Day: 01/20/2011

Identification of MicroRNAs in the Cerebrospinal Fluid as Marker for Primary Diffuse Large B-cell Lymphoma of the Central Nervous System

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The diagnosis of primary central nervous system lymphoma (PCNSL) depends on histopathology of brain biopsies, since disease markers in the cerebrospinal fluid (CSF) with sufficient diagnostic accuracy are not available yet. MicroRNAs (miRNAs) are regulatory RNA molecules that are deregulated in many disease types including cancer. Recently, miRNAs have shown promise as markers for cancer diagnosis. In the current study, we demonstrate that miRNAs are present in the CSF of patients suffering from PCNSL. Making use of a candidate approach and of miRNA quantification by RT-PCR, miRNAs with significant levels in the CSF of PCNSL patients were identified. MiR-21, miR-19, and miR-92a levels in CSF collected from PCNSL patients and controls with inflammatory CNS disorders and other neurologic disorders indicated a significant diagnostic value of this method. Receiver-operating characteristic analyses revealed area under the curves of 0.94, 0.98, and 0.97 for miR-21, miR-19, and miR-92a CSF levels in discriminating PCNSL from controls. More importantly, combined miRNA analyses resulted in an increased diagnostic accuracy with 95.7% sensitivity and 96.7% specificity. We also demonstrated a remarkable stability of miRNAs in the CSF. In conclusion, CSF miRNAs are potentially useful tools as novel non-invasive biomarker for the diagnosis of PCNSL.

 

Uric Acid as a Marker of Oxidative Stress in Dilatation of the Ascending Aorta

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Increased serum uric acid (UA) has been shown to directly promote oxidative stress. Recent studies point toward a role for oxidative stress in the pathogenesis of ascending aortic aneurysms (AscAAs). This study was designed to examine the relationship between serum UA concentrations, total antioxidant reductive capacity, and AscAAs.

Methods

The serum UA concentrations, total antioxidant reductive capacity were compared in 60 patients with ascending aortic dilatation (ectasia group (3.8–4.3 cm), 34 patients; aneurysmal group (≥4.4 cm), 26 patients) vs. 30 control subjects. The patients were evaluated by a complete transthoracic echocardiographic examination including measurement of the aortic dimensions.

Results

The serum UA concentration and total antioxidant reductive capacity were significantly higher in patients with AscAAs. In multiple linear regression analysis, hypertension and serum UA concentration were significantly associated with aortic dilatation (β = 0.3, P = 0.03; β = 0.15, P< 0.001, respectively).

Conclusions

In conclusion, we found that serum UA concentration and total antioxidant capacity (TAC) were significantly associated with aortic dilatation. The higher serum UA concentration may be responsible for the elevated serum antioxidant capacity that was observed among individuals with AscAA. Large-scale epidemiological studies conducted over several years are required to correlate the cross-sectional findings from this study with clinical outcome.

source: American Journal of Hypertension

 

Sugar-free approaches to cancer cell killing

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Tumors show an increased rate of glucose uptake and utilization. For this reason, glucose analogs are used to visualize tumors by the positron emission tomography technique, and inhibitors of glycolytic metabolism are being tested in clinical trials. Upregulation of glycolysis confers several advantages to tumor cells: it promotes tumor growth and has also been shown to interfere with cell death at multiple levels. Enforcement of glycolysis inhibits apoptosis induced by cytokine deprivation. Conversely, antiglycolytic agents enhance cell death induced by radio- and chemotherapy. Synergistic effects are likely due to regulation of the apoptotic machinery, as glucose regulates activation and levels of proapoptotic BH3-only proteins such as Bim, Bad, Puma and Noxa, as well as the antiapoptotic Bcl-2 family of proteins. Moreover, inhibition of glucose metabolism sensitizes cells to death ligands. Glucose deprivation and antiglycolytic drugs induce tumor cell death, which can proceed through necrosis or through mitochondrial or caspase-8-mediated apoptosis. We will discuss how oncogenic pathways involved in metabolic stress signaling, such as p53, AMPK (adenosine monophosphate-activated protein kinase) and Akt/mTOR (mammalian target of rapamycin), influence sensitivity to inhibition of glucose metabolism. Finally, we will analyze the rationale for the use of antiglycolytic inhibitors in the clinic, either as single agents or as a part of combination therapies.

source: nature oncology

 

 

 

Can We Identify Unstable Coronary Plaques Before They Rupture?

