[Periodic breathing Cheyne-Stokes type, predict excessively reduced exercise tolerance in patients with chronic heart failure].

INTRODUCTION: Periodic breathing (PB) is evident during exercise in some patients with chronic heart failure (CHF) and is accompanied by hyperventilation. AIM: To determine whether the presence of PB predicts excessive reduced exercise capacity in patients with severe CHF relative to patient with CHF of similar severity but with no PB. METHODS: Sixty-one CHF patients underwent cardiopulmonary exercise from 2009 to 2011 as part of their evaluation for cardiac transplantation. From this data, we selected patients in which the term "periodic breathing" appeared in their report. Matching patients with CHF without PB were identified from the same pool. RESULTS: Fifteen CHF patients with PB and 18 patients with CHF with similar ejection fraction but without PB (control) were identified from the pool of 61 patients. The PB group had a lower peak oxygen uptake related to body weight (VO2/ kg] and anaerobic threshold [AT) than the control group, by 30 +/- 11 and 39 +/- 4%, respectively (p < 0.05). The ventilatory equivalent for CO2 production (VE/VCO2) at the AT was higher and the end tidal pressure of CO2 (PETCO2) was lower in the control group as compared with the PB group (p < 0.05]. VE/ VCO2 at the AT was inversely correlated with peak VO2/kg [r = -0.45, p < 0.05]. DISCUSSION: PB in patients with severe CHF is associated with excessively reduced exercise capacity. Increased ventilatory requirement may enhance dyspnea and may add to exercise limitation in these patients. CONCLUSION: Periodic breathing reflects the severity of CHF and is associated with excessively reduced exercise tolerance in patients with CHF.

The expression of three genes in primary non-small cell lung cancer is associated with metastatic spread to the brain.

PURPOSE: Brain metastases affect 25% of patients with non-small cell lung cancer (NSCLC). We hypothesized that the expression of genes in primary NSCLC tumors could predict brain metastasis and be used for identification of high-risk patients, who may benefit from prophylactic therapy. EXPERIMENTAL DESIGN: The expression of 12 genes was measured by real-time quantitative reverse transcriptase PCR in 142 frozen NSCLC tissue samples. Univariate and multivariate Cox regression analysis was used to analyze the correlation between gene expression and the occurrence of brain metastasis. Immunohistochemistry on independent samples was used to verify the findings. RESULTS: A score based on the expression levels of three genes, CDH2 (N-cadherin), KIFC1, and FALZ, was highly predictive of brain metastasis in early and advanced lung cancer. The probability of remaining brain metastasis-free at 2 years after diagnosis was 90.0+/-9.5% for patients with stage I/stage II tumors and low score compared with 62.7+/-12% for patients with high score (P<0.01). In patients with more advanced lung cancer, the brain metastasis-free survival at 24 months was 89% for patients with low score compared with only 37% in patients with high score (P<0.02). These results were confirmed by immunohistochemical detection of N-cadherin in independent cohort of primary NSCLC. CONCLUSIONS: The expression levels of three genes in primary NSCLC tumors may be used to identify patients at high risk for brain metastasis who may benefit from prophylactic therapy to the central nervous system.

Altered adenosine-to-inosine RNA editing in human cancer.

Adenosine-to-inosine (A-to-I) RNA editing was recently shown to be abundant in the human transcriptome, affecting thousands of genes. Employing a bioinformatic approach, we identified significant global hypoediting of Alu repetitive elements in brain, prostate, lung, kidney, and testis tumors. Experimental validation confirmed this finding, showing significantly reduced editing in Alu sequences within MED13 transcripts in brain tissues. Looking at editing of specific recoding and noncoding sites, including in cancer-related genes, a more complex picture emerged, with a gene-specific editing pattern in tumors vs. normal tissues. Additionally, we found reduced RNA levels of all three editing mediating enzymes, ADAR, ADARB1, and ADARB2, in brain tumors. The reduction of ADARB2 correlated with the grade of malignancy of glioblastoma multiforme, the most aggressive of brain tumors, displaying a 99% decrease in ADARB2 RNA levels. Consistently, overexpression of ADAR and ADARB1 in the U87 glioblastoma multiforme cell line resulted in decreased proliferation rate, suggesting that reduced A-to-I editing in brain tumors is involved in the pathogenesis of cancer. Altered epigenetic control was recently shown to play a central role in oncogenesis. We suggest that A-to-I RNA editing may serve as an additional epigenetic mechanism relevant to cancer development and progression.