Expression of p53 protein in colorectal cancer and its relationship to cell proliferative activity and prognosis

The expression of p53 protein in 66 cases of colorectal cancer and its relationship to cell proliferative activity, lymph node metastasis as well as prognosis were investigated by means of AB-PAP immunohistochemical technique. The results showed that 62.1% of colorectal cancer was positive. The cell proliferative activity and the frequency of lymph node metastasis in p53-positive cases were significantly higher than those of p53-negative cases (P < 0.05). The survival rate in patients with p53-positive tumors was significantly shorter than those with p53-negative tumors (P < 0.05). Our results suggest that the abnormal expression of p53 and cell proliferation associated with mutations are involved in both human carcinogenesis and lymph node metastasis of colorectal cancer. Examination of p53 expression is of value in understanding the degree of malignancy, and evaluating prognosis of the disease.     

Low levels of hydrogen peroxide and L-histidine induce DNA double-strand breakage and apoptosis

The results presented in this study demonstrate that L-histidine triggers a lethal response in U937 cells exposed to nontoxic, albeit growth-inhibitory, levels of H2O2. Treatment for 1 h with the cocktail H2O2/L-histidine promotes the formation of a low level of DNA double-strand breaks that are rapidly rejoined, and this process is followed by secondary DNA fragmentation at about 7 h of post-treatment incubation, at which time cells are still viable. The appearance of oligonucleosomal DNA fragments associated with the detection of morphological changes typical of apoptosis strongly suggests that a portion of the cells was undergoing an apoptotic process. The relative level of cells with fragmented chromatin never exceeded 15-20% throughout the 20 h post-treatment incubation. Treatment with high concentrations of H2O2 in the presence of L-histidine was found to trigger necrotic cell death. The results presented in this paper provide further experimental evidence in support of the notion that DNA double-strand breaks mediate the lethal effects of the cocktail H2O2/L-histidine and suggest that this type of DNA lesion can promote both apoptotic and necrotic cell death, depending on the concentration of the oxidant.     

Prognostic significance of proliferative activity, DNA-ploidy, p53 and Ki-ras point mutations in colorectal liver metastases

Paired colorectal liver metastases (CLM) and normal tissue samples from a consecutive series of 36 patients were studied prospectively. MIB-1 expression was studied by immunohistochemistry on paraffin-embedded sections. DNA ploidy and S-phase fraction (SPF) measurements were performed by flow cytometry on frozen tissues. Mutations within the p53 (exons 5-8) and c-Ki-ras (codons 12 and 13) genes were detected by PCR single-strand conformation polymorphism analysis followed by sequencing. A high correlation was observed between the MIB-1 LI and SPF value (rho=0.81; P<0.01). Moreover, p53 gene mutations were associated with either high MIB-1 LI and high SPF. In univariate analysis, SPF and MIB-1 levels were related to risk of death. The association between overall survival and DNA-ploidy or p53 mutations did not reach statistical significance, but a slightly better survival was observed for patients either with DNA-diploid tumours or without mutations (P=0.05 and P=0.06, respectively). SPF was shown by multivariate Cox model analysis to be an independent prognostic variable and thus it might be a useful prognostic factor in patients with CLM.     

Expression of insulin-like growth factor-2 can predict the prognosis of human colorectal cancer patients: correlation with tumor progression, proliferative activity and survival

Exercise following exercise-induced dehydration (EID) has been shown to elevate concentrations of plasma norepinephrine (NE) and hypothalamic-pituitary-adrenal axis hormones. However, it is not known how intravenous (i.v.) rehydration (Rh) with isotonic (ISO) or hypotonic (HYPO) saline affects these hormone concentrations. It was hypothesized that HYPO, versus ISO, would lead to lower plasma NE and cortisol concentrations ([CORT]) during subsequent exercise following EID due to a decrease in plasma sodium concentration [Na+]. Eight non-heat acclimated men completed three experimental treatments (counterbalanced design) immediately following EID (33 degrees C) to -4% body mass loss. The Rh treatments were i.v. 0.9% NaCl (ISO, 25 ml x kg[-1]), i.v. 0.45% NaCl (HYPO, 25 ml x kg[-1]), and no fluid (NF). After Rh and rest (2 h total), the subjects walked at 53-54 percent of maximal O2 uptake for 45 min at 36 degrees C. After Rh, the following observations were made before/during exercise: percentage change in plasma volume (PV) was lower in NF compared to ISO and HYPO but similar between ISO and HYPO; delta[Na+] was similar between ISO and NF and higher in ISO compared to HYPO; delta plasma NE was higher in NF compared to ISO and HYPO, but similar between ISO and HYPO; delta plasma [CORT] was higher in NF compared to ISO and HYPO and higher in ISO compared to HYPO; rectal temperature was higher in NF compared to ISO and HYPO. These data would suggest that sympathetic nervous activity and [CORT] during exercise, subsequent to EID and Rh, was affected by lower PV (probably through cardiopulmonary baroreflexes) as well as core temperature. Furthermore, [CORT] was affected by delta[Na+] after Rh through an unknown mechanism.     