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Intravascular ultrasound uncovers some predictive plaque characteristics, but clinical application of the findings is still a long way off.

 

According to retrospective studies, many (if not most) lesions responsible for acute myocardial infarction (MI) and other acute coronary syndromes (ACS) are non–flow-limiting plaques that rupture, causing rapid progression, thrombosis, and vessel obstruction. This prospective, multicenter, industry-sponsored study included 697 patients (mean age, 58; 24% women; 17% with diabetes) who underwent successful percutaneous coronary intervention for ACS. To identify lesion-specific factors predictive of recurrent events, investigators performed both gray-scale and radiofrequency intravascular ultrasound (IVUS) of the proximal 6–8 cm of all major epicardial coronary arteries. Median follow-up was 3.4 years.

IVUS-related complications occurred in 1.6% of patients and included 10 dissections and 1 perforation, causing 3 nonfatal MIs (0.4%). At 3 years, the estimated cumulative rate of major adverse cardiovascular events (MACEs) was 20%, including rehospitalization for recurrent angina (18%), MI (3%), and cardiac death (2%). Of the events, about half were attributed to the original culprit lesion and half to nonculprit lesions.

In the nonculprit lesions judged responsible for subsequent MACE, mean angiographic stenosis was 32% at baseline and 65% at follow-up. Baseline IVUS characteristics that independently predicted events were plaque burden >70% (hazard ratio, 5.03), thin-cap fibroatheroma (HR, 3.35), and minimal luminal area of <4.0 mm2 (HR, 3.21). A MACE occurred in 18% of lesions that had all three of these characteristics and in <1% of lesions with none of them.

Comment: These investigators are the first to use ultrasound to prospectively examine nonobstructive lesion characteristics predictive of subsequent adverse cardiac events. They found that lesions with a large plaque burden, small luminal area, and thin cap are associated with the highest risk for causing later events. Although these findings are mechanistically interesting, their specificity is low, IVUS conferred procedural risk, and the appropriate therapeutic approach to these lesions is uncertain. Therefore, the strategy is presently unsuitable for clinical application.

— Howard C. Herrmann, MD

Published in Journal Watch Cardiology January 19, 2011

Intravascular ultrasound uncovers some predictive plaque characteristics, but clinical application of the findings is still a long way off.

 

According to retrospective studies, many (if not most) lesions responsible for acute myocardial infarction (MI) and other acute coronary syndromes (ACS) are non–flow-limiting plaques that rupture, causing rapid progression, thrombosis, and vessel obstruction. This prospective, multicenter, industry-sponsored study included 697 patients (mean age, 58; 24% women; 17% with diabetes) who underwent successful percutaneous coronary intervention for ACS. To identify lesion-specific factors predictive of recurrent events, investigators performed both gray-scale and radiofrequency intravascular ultrasound (IVUS) of the proximal 6–8 cm of all major epicardial coronary arteries. Median follow-up was 3.4 years.

IVUS-related complications occurred in 1.6% of patients and included 10 dissections and 1 perforation, causing 3 nonfatal MIs (0.4%). At 3 years, the estimated cumulative rate of major adverse cardiovascular events (MACEs) was 20%, including rehospitalization for recurrent angina (18%), MI (3%), and cardiac death (2%). Of the events, about half were attributed to the original culprit lesion and half to nonculprit lesions.

In the nonculprit lesions judged responsible for subsequent MACE, mean angiographic stenosis was 32% at baseline and 65% at follow-up. Baseline IVUS characteristics that independently predicted events were plaque burden >70% (hazard ratio, 5.03), thin-cap fibroatheroma (HR, 3.35), and minimal luminal area of <4.0 mm2 (HR, 3.21). A MACE occurred in 18% of lesions that had all three of these characteristics and in <1% of lesions with none of them.

Comment: These investigators are the first to use ultrasound to prospectively examine nonobstructive lesion characteristics predictive of subsequent adverse cardiac events. They found that lesions with a large plaque burden, small luminal area, and thin cap are associated with the highest risk for causing later events. Although these findings are mechanistically interesting, their specificity is low, IVUS conferred procedural risk, and the appropriate therapeutic approach to these lesions is uncertain. Therefore, the strategy is presently unsuitable for clinical application.

— Howard C. Herrmann, MD

Published in Journal Watch Cardiology January 19, 2011