Assignment of the gene GRM1 coding for metabotropic glutamate receptor 1 to human chromosome band 6q24 by in situ hybridization.
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Chromosome Banding↗
Biomedical subjects
S Ganesh
Publications and source records attributed to S Ganesh.
Temporal difference between testis and ovary determinations with possible involvement of testosterone and aromatase in gonadal differentiation in TSD lacking lizard, Calotes versicolor.
In the garden lizard, Calotes versicolor, which lacks identifiable sex chromosomes, incubation temperature also does not have a deterministic effect on the gender. However, the embryos reared at high temperature (33-35 degrees C) have a shorter duration of incubation as well as gonadal differentiation. In contrast, exogenous application of the male hormone testosterone to embryos at ambient temperature (28 degrees C) results in almost all individuals with only testis. Thus the testosterone treatment reverts genic females to males and accelerates the differentiation of testis, a feature similar to the high-temperature treatment. Treatment of eggs with estradiol shows no difference from that seen in the untreated eggs. The present series of experiments was done to establish the "window" of testosterone sensitivity and to understand the interaction between sex hormones and high temperature on gonadal differentiation. The period between day 5 and 15 of embryonic development was the window period of testosterone sensitivity for sex reversal. This period coincided with the formation of the genital ridge and its differentiation into cortex and medulla. Treatment of the 33 degrees C-reared embryos with testosterone resulted in hatchlings of both the sexes, in contrast to only males at the ambient temperature. In contrast, at the same temperature (33 degrees C), all the dihydrotestosterone (nonaromatisable testosterone)-treated embryos hatched into males. However, those given estradiol showed no sex bias regardless of the day of application and the concentration of drug. Eggs were also treated with aromatase inhibitor, CGS 16949 A, at ambient temperature and at 33 degrees C. All the 33 degrees C eggs to which the drug was given on day 25 hatched into males. These results suggest that though high temperature has no direct effect on sex determination in this species, it may have a stimulatory effect on aromatase activity, leading to the conversion of the exogenously applied testosterone into estradiol and permitting ovarian differentiation in the genic females. It also follows from the present report that the pathway of testis formation in Calotes versicolor is triggered much earlier, and irreversibly, than that for the ovary.
Animals↗
Isolation and characterization of mouse homologue for the human epilepsy gene, EPM2A.
Mutations in the novel gene, EPM2A, have been shown recently to cause the progressive myoclonus epilepsy of Lafora type. EPM2A is predicted to encode a putative protein-tyrosine phosphatase but its specific role in normal brain function and in the Lafora disease is not known. As a first step towards understanding the cellular function of EPM2A in an animal model, we have isolated cDNA clones for mouse EPM2A and analyzed its expression. Sequence analyses of the mouse cDNA clones revealed a complete ORF that supports the 5' coding sequence predicted for human EPM2A from the genomic sequence. When compared to EPM2A, the mouse homologue, named Epm2a, shows 86% identity at the nucleotide level and 88% identity and 93% similarity at the amino acid level. Similar to the human counterpart, Epm2a showed ubiquitous expression in Northern with a major transcript size of 3.5 kb. We have mapped the Epm2a to the proximal region of mouse chromosome 10 which is the syntenic region for human chromosome band, 6q24. Our results suggest that EPM2A is highly conserved in mammals and might have a conserved function.
3' Untranslated Regions↗
The influence of Helicobacter pylori on oesophageal acid exposure in GERD during acid suppressive therapy.
BACKGROUND: Helicobacter pylori exaggerates the effect of acid suppressive drugs on intragastric pH. It is unknown whether this is relevant for the treatment of GERD. AIM: To compare oesophageal acid exposure and symptoms in H. pylori-negative and H. pylori-positive GERD patients during low and profound acid suppression. METHODS: Barrett's oesophagus patients with gastro- oesophageal acid reflux were studied by 24-h oesophageal pH-metry at baseline and during randomized treatment with omeprazole 40 mg b.d. or ranitidine 150 mg b.d. H. pylori status was determined by a serum IgG ELISA. Symptoms were scored on a four-graded scale. RESULTS: Of 58 patients, 26 (14 H. pylori-negative, 12 H. pylori-positive) were randomized to omeprazole, 32 (16 H. pylori-negative, 16 H. pylori-positive) to ranitidine. At baseline, oesophageal acid exposure and symptoms did not differ between H. pylori-negative and H. pylori-positive: mean time proportion pH < 4 per 24 h was 16.1% (95% CI 11.5-23.2) in H. pylori-negative, and 15.8% (11.3-21.4) in H. pylori-positive patients. Omeprazole treatment resulted in a decrease of acid reflux per 24 h from 23.4% (7.9-39.3) to 0.0% (0.0-2.9) in H. pylori-negative, and from 17.3% (8.9-38.8) to 0.1% (0.0-1.7) in H. pylori-positive patients; ranitidine resulted in a decrease from 14.4% (10.5-18.5) to 9.3% (5.6-12.8) in H. pylori-negative, and from 15.1% (9.8-21.0) to 9.0% (3.1-20.1) in H. pylori-positive patients, the difference between H. pylori-negative and H. pylori-positive patients being N.S. There was no significant difference between H. pylori-negative and H. pylori-positive patients with respect to erect and supine acid reflux, or symptom scores in both treatment groups. CONCLUSIONS: H. pylori infection does not influence oesophageal acid reflux and symptoms in patients with Barrett's oesophagus, either at baseline or during low as well as profound acid suppressive therapy. We conclude that the dose of acid suppression does not have to be titrated upon H. pylori status in GERD.
