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To evaluate the diagnostic values of using autoantibodies in sera to a panel of eight tumor-associated antigens (TAAs) of P53, Koc, P62, C-myc, IMP1, Survivn, P16 and Cyclin B1 full-length recombinant proteins for early detection of patients with gastric cardia adenocarcinoma (GCA) and high-risk subjects screening. Enzyme-linked immunosorbent assay was used to detect autoantibodies against the eight selected TAAs in 383 sera samples from four groups, including 140 subjects with normal gastric cardia epithelia (NOR), 76 patients with chronic atrophic gastritis (CAG), 79 patients with gastric cardia dysplasia (DYS) and 88 patients with GCA. In addition, the expression of the eight antigens was analyzed in gastric cardia tissues by immunohistochemical method. The individual autoantibodies to six TAAs (P53, P62, IMP1, Survivn P16 and Cyclin B1) were significantly higher in sera from patients with GCA than that in normal subjects (P0.05). When autoantibody assay successively accumulated to seven TAAs (P53, Koc, P62, C-myc, IMP1, Survivn and P16), a stepwise increased detection frequency of autoantibodies was found in the four sera groups (13% in NOR, 39% in CAG, 46% in DYS, and 64% in GCA, respectively), the risks to CAG, DYS and GCA steadily increased about 4.4-, 5.7- and 12.0-fold. The sensitivity and the specificity for autoantibodies against the seven TAAs in diagnosing GCA reached up to 64% and 87%, respectively. The area under the receiver operating characteristic curve for the seven anti-TAA autoantibodies was 0.73 (95%CI: 0.68-0.78) No more increase in sensitivity was found with the addition of new anti-TAA autoantibodies. A combination detection of autoantibodies to TAAs might be helpful to distinguish GCA patients from normal subjects and the patients with gastric cardia precancerous lesions. In addition, further studies in patients with GCA and precancerous lesions using enlarged TAA panels might improve the sensitivity and specificity of cancer detection and high-risk subjects screening.

The aim of this study was to explore the association of C20orf54 functional single nucleotide polymorphism (SNP) with the susceptibility to esophageal squamous cell carcinoma (ESCC) in a northern China population. The C20orf54 SNP was genotyped by direct sequencing in 240 cancer patients and 198 controls in northern China. The results showed that drinking status, family history of ESCC, and body mass index have great influence on the risk of developing ESCC. The overall genotype frequencies of C20orf54 in ESCC patients have a significant difference with healthy controls (χ(2) = 8.06, P = 0.018). By using C/C genotype as the reference, the C/T genotype showed a significantly decreased risk to the development of ESCC. Thus, compared with the C/C genotype, smokers, drinkers with C/T genotype significantly decreased the risk of developing ESCC. A positive family history of ESCC with C/T and T/T genotype both increased the risk of developing ESCC. Body mass index between 18.5 and 24 with C/T genotype significantly decreased the risk of developing ESCC. The present study suggests that the C20orf54 functional SNP might be associated with a risk of development in ESCC.

Background: Oesophageal squamous cell carcinoma (SCC) causes the highest number of cancer deaths in some regions of Northern China. Previously, we narrowed down a critical region at 9q33-34, identified to be associated with tumour-suppressive function of deleted in oesophageal cancer 1 (DEC1) in oesophageal SCC. Methods: We generated DEC1 antibody and constructed tissue microarrays (TMAs) utilising tissue specimens from Henan, a high-risk region for oesophageal SCC, to investigate the importance of DEC1 expression in this cancer. Results: Tissue microarray immunohistochemical staining reveals significant loss of DEC1 from hyperplasia, to tumour, and to lymph node metastasis. In addition, the loss of DEC1 in tumour is age-dependent. Interestingly, there is significant abrogation of DEC1 expression in patients with a family history of oesophageal SCC. Deleted in oesophageal cancer 1 localises to both the cytoplasm and nucleus. The vesicular pattern of DEC1 in the cytoplasm appears to localise at the Golgi and Golgi-endoplasmic reticulum intermediate compartment. Conclusion: This is the first TMA study to suggest a clinical association of DEC1 in lymph node metastatic oesophageal SCC, early onset oesophageal SCC and familial oesophageal SCC development. Subcellular localisation of DEC1 and its expression in oesophageal SCC tissues provide important insight for further deciphering the molecular mechanism of DEC1 in oesophageal SCC development. © 2011 Cancer Research UK All rights reserved., published_or_final_version

