Promoter hypermethylation of p16INK4a, E-cadherin, O6-MGMT, DAPK and FHIT in adenocarcinomas of the esophagus, esophagogastric junction and proximal stomach

Although the incidence of Barrett's carcinomas (BC) and proximal gastric adenocarcinomas (PGC) is increasing, little is known about different epigenetic changes in these etiopathogenetically distinct entities. Therefore, 29 adenocarcinomas [10 BC, 7 PGC and 12 tumors of the esophagogastric junction (JC)] and corresponding non-tumor controls (NT) were examined using methylation-specific PCR. The most striking result was a significantly higher promoter methylation frequency of O6-methylguanine methyl transferase (MGMT) in BC compared with JC and PGC (0.7 vs. 0.08 vs. 0.29, respectively; p = 0.011; methylation exclusively in tumors), confirmed immunohistochemically by a significant loss of MGMT protein in BC (p = 0.006). Therefore, MGMT might become a prognosticator and key for chemotherapy with alkylating agents in BC. Frequencies of p16INK4a promoter methylation were 0.5 (BC), 0.42 (JC) and 0.29 (PGC; n.s.), but methylation was almost absent in NT controls. As immunonegative tumors slightly outnumber methylation-positive cases, other mechanisms of gene inactivation must be discussed. Methylation of E-cadherin was rarely observed (1/10 BC, 0/12 JC and 2/7 PGC). This is the first report on promoter methylation of death-associated protein kinase (DAPK) and fragile histidine triad gene (FHIT) in BC; both DAPK (BC 0.7, JC 0.92 and PGC 0.86) and FHIT (BC 0.88, JC 1.0 and PGC 1.0) were found to be highly methylated, suggesting that epigenetic silencing of these tumor suppressors is a common event in adenocarcinomas of the upper gastrointestinal tract, including BC. DAPK (0.54 on average) and FHIT methylation (0.77 on average) were also observed in NT samples. This might constitute an early epigenetic precursor lesion in the normally-appearing tissue surrounding the tumor.     

Comparison of relative forced expiratory volume of one second with dynamic magnetic resonance imaging parameters in healthy subjects and patients with lung cancer

PURPOSE: To assess relative forced expiratory volume in one second (FEV1/vital capacity (VC)) in healthy subjects and patients with a lung tumor using dynamic magnetic resonance imaging (dMRI) parameters. MATERIALS AND METHODS: In 15 healthy volunteers and 31 patients with a non-small-cell lung carcinoma stage I (NSCLC I), diaphragmatic length change (LE1) and craniocaudal (CC) intrathoracic distance change within one second from maximal inspiration (DE1) were divided by total length change (LE(total), DE(total)) as a surrogate of spirometric FEV1/VC using a true fast imaging with steady-state precession (trueFISP) sequence (TE/TR = 1.7/37.3 msec, temporal resolution = 3 images/second). Influence of tumor localization was examined. RESULTS: In healthy volunteers FEV1/VC showed a highly significant correlation with LE1/LE(total) and DE1/DE(total) (r > 0.9, P < 0.01). In stage IB tumor patients, comparing tumor-bearing with the non-tumor-bearing hemithorax, there was a significant difference in tumors of the middle (LE1/LE(total) = 0.63 +/- 0.05 vs. 0.73 +/- 0.04, DE1/DE(total) = 0.66 +/- 0.05 vs. 0.72 +/- 0.04; P < 0.05) and lower (P < 0.05) lung region. Stage IA tumor patients showed no significant differences with regard to healthy subjects. CONCLUSION: dMRI is a simple noninvasive method to locally determine LE1/LE(total) and DE1/DE(total) as a surrogate of FEV1/VC in volunteers and patients. Tumors of the middle and lower lung regions have a significant influence on these MRI parameters.     

WIN 55,212-2 decreases the spatial spread of neocortical excitation in vitro

The 'intrinsic optical signal' was used to monitor neuronal network excitability. The cannabinoid receptor type 1 agonist WIN 55,212-2 reduced the intensity and the spatial spread of the intrinsic optical signal and prolonged its kinetics in the rat neocortex in vitro. These effects were antagonized by the cannabinoid receptor antagonist SR141716A. Thus, our results suggest that neocortical network activity is modulated via the activation of cannabinoid receptors. The decrease of neocortical network excitability in the present study is probably due to a decreased excitability of glutamatergic neurons.     