Adult↗
Endoscopic regression of Barrett's oesophagus during omeprazole treatment; a randomised double blind study.
BACKGROUND: Barrett's oesophagus, columnar metaplasia of the epithelium, is a premalignant condition with a 50-100-fold increased risk of cancer. The condition is caused by chronic gastro-oesophageal reflux. Regression of metaplasia may decrease the cancer risk. AIMS: To determine whether elimination of acid gastro-oesophageal reflux induces a regression of metaplastic epithelium. METHODS: Sixty eight patients with acid reflux and proven Barrett's oesophagus were included in a prospective, randomised, double blind study with parallel groups, and were treated with profound acid secretion suppression with omeprazole 40 mg twice daily, or with mild acid secretion suppression with ranitidine 150 mg twice daily, for 24 months. Endoscopy was performed at 0, 3, 9, 15, and 24 months with measurement of length and surface area of Barrett's oesophagus; pH-metry was performed at 0 and 3 months. Per protocol analysis was performed on 26 patients treated with omeprazole, and 27 patients treated with ranitidine. RESULTS: Omeprazole reduced reflux to 0.1%, ranitidine to 9.4% per 24 hours. Symptoms were ameliorated in both groups. There was a small, but statistically significant regression of Barrett's oesophagus in the omeprazole group, both in length and in area. No change was observed in the ranitidine group. The difference between the regression in the omeprazole and ranitidine group was statistically significant for the area of Barrett's oesophagus (p=0. 02), and showed a trend in the same direction for the length of Barrett's oesophagus (p=0.06). CONCLUSIONS: Profound suppression of acid secretion, leading to elimination of acid reflux, induces partial regression of Barrett's oesophagus.
Adult↗
Epithelial cell proliferative activity of Barrett's esophagus: methodology and correlation with traditional cancer risk markers.
Barrett's esophagus (BE) is a premalignant condition, due to chronic gastroesophageal reflux. Effective antireflux therapy may diminish cancer risk. To evaluate this option an intermediate marker is needed. We developed a methodology for measurement of epithelial cell proliferative activity of Barrett's mucosa as an intermediate marker and correlated the activity with traditional cancer risk markers and other parameters. Fifty-six patients (21-74 years of age) with Barrett's esophagus and established acid gastroesophageal reflux were included. Biopsies were taken from Barrett's mucosa at 3-cm intervals. Reflux was measured by 24-hr pH-metry. Proliferative activity was determined using in vitro labeling with 5-bromodeoxyuridine and immunohistochemistry and was expressed as labeling index (LI). The length of BE correlated with erect acid reflux (P=0.002). LI in specialized columnar metaplasia was higher than in gastric metaplasia, especially in crypt epithelium (P < 0.05). Multiple regression analysis revealed independent positive correlations for surface LI with dysplasia (P=0.011), distance from the incisors (P=0.041), and crypt LI (P=0.000). Crypt LI showed an independent positive correlation with the length of BE (P=0.033) and type of metaplasia (P=0.007). In conclusion, epithelial cell proliferative activity of BE correlates with several known risk factors for cancer. Proliferative activity is an attractive intermediate marker to evaluate the effects of interventional measures to decrease cancer risk in Barrett's esophagus.
Adenocarcinoma↗
Is Barrett's esophagus characterized by more pronounced acid reflux than severe esophagitis?