Changes in cell proliferation and cell death might be key factors in regulating the rate of neoplasm progression and tumor growth. The extent of apoptosis and its possible relationship with cell proliferation at different stages of esophageal carcinogenesis, however, have not been characterized. In this study, 241 esophageal biopsy samples from symptom-free subjects and 38 surgically resected esophageal carcinoma tissues from a high-risk population for esophageal cancer in Henan, China, were used to analyze the changes of apoptosis and its relationship with cell proliferation as determined by proliferating cell nuclear antigen (PCNA). The apoptotic cells, identified morphologically, were located in the same proliferative compartment of hyperproliferative cell population in the esophageal epithelium. The apoptotic indices (total number of apoptotic cells and apoptotic bodies per mm2 of the tissue section) were low in the normal epithelia, and increased significantly as the lesions progressed from basal cell hyperplasia (BCH) to dysplasia (DYS) and to squamous cell carcinoma (SCC). The extent of apoptosis correlated well with the cell proliferation indices. The present findings indicate that apoptosis occurs in the early stage of esophageal carcinogenesis, and as the lesions progress, both the apoptotic index and PCNA labelled index increase, suggesting that hyperproliferative cells might be more susceptible to apoptosis.

The objective of this study was to evaluate the reproducibility of the biopsy sampling procedure in research on esophageal lesions. Biopsies were taken from the middle and lower thirds of the esophagus, one from each site, from 25 subjects in a high-incidence area for esophageal cancer in Xinye County of Henan Province, China. The biopsy sampling procedure was repeated on the same subjects 10 days later. When the biopsies were analyzed together and those with worse pathologies were used for diagnosis, 52% of the subjects had the same grade of lesions in the second biopsy examination, 32% had lower-grade lesions, and 16% had higher-grade lesions.

Multifocal occurrence of precancerous lesions of the esophagus has been observed among individuals in a high incidence area for esophageal carcinoma in Henan Province, China. Results from recent studies suggest that p53 protein accumulation and mutation occur early in the pathogenesis of esophageal carcinoma. Discordant p53 gene mutations have been observed in invasive carcinoma and preinvasive lesions from a patient with esophageal carcinoma. The p53 alterations in the multifocal precancerous lesions from symptom-free subjects, however, have not been investigated.Two biopsy samples, one each from the middle-third and the lower-third of the esophagus, from each subject, were taken from 55 symptom-free subjects in a high incidence area for esophageal cancer in Huixian, Henan Province, China. p53 protein accumulation and p53 gene mutation were analyzed in the multifocal esophageal precancerous lesions from these subjects.Histopathologic examination showed that among the 110 biopsies, 20 had dysplasia, 72 had basal cell hyperplasia, and 18 had normal epithelia. Concurrent lesions at the middle- and lower-third biopsy occurred in 2 subjects with dysplasia (2 of 55 subjects, 4%) and 26 subjects with basal cell hyperplasia (26 of 55 subjects, 47%). Analysis by immunohistochemistry showed high concurrent rates of p53 protein accumulation (51 of 55 subjects, 93%). p53 sequence analysis of 32 samples from 16 subjects identified missense mutations in 5. In one subject, there were three different mutations in the middle-third biopsy (codon 161, GCC--GAC) and the lower-third biopsy (codon 159, GCC--CCC). A single mutation was detected in the other four subjects in either the middle- or lower-third biopsy.The present findings indicate that p53 protein accumulation and mutations occur in the early stages of human esophageal carcinogenesis. Independent somatic mutations of the p53 tumor suppressor gene and protein accumulation in different regions of the esophageal "field" might be key molecular events in multifocal esophageal carcinogenesis.

The level of p53 protein was determined immunohistochemically in normal tissues and tissues with different severities of lesions (basal cell hyperplasia, dysplasia, carcinoma in situ, and carcinoma) from surgically resected human esophagi and esophageal biopsies of symptom-free subjects. The samples were from an area with high esophageal cancer incidence in northern China (Linxian and Huixian in the Henan province). Tissue sections were incubated with p53 antibodies for immunostaining. Conventional hematoxylin and eosin stain was also used. In surgically resected esophageal specimens, elevated p53 protein levels were found in the cell nuclei in tissues with precancerous and cancerous lesions. From basal cell hyperplasia to dysplasia to carcinoma in situ, the p53 immunostain-positive cells increased in number, and their distribution had roughly the same pattern as that of the proliferating cells. However, positive stain was not observed in the dividing basal cells of the normal epithelium of the surgically resected tissues. A similar pattern of immunostaining was observed in the abnormal tissues of the biopsy samples from the symptom-free subjects. An intriguing observation is that some p53 immunostain-positive cells were observed in 3 of 6 cases of histologically normal epithelia of biopsy samples. Only the papillary immunostaining pattern was observed in these three "normal" cases. Although the molecular basis for such positive stain remains to be investigated, it is possible that p53 protein accumulation occurs early in the pathogenesis of esophageal cancer and that p53 mutation is closely associated with the initiation of this cancer. The accumulation of p53 protein may be a promising early biomarker for identifying high-risk subjects for esophageal cancer.

