Autophagy and Bcl-2/BNIP3 death regulatory pathway in non-small cell lung carcinomas.

We recently showed that non-small cell lung carcinomas (NSCLCs) are of dismal prognosis when encompassing accelerated autophagic activity. The regulation of this abnormally functioning degradation system and its association with hypoxia and apoptosis in lung carcinoma patients is unexplored. In this study we used 115 NSCLC tissues to examine the immunohistochemical expression of four distinct molecules - the major regulator of autophagy Beclin 1, the anti-apoptotic and anti-autophagic protein Bcl-2, the pro-apoptotic and pro-autophagic protein BNIP3, and a marker of hypoxia and glucolysis, the glucose transporter Glut 1. Most cases showed reduced reactivity for Beclin 1 (62%) and Bcl-2 (82%) proteins, almost half of our sample revealed strong BNIP3 expression (57%), whereas most of the carcinomas strongly expressed Glut 1 antigen (71%). Beclin 1 expression showed no association with survival. Bcl-2 positivity was a marker of good prognosis (p = 0.04), whereas BNIP3 (p = 0.0004) and Glut 1 (p = 0.03) expression correlated with poor outcome in Stage I disease. Autophagic status was negatively associated with Bcl-2 (p = 0.0006), but positively with Glut 1 expression (p = 0.001). In conclusion, the accelerated autophagic status in NSCLC is unrelated to Beclin 1 and BNIP3 expression, but does show significant association with Bcl-2 reactivity. Furthermore, we showed important correlations between glucolysis and autophagy, guiding new pathways in future lung carcinoma research.

Acute pressure overload of the right ventricle. Comparison of two models of right-left shunt. Pulmonary artery to left atrium and right atrium to left atrium: experimental study.

BACKGROUND: In right ventricular failure (RVF), an interatrial shunt can relieve symptoms of severe pulmonary hypertension by reducing right ventricular preload and increasing systemic flow. Using a pig model to determine if a pulmonary artery-left atrium shunt (PA-LA) is better than a right atrial-left atrial shunt (RA-LA), we compared the hemodynamic effects and blood gases between the two shunts. METHODS: Thirty, male Large White pigs weighting in average 21.3 kg ± 0.7 (SEM) were divided into two groups (15 pigs per group): In group 1, banding of the pulmonary artery and a pulmonary artery to left atrium shunt with an 8 mm graft (PA-LA) was performed and in group 2 banding of the pulmonary artery and right atrial to left atrial shunt (RA-LA) with a similar graft was performed. Hemodynamic parameters and blood gases were measured from all cardiac chambers in 10 and 20 minutes, half and one hour interval from the baseline (30 min from the banding). Cardiac output and flow of at the left anterior descending artery was also monitored. RESULTS: In both groups, a stable RVF was generated. The PA-LA shunt compared to the RA-LA shunt has better hemodynamic performance concerning the decreased right ventricle afterload, the 4 fold higher mean pressure of the shunt, the better flow in left anterior descending artery and the decreased systemic vascular resistance. Favorable to the PA-LA shunt is also the tendency--although not statistically significant--in relation to central venous pressure, left atrial filling and cardiac output. CONCLUSION: The PA-LA shunt can effectively reverse the catastrophic effects of acute RVF offering better hemodynamic characteristics than an interatrial shunt.

Endothelial nitric oxide synthase gene polymorphisms -786T > C and 894G > T in coronary artery bypass graft surgery patients.

Polymorphisms in the endothelial nitric oxide synthase ( eNOS ) gene (- 786T > C and 894G > T ) enhance endothelial dysfunction and have been studied in relation to coronary artery disease (CAD). In the present study, we examined the association of the above polymorphisms with CAD, as well as with myocardial infarction (MI), hypertension, diabetes and smoking in CAD patients. Study subjects consisted of 154 consecutive coronary artery bypass graft (CABG) patients and 155 non-CAD controls. eNOS - 786T > C and 894G > T polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism. The estimated frequencies of the - 786C and 894T alleles did not differ between the two groups ( p = 0.46 and p = 0.84, respectively). The prevalence of eNOS polymorphisms was not associated with MI, hypertension or diabetes in CABG patients; however, we found that the 894TT genotype and 894T allele were significantly more frequent in current/past smoker CABG patients (16.7 per cent and 39.6 per cent, respectively) compared with never smoker CABG patients (6.1 per cent and 24.4 per cent, respectively) ( p = 0.01 and p < 0.01, respectively). We found no association of eNOS - 786C and 894T variant alleles with CAD; however, within CABG patients, a gene-environment interaction was found between the eNOS 894T allele and smoking.

