Topographic Spread of Inferior Colliculus Activation in Response to Acoustic and Intracochlear Electric Stimulation

The design of contemporary multichannel cochlear implants is predicated on the presumption that they activate multiple independent sectors of the auditory nerve array. The independence of these channels, however, is limited by the spread of activation from each intracochlear electrode across the auditory nerve array. In this study, we evaluated factors that influence intracochlear spread of activation using two types of intracochlear electrodes: (1) a clinical-type device consisting of a linear series of ring contacts positioned along a silicon elastomer carrier, and (2) a pair of visually placed (VP) ball electrodes that could be positioned independently relative to particular intracochlear structures, e.g., the spiral ganglion. Activation spread was estimated by recording multineuronal evoked activity along the cochleotopic axis of the central nucleus of the inferior colliculus (ICC). This activity was recorded using silicon-based single-shank, 16-site recording probes, which were fixed within the ICC at a depth defined by responses to acoustic tones. After deafening, electric stimuli consisting of single biphasic electric pulses were presented with each electrode type in various stimulation configurations (monopolar, bipolar, tripolar) and/or various electrode orientations (radial, off-radial, longitudinal). The results indicate that monopolar (MP) stimulation with either electrode type produced widepread excitation across the ICC. Bipolar (BP) stimulation with banded pairs of electrodes oriented longitudinally produced activation that was somewhat less broad than MP stimulation, and tripolar (TP) stimulation produced activation that was more restricted than MP or BP stimulation. Bipolar stimulation with radially oriented pairs of VP ball electrodes produced the most restricted activation. The activity patterns evoked by radial VP balls were comparable to those produced by pure tones in normal-hearing animals. Variations in distance between radially oriented VP balls had little effect on activation spread, although increases in interelectrode spacing tended to reduce thresholds. Bipolar stimulation with longitudinally oriented VP electrodes produced broad activation that tended to broaden as the separation between electrodes increased.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41383/1/10162_2004_Article_4026.pd

Alterations of frizzled (FzE3) and secreted frizzled related protein (hsFRP) expression in gastric cancer

Wnt signaling pathway is important for development and carcinogenesis. Alterations of this pathway, such as mutations in adenomatous polyposis coli (APC) gene and activation mutations of β-catenin, would result in stabilization of β-catenin and subsequent translocation to nucleus where genes are transcribed. Recently, a receptor of Wnt, FzE3 was found to be up-regulated in esophageal carcinoma while a non-receptor antagonist of Wnt, secreted frizzled related protein (hsFRP) was found to be down-regulated in some cancer. These findings suggested that FzE3 is a potential oncogene while hsFRP is a potential tumor suppressor gene. We aimed to investigate whether FzE3 and hsFRP were altered in gastric cancer. Twelve cases of gastric cancer, including 7 cases of intestinal type, 4 cases of diffuse type and 1 case of mixed type, were studied. FzE3 and hsFRP mRNAs were expressed in most of the paired normal gastric tissues. FzE3 was over-expressed in 9 cases (75%) of gastric carcinoma tissues while hsFRP was down-regulated in 2 cases (16%). β-catenin nuclear staining was identified in 3 cases (27%) and cyclin D1 was expressed in 5 cases (41%) of cancer samples. All these cases were associated with either up-regulation of FzE3 or down-regulation of hsFRP. Our results suggested that alterations of FzE3 or hsFRP were frequent in gastric cancer. These provide alternative mechanisms leading to activation of Wnt signaling pathway in gastric carcinogenesis. © 2001 Elsevier Science Inc. All rights reserved.link_to_subscribed_fulltex

Promoter hypermethylation of tumor-related genes in the progression of colorectal neoplasia