To determine whether dietary calcium supplementation affects esophageal precancerous lesions, 200 subjects with esophageal lesions in a high-risk area for esophageal cancer in China (Huixian, Henan) were randomly divided into 2 groups (100 subjects/group). Subjects in one group received an oral supplementation of calcium carbonate tablets (1200 mg of calcium daily), and subjects in the other group received placebo pills for 11 months. At the entry and the end of the trial, esophagoscopy was performed, and 2 or 3 biopsy specimens were taken from the middle and lower thirds of the esophagus and from macroscopic lesions, if any, of each subject for histopathology and cell proliferation analysis with deoxythymidine labeling. In comparison to normal epithelium, increased proliferative compartment size was observed in epithelia with hyperplasia or dysplasia. After the intervention, the percentage of individuals with "normal epithelium," "basal cell hyperplasia," "basal cell hyperplasia II," and "basal cell hyperplasia III and dysplasia" were 44, 31, 13, and 11% in the calcium group and 35, 39, 17, and 6% in the placebo group, respectively. The labeling index was 0.046 in the calcium group and 0.044 in the placebo group. After the intervention, the labeling index in basal cell layers 1 to 5, the major zone of cell proliferation, fell 38% in the calcium group and 44% in the placebo group from before the intervention. Therefore, in this study, calcium supplementation was not shown to have beneficial effects in alleviating precancerous lesions and abnormal cell proliferation patterns.

This paper reports the prevalence of chronic esophagitis and nutritional status among 538 persons 15-26 years old in the high-risk area of esophageal cancer. 166 subjects were from households with history of esophageal cancer while 372 from households without. The frequency of chronic esophagitis among male and female adolescents in the high risk areas (37.6% and 36%) was significantly, higher than that in the low risk areas. Furthermore, the frequency of chronic esophagitis in the adolescents in households with history of esophageal cancer was also higher than that without history of this cancer. There was a positive correlation between avitaminosis C and chronic esophagitis. Suffering from avitaminosis C and B2, these people are prone to develop chronic esophagitis which, in turn, may serve as an early phase in the carcinogenesis of esophageal epithelium.

Effect of secretin on gastric motility was studied on the preparation of isolated vascular perfused rat stomach. The results showed: (1) Secretin markedly inhibited spontaneous as well as pentagastrin stimulated antral motility. (2) Antisecretin serum completely abolished the inhibitory effect of secretin on antral motility. (3) Antisomatostatin serum and indomethacin blocked the inhibitory effect on antral motility induced by secretin. The results indicated that the inhibitory effect of secretin might be produced through direct action of secretin on secretin receptors and mediated partially by the local somatostatin and prostaglandin in gastric antrum.

A randomized double blind intervention trial was carried out in Huixian County Henan Province, a high risk area for esophageal cancer, to observe the effect of oral calcium supplementation on esophageal precancerous lesions. Two hundred and fourteen cases with basal cell hyperplasia and 40 with dysplasia of the esophagus aged 25-75 randomly received daily oral supplementation of 600 mg calcium or placebo for 7 months. In the calcium supplementation group, the basal cell hyperplasia and dysplasia of the esophagus were significantly improved and the profile of esophageal epithelial proliferation cells labeled with 3H-TdR approached that of the normal subjects in low risk area for esophageal cancer. The results indicate that calcium supplementation can inhibit basal cell hyperplasia and dysplasia of the esophageal epithelium in high risk area for esophageal cancer. The mechanism of interruption of esophageal precancerous lesions by calcium is discussed.

Effects of secretin and somatostatin on acid secretion and its relation to prostaglandin E, I2 release in the totally isolated vascularly perfused rat stomach were studied. The results showed: (1) Secretin and somatostatin both markedly inhibited acid secretion stimulated by pentagastrin. Indomethacin could reverse the inhibitory effects of acid secretion by secretin and somatostatin. (2) Secretin increased PGE and PGI2 metabolite 6-Keto-PGF1 alpha release significantly. Somatostatin only increased PGE release. Indomethacin could block stimulatory affects of secretin on PGE, 6-Keto-PGF1 alpha release and somatostatin on PGE release. These results indicated that: (1) inhibition of acid secretion by secretin was mediated by PGI2 and PGE release; (2) inhibition of acid secretion by somatostatin was mediated only by PGE release.