OBJECTIVE: Barrett's esophagus is related to gastroesophageal reflux disease (GERD). However, only a small fraction of patients with GERD develop Barrett's esophagus. We evaluated whether gastroesophageal acid reflux is more pronounced in Barrett's patients than in patients with moderate or severe endoscopic esophagitis. METHODS: Retrospective evaluation of results of esophageal manometry and 24 hour ambulatory pH monitoring performed between 1990 and 1996 at the Leiden University Medical Center in those patients who also underwent endoscopy < or = 3 months before pH-metry. Included were 51 patients with Barrett's esophagus, 30 patients with severe esophagitis, 45 patients with moderate esophagitis, and 24 healthy control subjects. RESULTS: Patients with Barrett's esophagus had significantly increased acid reflux time (p < 0.01-0.05) compared to patients with moderate, but not compared to patients with severe esophagitis. Distal esophageal body motility and LES pressure were significantly (p < 0.01-0.05) reduced in patients with Barrett's esophagus compared to patients with moderate esophagitis but not compared to those with severe esophagitis. CONCLUSION: Although acid reflux is increased in patients with Barrett's esophagus and esophageal motility is impaired, other factors apart from acid exposure and motility contribute to the development of Barrett's esophagus.
Analysis of Variance↗
A zinc finger domain gene in the lizard, Calotes versicolor, shows extensive homology with the mammalian ZFX and is expressed embryonically.
A 590-bp long zinc finger domain DNA fragment has been isolated by polymerase chain reaction from the lizard, Calotes versicolor, employing the primers used for amplifying the zinc finger domain of the human Y-chromosomal gene, ZFY. Cloned in pUC18, the fragment, called CvZfa, was sequenced and its expression during development was studied. At the nucleotide and amino acid level CvZfa shows respectively 83% and 90% identity with the human ZFY, but its extent of homology is greater with the ZFX of human (86% at nucleotide and 92% at amino acid level) and the ZFY-like genes of turtle and chick. Similarly its homology with the mouse Zfx and Zfa is much greater than that with Zfy-1 and Zfy-2. It appears that the mammalian ZFX (Zfx) evolved from reptilian ancestors with a considerable degree of conservation, but the ZFX to ZFY divergence within the class mammalia was more rapid. The CvZfa transcripts were seen in all the embryonic stages from which RNA was analysed. The whole mount in situ hybridization with the posteriorly placed mesonephros and the gonadal primordia of 10 to 25 day old embryos showed signal selectively in mesonephros of the 20 and 25 day embryos. There was no signal in the genital ridge. Thus CvZfa may not have a direct role in gonadogenesis of C. versicolor, but the possibility of its inductive role in the formation of adreno-gonadal axis through mesonephros cannot be discounted.
Amino Acid Sequence↗
CvSox-4, the lizard homologue of the human SOX4 gene, shows remarkable conservation among the amniotes.
SOX family genes share a high sequence similarity with the HMG box region of the human Y chromosomal gene, SRY. We have cloned and sequenced the HMG box motif of a Sox gene of the lizard, Calotes versicolor. A database search for the cloned sequence, CvSox-4, revealed 100% identity with the SOX4 gene of the human and its homologue in a bird. The result strongly suggests that SOX4 evolved prior to the diversification of amniotes and is highly conserved.
Amino Acid Sequence↗
Male-biased distribution of the human Y chromosomal genes SRY and ZFY in the lizard Calotes versicolor, which lacks sex chromosomes and temperature-dependent sex determination.
In the present investigation on the lizard Calotes versicolor, which lacks temperature-dependent sex determination, all the conventional cytological techniques used failed to resolve a distinguishable pair of sex chromosomes. However, probing of the genome with the human Y-linked genes SRY and ZFY showed sex-specific bias in their distribution. While the SRY probe hybridized to all the males, more than half of the females examined did not show any hybridization. ZFY hybridized to both the sexes, giving two bands; one was common to all the individuals of both sexes, but the other, of the lower molecular length, occurred in all the males but in less than 50% of females. This predominantly male-specific band is named AMF. The SRY-positive females were also positive for the AMF of ZFY. As positive as well as negative females were fertile and none of the males lacked SRY, it appears that SRY is essential for males only and that both the genes are syntenic in this species. This report raises interesting possibilities on the differentiation of the sex chromosomes in C. versicolor and evolution of SRY/ZFY on the Y chromosome of eutherian mammals through the ancestral group(s) that harbour sex-independent SRY- and ZFY-related genes.
Animals↗
Contribution of plasminogen activators and their inhibitors to the survival prognosis of patients with Dukes' stage B and C colorectal cancer.
