The prognostic value of plasma fibrinogen concentrations of patients with ST-elevation myocardial infarction and treated by primary percutaneous coronary intervention: a cautionary message.

BACKGROUND: Fibrinogen elevation is associated with a worse prognosis in patients with acute coronary syndrome (ACS). The aim of the present study was to assess the prognostic value of increased fibrinogen concentrations in ST-elevation myocardial infarction (STEMI) patients treated with primary percutaneous coronary intervention (PCI). METHODS: A total of 428 STEMI patients treated with primary PCI were retrospectively selected (median age: 62 years; 82.5% males) from a continuous case series of 832 ACS patients. Plasma fibrinogen concentrations were measured before PCI and after 24, 48, and 72 hours. In the 4-year follow-up, one major adverse cardiovascular event (MACE) occurred in 111 patients (40%): 17 re-STEMI (7%), 64 re-PCI (22%), 22 cardiac deaths (7%), and eight non ST-elevated acute coronary syndromes (NSTEACS, 4%). RESULTS: According to the reference change value, fibrinogen concentrations increased in 25% of patients at 24 h, 64% at 48 h and 19% at 72 h. Only fibrinogen concentrations at 48 h showed a mild association with overall MACEs (p = 0.036): the risk increased, starting from a concentration of 4 g/L. However a further multivariate model did not confirm any prognostic value. No association with specific MACEs emerged. CONCLUSIONS: In contrast to NSTEACS patients, fibrinogen concentrations increased slightly in STEMI patients after primary PCI, however, they were not as prognostic as for MACEs.

Sex differences in lipid profiles in relation to the progression of glucose abnormalities.

BACKGROUND: In the present study, we investigated the role of changes in blood lipids in the abolition of the lower cardiovascular risk associated with the female gender in individuals with type 2 diabetes mellitus (T2DM). METHODS: An oral glucose tolerance test (OGTT) was performed in 1091 consecutive patients (478 men and 613 women) and patients were divided into groups as follows: (i) those with normal glucose tolerance (NGT; n = 589); (ii) those with pre-diabetes (pre-T2DM), who were further divided into those with impaired fasting glucose (IFG; n = 212), impaired glucose tolerance (IGT; n = 84), and both IFG and IGT (IFG/IGT; n = 102); and (iii) those with T2DM (n = 104). Total cholesterol, triglycerides, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), apolipoprotein (apo) A-I, apoB, and the apoB:apoA-I ratio were determined in each patient. Differences in lipids between the different groups were assessed using Student's t-test. RESULTS: Significantly higher triglyceride levels and an apoB:apoA-I ratio were found in NGT men (P < 0.0001), along with lower HDL-C and apoA-I (P < 0.0001). Men in the pre-T2DM group maintained a higher apoB:apoA-I ratio (P < 0.05) and lower HDL-C (P < 0.0001) compared with women. In the T2DM group, only HDL-C was lower in men compared with women (P < 0.05). CONCLUSIONS: The progression of glucose intolerance from NGT to pre-T2DM and T2DM exhibits striking sex differences regarding the lipid profile. The data demonstrate a worsening of plasma lipid composition in women who become diabetic. This could explain, at least in part, the loss of the more favorable cardiovascular risk normally associated with NGT women.

A role for the transcription factor HEY1 in glioblastoma.

Abstract Glioblastoma multiforme (GBM), the highest-grade glioma, is the most frequent tumour of the brain with a very poor prognosis and limited therapeutic options. Although little is known about the molecular mechanisms that underlie glioblastoma formation, a number of signal transduction routes, such as the Notch and Ras signalling pathways, seem to play an important role in the formation of GBM. In the present study, we show by in situ hybridization on primary tumour material that the transcription factor HEY1, a target of the Notch signalling pathway, is specifically up-regulated in glioma and that expression of HEY1 in GBM correlates with tumour-grade and survival. In addition, we show by chromatin immunoprecipitations, luciferase assays and Northern blot experiments that HEY1 is a bona fide target of the E2F family of transcription factors, connecting the Ras and Notch signalling pathways. Finally, we show that ectopic expression of HEY1 induces cell proliferation in neural stem cells, while depletion of HEY1 by RNA interference reduces proliferation of glioblastoma cells in tissue culture. Together, these data imply a role for HEY1 in the progression of GBM, and therefore we propose that HEY1 may be a therapeutic target for glioblastoma patients. Moreover, HEY1 may represent a molecular marker to distinguish GBM patients with a longer survival prognosis from those at high risk.

EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer.

Recent experiments have demonstrated that the Polycomb group (PcG) gene EZH2 is highly expressed in metastatic prostate cancer and in lymphomas. EZH2 is a component of the PRC2 histone methyltransferase complex, which also contains EED and SUZ12 and is required for the silencing of HOX gene expression during embryonic development. Here we demonstrate that both EZH2 and EED are essential for the proliferation of both transformed and non-transformed human cells. In addition, the pRB-E2F pathway tightly regulates their expression and, consistent with this, we find that EZH2 is highly expressed in a large set of human tumors. These results raise the question whether EZH2 is a marker of proliferation or if it is actually contributing to tumor formation. Significantly, we propose that EZH2 is a bona fide oncogene, since we find that ectopic expression of EZH2 is capable of providing a proliferative advantage to primary cells and, in addition, its gene locus is specifically amplified in several primary tumors.