Coronary artery bypass surgery in a patient with Kartagener syndrome: a case report and literature review.

Kartagener syndrome consists of congenital bronchiectasis, sinusitis, and total situs inversus in half of the patients. A patient diagnosed with Kartagener syndrome was referred to our department due to 3-vessel coronary disease. An off-pump coronary artery bypass operation was performed using both internal thoracic arteries and a saphenous vein graft. We performed a literature review for cases with Kartagener syndrome, coronary surgery and dextrocardia. Although a few cases of dextrocardia were found in the literature, no case of Kartagener syndrome was mentioned.

Renin-angiotensin-aldosterone system gene polymorphisms in coronary artery bypass graft surgery patients.

INTRODUCTION: Candidates for coronary artery bypass grafting (CABG) represent a group of patients with well documented, severe coronary artery disease (CAD). Genetic polymorphisms of renin-angiotensin-aldosterone system (RAAS) components have been associated with CAD. We examined the association of polymorphisms of angiotensin-converting enzyme (ACE), angiotensinogen (AGT), and angiotensin II type 1 receptor (AT(1) receptor) with severe CAD in CABG patients. MATERIALS AND METHODS: One hundred and fifty-four CABG patients and 155 non-CAD controls were included in the study. Established PCR methods were used for genotyping of AGT M235T, AGT T174M, AT(1) receptor A1166C, and ACE I/D polymorphisms. Cumulative effect of analysed polymorphisms was assessed by calculation of each individual's RAAS gene score (addition of 0.5 points for each variant allele and then calculating the sum for all four polymorphisms). RESULTS: No association between AGT M235T, AGT T174M, ACE I/D and AT(1) receptor A1166C polymorphisms and CAD was observed. Within CABG patients, the frequency of homozygous AGT 235TT genotype was higher in hypertensive compared to normotensive CABG patients (21.7% vs. 6.3%, p=0.03). RAAS gene score did not differ between CABG patients and non-CAD controls. CONCLUSIONS: There is no association of the analysed RAAS polymorphisms with severe CAD in CABG patients. However, within these patients, an association was found between AGT 235TT genotype and hypertension.

Expression of prolyl-hydroxylases PHD-1, 2 and 3 and of the asparagine hydroxylase FIH in non-small cell lung cancer relates to an activated HIF pathway.

The oxygen sensitive prolyl-hydroxylase domain enzymes (PHDs) and the asparagines hydroxylase (FIH, factor inhibiting HIF) regulate the transcriptional activity of HIFs. We assessed the expression of these enzymes in a series of 73 non-small cell lung carcinomas (NSCLC). A direct association of PHDs with FIH and of the PHDs/FIH with HIFs expression was noted. Thirty three of 73 cases had high HIF/PHD expression, predicting intense HIF activity; 19/73 cases had low HIF and high PHD expression mimicking the normal bronchial pattern; and 18/73 cases had low HIF/PHD (inactive HIF pathway). High lactate dehydrogenase LDH5 expression was noted in cases with high HIF/PHD phenotype. The value of such a classification in defining different metabolic phenotypes of NSCLC deserves further evaluation.

Hypofractionated accelerated radiochemotherapy with cytoprotection (Chemo-HypoARC) for inoperable non-small cell lung carcinoma.

BACKGROUND: Concurrent radiochemotherapy and altered radiotherapy fractionation are under thorough investigation in locally advanced non-small cell lung carcinoma (NSCLC). PATIENTS AND METHODS: The efficacy and tolerance of hypofractionated accelerated radiochemotherapy supported with high dose (up to 1000 mg daily) amifostine cytoprotection (hypoARC) was examined in 31 patients. Fifteen fractions of 3.5 Gy were delivered within 28-35 days. Liposomal doxorubicin and oxaliplatin were concurrently given. RESULTS: A total of 65% of patients tolerated a daily amifostine dose of 750-1000 mg. Chemotherapy had an excellent tolerance. Grade 3 oesophagitis was noted in 7/31 (22.5%) patients. Radiation pneumonitis was absent and radiation fibrosis minimal. Complete and partial response were observed in 12/31 (38.6%) and 17/31 (54.8%) patients, respectively. The 2-year estimated local progression-free and overall survival interval were 58% and 45%, respectively. CONCLUSION: Given the simplicity of HypoARC, the very low morbidity, and the high complete response and survival rates obtained, HypoARC regimens deserve further testing.