Despite the advances in pre-, peri- and post-operative medical care of colorectal carcinoma patients, the prognosis has improved only marginally over recent decades. Thus, additional prognostic indicators would be of great clinical value to select patients for adjuvant therapy. In previous studies we found that colorectal carcinomas have a marked increase of the urokinase-type of plasminogen activator (u-PA), and the inhibitors PAI-1 and PAI-2, whereas the tissue-type plasminogen activator (t-PA) is found to be decreased in comparison with adjacent normal mucosa. In the present study we evaluated the prognostic value of several plasminogen activation parameters, determined in both normal and carcinomatous tissue from colorectal resection specimens, for overall survival of 136 Dukes' stage B and C colorectal cancer patients, in relation to major clinicopathological parameters. Uni- and multivariate analyses indicated that a high PAI-2 antigen level in carcinoma, a low t-PA activity and antigen level and a high u-PA/t-PA antigen ratio in adjacent normal mucosa are significantly associated with a poor overall survival. A high ratio of u-PA antigen in the carcinomas and t-PA antigen in normal mucosa, i.e. u-PA(C)/t-PA(N), was found to be predictive of a poor overall survival as well. All these parameters were found to be prognostically independent of the clinicopathological parameters. Multivariate analysis of combinations of these prognostically significant plasminogen activation parameters revealed that they are important independent prognostic indicators and have in fact a better prognostic value than their separate components. Based on these combined parameters, subgroups of patients with Dukes' stage B and C colorectal cancer could be identified as having either a high or a low risk regarding overall survival. In conclusion, these findings emphasize the relevance of the intestinal plasminogen activation system for survival prognosis of patients with colorectal cancer and, in the future, might constitute a patient selection criterion for adjuvant therapy.
Aged↗
Prognostic value of the plasminogen activation system in patients with gastric carcinoma.
BACKGROUND: Patients with gastric cancer have a poor prognosis and can be cured by surgery only if the cancer is detected in an early stage. Extended surgery, down staging with chemotherapy before operation, and new postoperative treatments are recent approaches to increase survival rates. Categorizing patients' prognoses as good or poor by pathophysiologic markers, however, may be of great help in selecting therapies for these patients. For example, plasminogen activation (PA) parameters, that play an important role in tumor invasion and metastasis, have prognostic value for several human malignancies. METHODS: We evaluated the relation between several PA parameters in tissue with standard clinicopathologic parameters and with the overall survival of 50 consecutive patients with gastric carcinoma. RESULTS: Univariate analysis showed that a low tissue-type plasminogen activator (t-PA) activity in normal mucosa and in carcinomas and a high antigen level of inhibitor type-1 (PAI-1), and, to a lesser extent, of urokinase-type plasminogen activator (u-PA) receptor, in carcinomas are associated with a poor overall survival of the patients. In contrast, of the 14 clinicopathological parameters only the number of eosinophils in the tumors was associated with survival. Multivariate analysis revealed that the t-PA and PAI-1 levels are independently associated with survival. CONCLUSIONS: Plasminogen activation parameters in both normal and carcinomatous tissue of the stomach of patients with gastric carcinoma are of particular clinical interest because of their prognostic impact on overall survival.
Aged↗
Tissue levels of matrix metalloproteinases MMP-2 and MMP-9 are related to the overall survival of patients with gastric carcinoma.
Proteinases are involved in tumour invasion and metastasis. Several matrix metalloproteinases (MMPs) have been shown to be increased in various human carcinomas. We assessed the levels of MMP-2 (gelatinase A) and MMP-9 (gelatinase B) in 50 gastric carcinomas and corresponding mucosa using quantitative gelatin zymography. Both MMP levels were significantly enhanced in gastric carcinomas compared with adjacent mucosal tissue, showed a relatively poor intercorrelation and no relation was found with histopathological carcinoma classifications according to Laurén, WHO and tumour-node-metastasis (TNM). Cox's multivariate proportional hazards analyses revealed that high carcinomatous MMP values are of prognostic significance for a poor overall survival of the patients, independent of the major clinicopathological parameters.
Aged↗
Flow cytometric determination of aminopeptidase activities in viable cells using fluorogenic rhodamine 110 substrates.
Aminopeptidases (AP) are ubiquitously occurring, nonspecific exopeptidases involved in protein degradation. They cleave the N-terminal amino acid of peptides and occur in practically all mammalian cells and tissues. Physiological and pathological processes such as metastasis of tumors and inflammation have been thought to involve changes in AP activities. Determination of AP (EC 3.4.11.X) activity in viable cells by flow cytometry was the subject of this study because of its general biological and clinical interest. Different bis-substituted rhodamine 110 (R110) peptide derivatives were synthesised and used as AP- and exopeptidase (EC 3.4.13.X-EC 3.4.14.X) substrates for flow cytometric measurements. Intracellular AP activities in viable lympho-, mono-, granulo-, and thrombocytes were detected by fluorescence increase from R110 following intracellular substrate cleavage. Eukaryotic-AP do not cleave D-amino acids and hence NH2(D-Leu)2R110 substrate served as negative control. Specific substrate cleavage by AP is shown by complete inhibition of flFLuorescence generation following preincubation of cells with leucine-chloromethylketone inhibitor. R110 AP- and exopeptidase substrates are suitable indicators for coupled endopeptidase reactions due to their rapid cleavage and largely pH independent generation of intracellular fluorescence.