Gene promoter hypermethylation is increasingly recognized to play an important role in cancer development through silencing of gene transcription. This study determined the methylation profiles of primary colorectal cancers and adenomas to elucidate the role of epigenetic changes in different stages of colorectal carcinogenesis. We examined the methylation profiles of 47 sporadic colorectal cancers, 36 colonic adenomas from patients without cancer and 34 colonic biopsies from patients without colonic lesions. Paired adjacent dysplasia tissues obtained from 17 cancer patients were also examined. Promoter hypermethylation in 10 tumor-related genes (APC, ATM, GSTPI, HLTF, MGMT, hMLH1, p14, p15, SOCS-1 and TIMP-3) were studied by methylation-specific PCR. Promoter hypermethylation was frequently detected in more than 40% of colonic cancers and adenomas in APC, ATM, HLTF, MGMT and hMLH1 genes (p < 0.0001 vs. normal). While low level of methylation was detected in p14, p15 and TIMP-3, there was no methylation detected in GSTPI and SOCS-1. The frequencies of methylation were comparable between tumors and adenomas, and advanced and non-advanced adenoma. In contrast, K-ras mutation was only detected in advanced adenomas and cancers. Concurrent methylation in ≥ 3 genes was found in 66.7% adenomas and 68.1% cancers but not in normal colonic tissues. Methylation was associated with reduced protein expressions in colorectal adenomas and cancers. Moreover, methylation in ATM was more common in older cancer patients (p = 0.002), but there was no significant association between promoter hypermethylation and other clinicopathologic characteristics of cancer. Our study demonstrated the early and specific involvement of promoter hypermethylation in the colorectal adenoma-carcinoma sequence. © 2004 Wiley-Liss, Inc.link_to_subscribed_fulltex

Detection of gene promoter hypermethylation in the tumor and serum of patients with gastric carcinoma

Purpose: Aberrant promoter methylation, an alternative mechanism for gene silencing, is frequently detected in gastric cancer. We studied the feasibility of detecting aberrant methylation in serum of gastric cancer patients. Experimental Design: Patients (54) with gastric adenocarcinoma were studied. The tumor and the paired serum were examined for aberrant methylation in DAP-kinase, E-cadherin, GSTP1, p15, and p16 by methylation-specific PCR. Serum from 30 age-matched noncancer patients was used as control. Results: Promoter methylation in DAP-kinase, Ecadherin, GSTP1, p15, and p16 were detected in 70.3, 75.9, 18.5, 68.5, and 66.7% of primary tumor. In serum of gastric cancer patients, methylation in DAP-kinase, Ecadherin, GSTP1, p15, and p16 were detected in 48.1, 57.4, 14.8, 55.6, and 51.9%, respectively. None of the control serum showed aberrant methylation. Aberrant methylation in serum DNA was all accompanied with methylation in the corresponding tumor samples. In general, >60% of serum from cancers with aberrant methylation demonstrated these epigenetic alterations. Conclusion: Our findings suggest that aberrant promoter methylation in serum can be detected in a substantial proportion of gastric cancer patients, and this strategy should be evaluated in the screening and surveillance of gastric cancer.link_to_subscribed_fulltex

Inverse association between cyclooxygenase-2 overexpression and microsatellite instability in gastric cancer

This study examined the association between cyclooxygenase-2 (COX-2) overexpression and microsatellite instability (MSI) in gastric cancer. COX-2 expression was assessed by immunohistochemistry and scored in a semi-quantitative manner whereas MSI status was characterized by nine microsatellite markers. The clinicopathological features of cancers including survival data were analyzed. Of the 109 gastric cancers studied, COX-2 overexpression and high level of MSI (MSI-H) was detected in 64.2 and 22.0% cases respectively. Gastric tumors with MSI-H phenotypes had significantly lower level of COX-2 expression levels when compared to MSI-L and MSS tumors (P = 0.002). Moreover, COX-2 overexpression was associated with tumor invasion beyond submucosa (P = 0.045) and there was a trend favoring better survival in gastric cancers without COX-2 overexpression (P = 0.07). The results from this study suggest that gastric cancer with microsatellite instability or COX-2 overexpression present with diverse clinicopathological features. © 2001 Elsevier Science Ireland Ltd.link_to_subscribed_fulltex

Detection of gene promoter hypermethylation in the tumor and serum of patients with gastric carcinoma