Influence of bispectral index monitoring on decision making during cardiac anesthesia.

STUDY OBJECTIVE: To assess bispectral index (BIS) monitoring on decision making during cardiac surgery with cardiopulmonary bypass (CPB) by measuring the number of preset standardized comments with and without knowing the BIS value and by classifying the interventions following the BIS data. DESIGN: Prospective, randomized study. SETTING: University Hospital. PATIENTS: One hundred twenty-one patients scheduled for elective cardiac surgery (89 coronary patients, 24 valve replacement patients, and 8 valve replacement and coronary surgery). INTERVENTIONS: Patients were divided into 3 groups. An observing anesthesiologist recorded on a special form ("parallel" anesthesia record) data from the devices of the workstation and the BIS monitor. Conditions in which BIS monitoring was subjectively considered that might have been useful in anesthetic decision making were recorded as "events." In group A (36 patients), the responsible anesthesiologist had continuous access to BIS information. In group B (44 patients), intraoperative anesthetic management was "blinded" to BIS values, whereas in group C (41 patients), the anesthesiologist observing the BIS monitor was free to inform the attending anesthesiologist about the BIS score. The number of events was considered as negatively reflecting the quality of the clinical course of a patient. The reduction of events was considered as improvement in decision making. All patients received the same anesthetic regimen (propofol + remifentanil). Monitoring was equal in all cases. Mild hypothermic CPB was applied in 73 patients. Statistical analysis used 1-way analysis of variance, Student 2-tailed t test, and chi2 analysis. MAIN RESULTS: Patient demographic data, underlying pathology, operation performed, hypothermia application, times of anesthesia, duration of operation, and CPB were similar in the 3 groups. In group B, the BIS value was considered by the observer as useful to know in 220 events (5.00 +/- 1.58 per patient). In group C, the BIS value was considered by the observer as useful to know in 143 events (3.49 +/- 1.31 per patient, P < 0.001) and, at the same time, the attending anesthesiologist was informed about BIS. In 112 (78.3%) cases, measures were taken. Titration of anesthetic drugs was done in 79 (70.5%) patients, whereas titration of vasoactive drugs was done in 9 (8.0%) patients, titration of both in 13 (11.6%) patients, and other diagnostic or corrective actions in 11 (9.8%) patients. Distributions of BIS values did not differ statistically (39.19 +/- 10.32, 37.38 +/- 10.21, and 38.29 +/- 10.01 in group A, group B, and group C, respectively). "Zenith" and "nadir" BIS values after induction also did not differ statistically. Awakening and extubation times were similar in both groups. CONCLUSIONS: Subjectivity, although reduced as much as possible, can play a confining role in the value of our results. The usefulness of BIS monitoring is shown by the fact that BIS data resulted in corrective measures. Attending anesthesiologist's actions, based on BIS information, reduced the events in group C.

VEGF gene sequence variation defines VEGF gene expression status and angiogenic activity in non-small cell lung cancer.

Different vascular endothelial growth factor (VEGF) gene polymorphisms have been shown to result in different VEGF gene responsiveness to various stimuli and different capacity for VEGF protein production. In the present study, we examined four VEGF gene polymorphisms in thirty-six individuals with non-small cell lung cancer (NSCLC). Gene polymorphisms were correlated with the VEGF protein expression in cancer cells and the tumor angiogenic activity. The -2578C/C, -634G/G and -1154A/A and G/A alleles in the VEGF gene were linked with low VEGF expression, while the -2578C/A, the -634 G/C and the -1154G/G alleles were linked with high VEGF expression. Tumors with -2578C/C had a significantly lower vascular density (VD) compared to the -2578C C/A. Similarly, cases with the -634G/G VEGF polymorphism had a singinificanltly lower vascular density compared to the combined C/C and G/C groups. In addition, the -1154A/A polymorphism seemed to relate with poor vaccularization but the difference did not reach significance. It is concluded that inherited VEGF sequence variations, which characterize the tumor genome itself, are strong determinants of the molecular VEGF and VEGF-downstream phenotype of NSCLC. The large variation in angiogenicity between tumors of similar histologic morphology emerges as a consequence of the 'parental' VEGF gene ability to produce VEGF.