced tumor growth in engrafted ALCL mouse models. In addition to future therapeutical and diagnostic applications, it will be of interest to study the physiological implications and prognostic value of the identified miRNA profiles.micro-RNA | mTOR | miR-155 | miR-101
Anaplastic Large Cell Lymphoma (ALCL) is a Non-Hodgkin lymphoma found in children and young adults with poor survival rates. ALCLs frequently carry a chromosomal translocation that results in expression of the oncoprotein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). The key molecular downstream events required for NPM-ALK triggered lymphoma growth are still not entirely clear. Here we show that the AP-1 proteins cJun and JunB promote lymphoma development and tumor dissemination in a murine NPM-ALK lymphomagenesis model via transcriptional regulation of PDGFRB. Therapeutic inhibition of PDGFRB markedly prolonged survival of NPM-ALK transgenic mice and increased the efficacy of an ALK-specific inhibitor in transplanted NPM-ALK tumors. Remarkably, inhibition of PDGFRs in a late stage patient with refractory NPM-ALK-positive ALCL resulted in complete and sustained remission within 10 days of treatment. Our data identify PDGFRB as novel cJun/JunB target that could be utilized for a highly effective therapy to cure ALCL. 3ALCLs are T-cell lymphomas 1,2 that comprise 10-20% of all Non-Hodgkin's lymphoma cases in children and 3% in adults 3 . About half of ALCL cases are positive for NPM-ALK fusion proteins caused by t(2;5)(p23;q35) translocation 4 . ALK translocations or point mutations have also been described in DLBCLs (diffuse large B-cell lymphomas) and in several nonlymphoid neoplasms [5][6][7][8] . Inhibition of ALK fusion proteins by specific compounds such as crizotinib showed promising clinical responses in ALCL and NSCLC (non-small cell lung cancer) 9,10 . However, ALK mutations conferring resistance to crizotinib have also been reported 11 .Recent studies have linked NPM-ALK expression to induction of AP-1 transcription factors JunB and cJun 12,13 . To investigate their role in NPM-ALK-driven T-cell lymphomas, we conditionally deleted cJun and/or JunB in T-cells of transgenic mice carrying the human NPM-ALK fusion-tyrosine-kinase under the control of the murine CD4-promotor 14 (CD4-NPM-ALK) (Fig. 1a). Gene deletion was confirmed by DNA genotyping (data not shown), real-time PCR, Western blotting and immunohistochemistry (IHC) (Suppl. (Fig.1b), however, inactivation of both, cJun and JunB, in CD4-NPM-ALK-CD4 ΔΔJun mice resulted in significantly prolonged survival (Fig. 1b). CD4-NPM-ALK-CD4 ΔΔJun lymphomas showed markedly reduced proliferation and significantly increased apoptosis when compared to CD4-NPM-ALK lymphomas ( Fig. 1c; Suppl. Fig. S2a,b). Consistently, (Fig. 2d) suggesting a transcriptional regulation of PDGFRB by Jun proteins. Consistently, AP-1 consensus sequences were identified within the murine PDGFRB promoter and first intron that were conserved among other species (Suppl. Fig. S3b,c) 15,16 . Moreover, analysis of ENCODE transcription factor binding tracks revealed binding of cJun and JunB to the PDGFRB intronic AP-1 site in the human K562 leukemia cell line (Suppl. Fig. S3d) 15,17 . CD4-NPM-ALK-CD4EMSA analysis of nuclear extracts from NPM-ALK lymphomas demonstrated AP-1 DNA ...