Frequency and type of colorectal tumors in asymptomatic high-risk individuals in families with hereditary nonpolyposis colorectal cancer

In hereditary nonpolyposis colorectal cancer (HNPCC, or Lynch syndrome) a close surveillance is usually proposed to high-risk family members with the ultimate goal of reducing cancer incidence and mortality. Through a specialized registry, between 1984 and 1996, we identified 31 families with clinical features of HNPCC. A total of 390 first-degree relatives of affected patients were considered at high risk for colorectal cancer. The main purposes of this study were: (a) to assess overall compliance; and (b) to evaluate the frequency and morphological features of tumors detected at endoscopy. Two hundred twenty-three subjects could be directly interviewed and colonoscopy strongly recommended. Each of the 86 individuals who underwent colonoscopy was matched to a control of the same age (+/-3 years) and sex (control subjects were seeking endoscopy for constipation, rectal bleeding or abdominal discomfort). Of the 390 individuals traced as "at risk," 223 (57.2%) could be contacted, and, of these, 86 (38.6%, or 22.0% of the total) underwent colonoscopy. One or more colorectal lesions were found in 35 of 86 (40.7%) HNPCC asymptomatic family members and in 15 (17.4%; P < 0.001) controls. In the former group, 29 adenomas were detected in 20 individuals as opposed to 11 adenomas in 9 subjects among controls (P < 0.03). Moreover, adenomas in family members were significantly larger [9.1 +/- 5.9 mm (mean +/- SD) versus 5.8 +/- 3.7 mm; P < 0.02] and more frequently showed a tubulovillous histological type and a high degree of dysplasia. Five colorectal carcinomas (in four patients) were detected among cases (four of which were located between the cecum and the hepatic flexure); only one was detected among controls. Surveillance of high-risk subjects in HNPCC families can be carried out only in a fraction of them, because the majority cannot be reached or refuse to collaborate. On the other hand, the frequency of newly detected lesions among family members and the possible aggressive behavior of the lesions render pancolonoscopy necessary at regular intervals of time.     

Association between high levels of ornithine decarboxylase activity and favorable prognosis in human colorectal carcinoma

Several studies have documented increased expression of ornithine decarboxylase (ODC) in neoplastic colorectal tissue versus normal-appearing colonic mucosa. The present study was undertaken to determine whether there is an association between the degree of overexpression of ODC in colorectal carcinomas and survival in a series of 74 patients. A high level of tumor ODC expression was found to be significantly associated with greater survival in our patient series. Patients with tumor ODC activities greater than the median and especially in the highest quartile experienced a more favorable outcome than those patients with ODC values below the median or in the lowest quartile (P = 0.03 and 0.02, respectively). The presence of a GTP-activatable isoform of ODC was also significantly associated with a favorable prognosis but only in tumors of the right colon (P = 0.01). There was no association found between ODC activity and tumor grade, tumor size, or patient age, sex, or race. Our results demonstrate that high levels of ODC expression (and presence of a GTP-activatable isoform for right-sided colon tumors) predict a favorable prognosis in human colorectal carcinoma. Knowledge of a patient's ODC status at the time of surgery may be useful in decisions regarding adjuvant therapy. Understanding the mechanism(s) involved should lead to new therapeutic approaches for advanced colorectal carcinoma.     

Telomerase and proliferative activity in placenta from women with and without fetal growth restriction

-Natriuretic peptides suppress adrenergic neurotransmission by a mechanism sensitive to pertussis toxin, suggesting that GTP-binding proteins are involved in the response. The major GTP-binding proteins present in the pheochromocytoma (PC12) cells used in this report are Goalpha and Gialpha2. We tested the hypothesis that the more abundant GTP-binding protein, Goalpha, mediates natriuretic peptide effects in PC12 cells by selectively ablating Goalpha from the cells with antisense oligodeoxynucleotides. The results indicate that a selective ablation of Goalpha with this technique eliminated C-type natriuretic peptide (CNP) effects and suppressed dopamine efflux evoked by a depolarizing stimulus. However, the activation of guanylyl cyclase (GC) by CNP was sustained after the Goalpha ablation. Further, Nomega-nitro-L-arginine methyl ester suppressed evoked dopamine efflux equally in the presence and absence of Goalpha. These results suggest that CNP attenuates evoked catecholamine efflux from PC12 cells by a mechanism requiring Goalpha but independent of GC activation.     