Temporary inactivation of the rostral perirhinal cortex induces an anxiolytic-like effect on the elevated plus-maze and on the yohimbine-enhanced startle response

The present study investigated whether the rostral perirhinal cortex is involved in aversive information processing, particularly in unconditioned fear (anxiety). We temporarily inactivated the rostral perirhinal cortex by local injections of the GABA(A) agonist muscimol (0.0, 1.1, and 4.4 nmol/0.5 microl) and tested whether these injections affected the behavior of rats in the elevated plus-maze and in the yohimbine-enhanced startle test. Temporary inactivation of the rostral perirhinal cortex increased the number of open arm entries and the open arm ratio in the elevated plus-maze. In addition, startle response enhancement caused by the anxiogenic drug yohimbine was reduced by perirhinal cortex inactivation. Taken together, these data clearly show that the rostral perirhinal cortex is involved in the processing of emotional stimuli and is critical for the expression of unconditioned fear (anxiety).     

Differential effects of N-peptidyl-O-acyl hydroxylamines on dynorphin-induced antinociception in the mouse capsaicin test

In the capsaicin test, intrathecal (i.t.) dynorphins are antinociceptive. Cysteine protease inhibitors such as p-hydroxymercuribenzoate (PHMB) given i.t. augment and prolong their activity. The effect of two novel cysteine protease inhibitors, N-peptidyl-O-acyl hydroxylamines, on the antinociception induced by i.t. administered dynorphin A or dynorphin B has been investigated. When administered i.t. 5 min before the injection of capsaicin (800 ng) into the plantar surface of the hindpaw, dynorphin A (62.5-1000 pmol) or dynorphin B (0.5-4 nmol) produced a dose-dependent and significant antinociceptive effect. The effect of dynorphin A (1 nmol) and dynorphin B (4 nmol) disappeared completely within 180 and 60 min, respectively. PHMB (2 nmol) and Boc-Tyr-Gly-NHO-Bz (BYG-Bz) (2 nmol) co-administered with dynorphin A or dynorphin B significantly prolonged antinociception induced by both. On the other hand, Z-Phe-Phe-NHO-Bz (ZFF-Bz) (1 and 2 nmol) only prolonged antinociception induced by dynorphin A. The results suggest that Z-Phe-Phe-NHO-Bz is an inhibitor of cysteine proteases preferring cleavage of dynorphin A, with less specificity towards dynorphin B in the mouse spinal cord.     

Association of peroxisome proliferator-activated receptor gamma 2 Pro-12-Ala polymorphism with endometriosis

We explored the association of the PPAR-gamma2 (peroxisome proliferator-activated receptor) Pro-12-Ala polymorphism with endometriosis in a case-control study with 51 women with endometriosis stages I-IV and 55 control women without endometriosis. The 12-Pro allele of PPAR-gamma2 may have protective effects avoiding the development and progression of endometriosis.     

Time-resolved contrast-enhanced three-dimensional pulmonary MR-angiography: 1.0 M gadobutrol vs. 0.5 M gadopentetate dimeglumine

PURPOSE: To compare contrast characteristics and image quality of 1.0 M gadobutrol with 0.5 M Gd-DTPA for time-resolved three-dimensional pulmonary magnetic resonance angiography (MRA). MATERIALS AND METHODS: Thirty-one patients and five healthy volunteers were examined with a contrast-enhanced time-resolved pulmonary MRA protocol (fast low-angle shot [FLASH] three-dimensional, TR/TE = 2.2/1.0 msec, flip angle: 25 degrees, scan time per three-dimensional data set = 5.6 seconds). Patients were randomized to receive either 0.1 mmol/kg body weight (bw) or 0.2 mmol/kg bw gadobutrol, or 0.2 mmol/kg bw Gd-DTPA. Volunteers were examined three times, twice with 0.2 mmol/kg bw gadobutrol using two different flip angles and once with 0.2 mmol/kg bw Gd-DTPA. All contrast injections were performed at a rate of 5 mL/second. Image analysis included signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) measurements in lung arteries and veins, as well as a subjective analysis of image quality. RESULTS: In patients, significantly higher SNR and CNR were observed with Gd-DTPA compared to both doses of gadobutrol (SNR: 35-42 vs.17-25; CNR 33-39 vs. 16-23; P < or = 0.05). No relevant differences were observed between 0.1 mmol/kg bw and 0.2 mmol/kg bw gadobutrol. In volunteers, gadobutrol and Gd-DTPA achieved similar SNR and CNR. A significantly higher SNR and CNR was observed for gadobutrol-enhanced MRA with an increased flip angle of 40 degrees. Image quality was rated equal for both contrast agents. CONCLUSION: No relevant advantages of 1.0 M gadobutrol over 0.5 M Gd-DTPA were observed for time-resolved pulmonary MRA in this study. Potential explanations are T2/T2*-effects caused by the high intravascular concentration when using high injection rates.