Purpose: Aberrant promoter methylation, an alternative mechanism for gene silencing, is frequently detected in gastric cancer. We studied the feasibility of detecting aberrant methylation in serum of gastric cancer patients. Experimental Design: Patients (54) with gastric adenocarcinoma were studied. The tumor and the paired serum were examined for aberrant methylation in DAP-kinase, E-cadherin, GSTP1, p15, and p16 by methylation-specific PCR. Serum from 30 age-matched noncancer patients was used as control. Results: Promoter methylation in DAP-kinase, Ecadherin, GSTP1, p15, and p16 were detected in 70.3, 75.9, 18.5, 68.5, and 66.7% of primary tumor. In serum of gastric cancer patients, methylation in DAP-kinase, Ecadherin, GSTP1, p15, and p16 were detected in 48.1, 57.4, 14.8, 55.6, and 51.9%, respectively. None of the control serum showed aberrant methylation. Aberrant methylation in serum DNA was all accompanied with methylation in the corresponding tumor samples. In general, >60% of serum from cancers with aberrant methylation demonstrated these epigenetic alterations. Conclusion: Our findings suggest that aberrant promoter methylation in serum can be detected in a substantial proportion of gastric cancer patients, and this strategy should be evaluated in the screening and surveillance of gastric cancer.link_to_subscribed_fulltex

Promoter hypermethylation of tumor-related genes in gastric intestinal metaplasia of patients with and without gastric cancer

Promoter hypermethylation is an alternative mechanism of gene silencing in human cancers including gastric cancer. While intestinal metaplasia (IM) is generally regarded as a precancerous lesion of the stomach, our study examines the presence of gene promoter hypermethylation in IM of patients with and without gastric cancer. We examined 31 samples of gastric cancer, 36 gastric IM (21 associated with gastric cancer and 15 from noncancer patients) and 10 normal gastric biopsies. Tissues containing foci of IM were carefully microdissected from paraffin-embedded section. Bisulfite-modifiedDNA was examined for gene promoter hypermethylation in DAP-kinase, E-cadherin, GSTP1, p14, p15, p16, RASSFIA and hMLH1 by methylation-specific-PCR. None of the control gastric tissues had hypermethylation detected, but gene promoter hypermethylation was frequently detected in gastric cancer and IM. The mean number of methylated genes in cancer and IM was 3.0 and 1.4, respectively (p < 0.0001). Methylation in IM from cancer patients was all associated with concurrent methylation in the corresponding tumor samples. The numbers of methylated genes were similar in IM obtained from cancer and noncancer patients. By examining the methylation patterns of these genes, 3 differential methylation patterns were recognized: hypermethylation was more frequent in cancer than in IM (DAP-kinase, p14, p15 and p16); comparable frequencies of methylation in cancer and IM (E-cadherin and hMLH1); and no methylation (GSTP1). Aberrant methylation in tumor-related genes is frequently detected in gastric IM of both cancer and noncancer patients, suggesting their early involvement in the multistep progression of gastric carcinogenesis. © 2002 Wiley-Liss, Inc.link_to_subscribed_fulltex

Quantitative Epstein-Barr virus DNA analysis and detection of gene promoter hypermethylation in nasopharyngeal (NP) brushing samples from patients with NP carcinoma

Purpose: Nasopharyngeal carcinoma (NPC) is highly prevalent in southern China and characterized by a strong association with EBV. We aimed to detect EBV DNA and cancer-related gene promoter hypermethylation in nasopharyngeal (NP) brushing samples and provide a novel noninvasive approach for NPC detection. Experimental Design: Twenty-eight NPC cases and 26 noncancerous subjects were prospectively recruited. NP brushing samples were subjected to quantitative real-time PCR analysis of EBV DNA and methylation-specific PCR analysis of the DAP-kinase, RASSF1A, and p16 genes. Results: EBV DNA quantity in NP brushing samples from NPC patients (median, 8.94 copies/actin) was significantly higher than that of controls (median, 0 copies/actin; P < 0.0001). Twenty-seven of 28 NPC patients had detectable EBV DNA in NP brushes, whereas 25 of 26 controls had undetectable or very low levels of EBV DNA. Elevated EBV DNA level in brushing samples as a tumor marker had a sensitivity of 96.4% and a specificity of 96.2% for NPC detection. Moreover, T 1 disease had a significantly lower EBV DNA level as compared with locally more advanced disease (P = 0.037). In brushing samples of NPC patients, the frequencies of DAP-kinase, RASSF1A, and p16 promoter hypermethylation were 50.0%, 39.3%, and 46.4%, respectively. Seventy-eight percent of cases showed methylation of at least one gene. No aberrant hypermethylation was detected in control samples. Conclusions: Our study demonstrated the feasibility of detecting multiple molecular tumor markers in NP brushing samples with a high sensitivity and specificity for NPC detection. It offers a powerful yet noninvasive approach for the diagnosis of NPC in high-risk populations.link_to_subscribed_fulltex