Background— The underlying pathophysiology of heart failure with preserved ejection fraction (HFPEF) is incompletely understood, but myocardial extracellular matrix accumulation is thought to play a major role. Our aims were to estimate myocardial extracellular matrix using cardiac magnetic resonance T1 mapping and to assess the relationship between pathobiology/pathophysiology and prognosis. Methods and Results— Patients with suspected HFPEF (n=100) were enrolled in this prospective, observational study. Confirmatory diagnostic tests, cardiac magnetic resonance imaging including T1 mapping, and invasive hemodynamic assessments were performed at baseline. Sixty-one patients with confirmed HFPEF entered a longitudinal outcome-monitoring phase (mean, 22.9±5.0 months), during which 16 had a cardiac event. Cardiac magnetic resonance T1 time (hazard ratio, 0.99; 95% confidence interval, 0.98–0.99; P =0.046), left atrial area (hazard ratio, 1.08; 95% confidence interval, 1.03–1.13; P <0.01), and pulmonary vascular resistance (hazard ratio, 1.01; 95% confidence interval, 1.00–1.01; P =0.03) were significantly associated with cardiac events. Patients with T1 times below the median (<388.3 ms) were at greater risk of cardiac events than the rest of the group ( P <0.01). Extracellular matrix of left ventricular biopsies (n=9), quantified by TissueFAXS technology correlated with T1 time ( R =0.98; P <0.01). T1 time also correlated with right ventricular–pulmonary arterial coupling (pulmonary vascular resistance: R =−0.36; P <0.01; right ventricular ejection fraction: R =0.28; P =0.01). Conclusions— In the present preliminary study, cardiac magnetic resonance postcontrast T1 time is associated with prognosis in HFPEF, suggesting postcontrast T1 as possible biomarker for HFPEF.
Abstract. The present study investigates extracts of Neuolaena lobata, an anti-protozoan ethnomedicinal plant of the Maya, regarding its anti-neoplastic properties. Firstly, extracts of increasing polarity were tested in HL-60 cells analyzing inhibition of cell proliferation and apoptosis induction. Secondly, the most active extract was further tested in anaplastic large cell lymphoma (ALCL) cell lines of human and mouse origin. The dichloromethane extract inhibited proliferation of HL-60, human and mouse ALCL cells with an IC 50 of ~2.5, 3.7 and 2.4 µg/ml, respectively and arrested cells in the G2/M phase. The extract induced the checkpoint kinases Chk1 and Chk2 and perturbed the orchestrated expression of the Cdc25 family of cell cycle phosphatases which was paralleled by the activation of p53, p21 and downregulation of c-Myc. Importantly, the expression of NPM/ALK and its effector JunB were drastically decreased, which correlated with the activation of caspase 3. Subsequently also platelet derived growth factor receptor β was downregulated, which was recently shown to be transcriptionally controlled by JunB synergizing with ALK in ALCL development. We show that a traditional healing plant extract downregulates various oncogenes, induces tumor suppressors, inhibits cell proliferation and triggers apoptosis of malignant cells. The discovery of the 'Active Principle(s)' is warranted.
1659 Anaplastic Large Cell Lymphoma (ALCL) is a non-Hodgkin lymphoma of children and young adults with poor survival rates. ALCLs often occur with a chromosomal translocation that results in expression of the NPM-ALK oncoprotein. The molecular mechanism of NPM-ALK resulting in lymphoma growth are not fully understood. In a murine NPM-ALK lymphoma-model with T-cell specific deletion of cJun and JunB we could drastically delay lymphoma development and metastases. We identified PDGFRB as a direct transcriptional target of cJun and JunB. Blockage of the PDGFRβ activity significantly prolonged survival of NPM-ALK transgenic mice and severely reduced the growth of xenografted NPM-ALK tumors. In addition, we demonstrate that PDGFRβ is upregulated in human ALCL tumor specimens. Inhibition of the PDGFRβ in a terminal stage patient with NPM-ALK expressing ALCL which was refractory to any conventional therapy resulted in full remission within 10 days of treatment. We herwith certify the PDGFRB as a novel cJun/JunB target essential for ALCL development. Our data for the first time unravel a highly effective targeted therapy with the outlook to make ALCL a curable disease. Disclosures: Off Label Use: Imatinib for treatment of ALCL.
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