Amino Acids↗
Glutathione S-transferase pi in colorectal tumors is predictive for overall survival.
Glutathione S-transferases (GSTs) are enzymes involved in the detoxification of xenobiotics and are divided into four subclasses, alpha, mu, pi, and theta, with different although overlapping substrate specificities. Most human gastrointestinal tumors contain increased amounts of GST-pi and GST enzyme activity. The relationship between GST parameters and tumor and patient characteristics, including overall survival, were studied retrospectively in 100 primary colorectal adenocarcinomas. Levels of GST-alpha, GST-mu, GST-pi, and GST enzyme activity were not related to the Dukes stage, differentiation grade, localization, histological type and diameter of the tumor, or gender and age of the patient. Fifty-seven patients died (median survival, 21 months; range, 1-65 months) during follow-up, and 43 patients were still alive at the closing date of the study (median follow-up, 68 months; range, 60-87 months). Optimal dichotomization and uni- and multivariate analyses were done with the Cox proportional hazard model. Multivariate analysis with all clinicopathological parameters revealed higher Dukes stage (hazard ratio, 2.7; P < 0.001) and older age (hazard ratio, 2.8; P = 0.001) to be the only independent prognostic variables for overall survival. In contrast to GST-alpha and GST-mu, high levels of GST-pi (hazard ratio, 3.1; P = 0.002) and GST enzyme activity (hazard ratio, 2.0; P = 0.020) in the tumors were found to have a significant prognostic value independent from the clinicopathological parameters when added separately to this Cox model. Thus, this study indicates that GST subclass levels in colorectal adenocarcinomas are not related to clinicopathological parameters and that the GST-pi level and GST enzyme activity have a prognostic value for the overall survival of the patients.
Adenocarcinoma↗
Plasminogen activators and inhibitor type 1 in neoplastic colonic tissue from patients with familial adenomatous polyposis.
The plasminogen activation cascade is involved in carcinogenesis, invasion and metastasis. In this study plasminogen activators and their type 1 inhibitor were evaluated in colonic tissue from 19 patients with familial adenomatous polyposis coli, an inherited disorder characterised by the presence of thousands of adenomatous polyps in the colorectum which predispose to colorectal cancer. The conversion of normal-appearing colonic mucosa to neoplastic tissue in these patients was associated with an increase in urokinase-type plasminogen activator and plasminogen activator inhibitor type 1, accompanied by a decreased level of tissue-type plasminogen activator. These observations are essentially similar to those found in solitary adenomas and carcinomas of the colon, and illustrate the uniform involvement of the plasminogen activation system in colorectal carcinogenesis.
Adenocarcinoma↗
Urokinase receptor and colorectal cancer survival.
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Colorectal Neoplasms↗
Prognostic relevance of plasminogen activators and their inhibitors in colorectal cancer.
Human colorectal carcinogenesis has been shown previously to be associated with impressive changes in the tissue levels of plasminogen activators and their inhibitors, exemplified by an increase in the urokinase-type plasminogen activator (u-PA) and the inhibitors PAI-1 and PAI-2, and a decrease in tissue-type plasminogen activator (t-PA). In the present study we evaluated the prognostic significance of these parameters to the overall survival of patients with colorectal cancer, in conjunction with several major clinicopathological parameters like age, gender, differentiation grade, and Dukes' stage. Univariate analyses revealed that a low t-PA antigen level, low t-PA activity, and high u-PA/t-PA antigen ratio in normal mucosa and a high u-PA and PAI-2 antigen level in carcinomas are prognostic for a poor overall survival of patients with colorectal cancer. The prognostic value of t-PA antigen and activity in normal mucosa, the antigen ratio of u-PA in carcinoma (C) and t-PA in corresponding normal (N) mucosa [u-PA(C)/t-PA(N) antigen ratio], and PAI-2 antigen in carcinomas was found to be independent from clinicopathological parameters by multivariate analyses. These observations illustrate the clinical importance of the plasminogen activation cascade at the tissue level in colorectal cancer invasion, metastasis, and survival.
Aged↗