Sucrase-isomaltase and other brush border glycosidases in colorectal tumors

CD28 ligation delivers a costimulatory signal important in T cell activation. This study demonstrates that the disruption of the CD28/B7 pathway early in the nonobese diabetic mouse strain, using CD28-/- and CTLA41g transgenic mice, promoted the development and progression of spontaneous autoimmune diabetes. Functional analyses of T cells isolated from CD28-deficient mice demonstrated that the GAD-specific T cells produced enhanced Th1-type cytokines (IL-2 and IFN gamma) and diminished Th2-type cytokine, IL-4. Moreover, there was a significant decrease in serum levels of anti-GAD antibodies of the IgG1 isotype consistent with a profound suppression of Th2-type responses in these animals. Thus, the early differentiation of naive diabetogenic T cells into the Th2 subset is dependent upon CD28 signaling and extends our understanding of the importance of Th1/Th2 balance in the regulation of this spontaneous autoimmune disease.     

Starch intake and colorectal cancer risk: an international comparison

Intakes of starch, non-starch polysaccharides (NSPs), protein and fat have been compared with colorectal cancer incidence in 12 populations worldwide. There were strong inverse associations between starch consumption and large bowel cancer incidence (large bowel r = -0.70, colon r = -0.76). There was no significant relation with NSPs, although the association with large bowel cancer incidence was still significant when NSP was combined with resistant starch (RS) to give an estimate of fermentable carbohydrate (large bowel r = -0.52, colon r = -0.60). The relationships between starch, RS and NSPs and cancer incidence remained statistically significant after adjusting for fat and protein intakes. The strong inverse associations found here suggest a potentially important role for starch in protection against colorectal cancer and correspond with the hypothesis that fermentation in the colon is the mechanism for preventing colorectal cancer. Measures of both starch and NSPs need to be included in future epidemiological studies of diet and bowel cancer.     

Increased proliferative activity of osteoblasts in congenital hemifacial hypertrophy

Congenital hemifacial hypertrophy is expressed in facial asymmetry resulting from unilateral overgrowth. We examined proliferative activity of primary cultured osteoblasts taken from the hemifacial hypertrophic side of an 18-year-old woman compared with the normal side. Both fetal calf serum and basic fibroblast growth factor stimulated osteoblast DNA synthesis, and cultured osteoblast proliferation was markedly increased in the hypertrophic side. Neutralizing antibody against basic fibroblast growth factor was effective to partially block fetal calf serum-induced DNA synthesis. These results suggest that fibroblast growth factor and its receptor signal transduction axis may be selectively involved in affected osteoblasts, leading to progression of congenital hemifacial hypertrophy.     

Prognostic significance of proliferative activity and ploidy in node-negative breast cancers

Cardiac disease continues to be the leading cause of morbidity and mortality following peripheral vascular surgical procedures. Although the mechanism of sudden myocardial infarction remains elusive, many possibilities exist. The role of catecholamines is intriguing in view of the evidence that beta-adrenergic blockers reduce cardiac morbidity and mortality in vascular surgical patients. To ascertain whether the plasma catecholamine levels rise significantly during abdominal aortic aneurysm repair, serial determinations of plasma epinephrine and norepinephrine levels were performed in 18 patients. Epinephrine levels rose significantly from preoperative baseline values both during the operation and postoperatively, and norepinephrine levels rose significantly at 24 hours postoperatively. Although only one patient studied developed a myocardial infarction, the finding that patients undergoing aortic surgery uniformly experienced abnormally high serum catecholamine levels supports other evidence that perioperative myocardial ischemic events have a hormonal component.     

Expression of p53 protein and proliferative activity in multiform glioblastoma

The aim of the study of 41 multiform glioblastomas was the analysis of p53-protein immunoreactivity in neoplastic cells and evaluation of relationship of this biologic marker to tumour proliferation activity. Positive p53 expression was observed in 24 (58.5%) tumours, the negative one in 17 tumours (41.5%). Proliferation indexes of PCNA, anti-Ki6 and AgNORs showed high values in the multiform glioblastoma p53 positive group, but without statistical differences in comparison with the group of p53-negative glioblastomas. Significant differences were observed in survival time of patients with p53 positive tumours in comparison with p53-negative ones. In 15 patients with p53-positive multiform glioblastomas survival time was less than 6 months (62.5%) on the contrary with only 4 patients with similar survival time in p53-negative glioblastoma group (23.5%). Our results suggest that p53 expression in multiform glioblastoma cells, generally considered as the indirect index of p53 suppressor gene, reflects aggressive stadium of neoplastic disease and significantly worsens the prognosis.     

Telomerase activity in benign proliferative breast disease and breast cancer

The application of telomerase activity is expected to serve as a reliable indicator of biological malignancy in breast tumors. We performed a study to quantify telomerase activity, the results of which revealed that this activity tends to be unexpectedly low in scirrhous carcinoma having low histological differentiation. It is therefore felt that additional studies at the tissue level using in situ hybridization will be required in the future. Although we think that atypical cystic duct is a true pre-cancerous lesion in the sense of having a high possibility of progressing into breast cancer, it will be interesting to determine whether or not the tissue is composed of cells having telomerase activity.     

Intra-abdominal lymphangiomas in children and adults. Assessment of proliferative activity

OBJECTIVE: Intra-abdominal lymphangiomas are rare in children and even more exceptional in adults. Because these lesions occasionally progressively enlarge, we analyzed seven adult and four pediatric cases for evidence of proliferative activity. DESIGN: Immunohistochemical analysis was performed retrospectively on representative tissue sections using antibodies to the following antigens: Ki-67, proliferating cell nuclear antigen, and p53 gene product (eight cases). DNA ploidy was examined in five cases. PATIENTS: The study group consisted of seven adult women (aged 24 to 73 years), a 3.5-year-old girl, and two boys, aged 3.5 and 9 years, the last with a recurrence at age 15. The lymphangiomas ranged from 1.7 to 23 cm in maximum size. RESULTS: Ranges of percentages of cells staining for proliferating cell nuclear antigen, Ki-67, and p53 were similar between the pediatric and adult cases. Antibody to Ki-67 stained from 0.5% to 17% of the stromal and endothelial components of the lymphangiomas. Proliferating cell nuclear antigen activity was noted in 16% to 52% of lesional cells. Reactivity was noted almost exclusively in areas of inflammation and fibroplasia. For comparison, 10% to 50% of intermixed lymphocytes stained for Ki-67 and proliferating cell nuclear antigen. There was no labeling with p53. DNA content was uniformly diploid. CONCLUSIONS: The scant staining for Ki-67 in the majority of the lesions, combined with proliferative rates that were only focally elevated, suggests that lymphangiomas in children and adults are quiescent lesions whose enlargement is due to engorgement by chyle and localized secondary inflammation rather than primary tumoral growth.     

Increase of serum complement levels in cancer patients with progressing tumors

Complement levels (CH50, C3, C4 and C1q) were determined in sera of 90 healthy subjects and 200 cancer patients. Complement levels of cancer patients were significantly higher than those of the healthy subjects, but there was a stage-linked increase of complement levels. Patients in remission had nearly normal complement levels, but patients with local tumor had increased complement levels, and a further increase was observed in patients with distant metastases. Treatment of these patients with radiotherapy or cytostatic drugs lowered the complement levels. At the terminal phase of the disease we also noted a drop in complement levels.     

Dietary sources and background levels of hippuric acid in urine: comparison of Philippine and Japanese levels

Levels of sodium benzoate in processed food from the Philippines and Japan were analyzed by high performance liquid chromatography. Results showed that of the 44 samples from the Philippines, 31 (70%) contained the compound. The samples with sodium benzoate included 19 juice, 6 softdrink and 6 soy sauce varieties. As for the Japanese products, only 8 (26%) out of 31 food items tested positive for sodium benzoate. The values of the compound in the Philippine samples ranged from 20 micrograms/ml to more than 2,000 micrograms/ml; the Japanese products showed a range of 50 to 200 micrograms/ml. Background urinary hippuric acid levels in 43 male Filipinos and 34 male Japanese with no occupational exposure to toluene were also measured using a high performance liquid chromatograph. Hippuric acid levels expressed as geometric means (SD) were 0.11 g/g creatinine (0.41) for the Filipino subjects and 0.09 g/g creatinine (0.39) for the Japanese subjects. No statistically significant difference in hippuric acid values in the 2 groups was noted. Possible explanations for the lack of any difference in background urinary hippuric acid levels between Filipino and Japanese subjects were discussed.     

Stent recoil: comparison of the Wiktor-GX coil and the Palmaz-Schatz tubular coronary stent

Wiktor-GX coil stents and Palmaz-Schatz 154A tubular stents were implanted in a consecutive series of 40 patients and 45 arteries undergoing successful primary stent placement in de novo lesions treated with single stents in order to compare the acute recoil of a coil stent to a tubular stent in native coronary arteries. Acute stent recoil was determined by measuring the difference between the maximum inflated diameter of the stent deployment balloon and the minimum lumen diameter after stent deployment. There was no difference between the two groups for reference vessel diameter, nominal balloon diameter, maximum inflated balloon diameter, maximum inflation pressure, or poststent vessel minimum lumen diameter. Acute recoil averaged 0.15 +/- 0.2 mm for the Wiktor-GX and 0.13 +/- 0.1 for the Palmaz-Schatz (P = 0.58). In this series of patients, there was no significant difference between the acute recoil of the coil stent compared to the tubular stent.