bcl-2 and p53 oncoprotein expression during colorectal tumorigenesis

AMS is a preventable disease about which travellers are frequently uninformed and one which physicians may wrongfully assume is limited to the population of ultra high altitude adventurers. These studies on incidence, while not without flaws, point out the frequency of AMS, as well as its significant incidence at moderate and commonly frequented altitudes. The current literature does not fully answer questions about incidence at moderate altitudes, nor about the full effects of altitude on children. Certainly AMS is not a rare complication of travel to altitudes and may indeed be under-recognized and under-treated. Both acetazolamide and dexamethasone provide adequate prophylaxis, and the choice of medications can be to some extent based on experience and patient profile. The best prophylaxis is a slow stepwise ascent, and the best treatment descent. The availability of medications for the amelioration or prevention of symptoms, and succinct advice on prevention by travel planning will make many of our patients' holidays more enjoyable and business trips more productive.     

DNA ploidy and expression of p53 and C-erbB-2 in extramammary Paget''s disease of the vulva

We report a case of total pulse alternans in a patient with paroxysmal ectopic atrial tachycardia and echocardiographic findings obtained before and after radiofrequency catheter ablation (RFCA) that terminated the arrhythmia. The patient was a 27-year-old man with history of paroxysmal palpitations with worsening episodic dizziness, chest tightness, and dyspnea. Electrocardiography (ECG) showed atrial tachycardia at 160 to 170 beats/min while the simultaneous pulse was in the 80s beats/min. Echocardiogram showed that aortic and mitral valves opened with alternating excursions and outflow velocities. Furthermore, despite similar ventricular wall thickening during systole of consecutive cardiac cycles, there was alternating mitral valve opening during diastole of the same cycles, providing direct evidence that ineffective diastolic filling and mitral valve opening may play a role in the pathogenesis of pulse alternans. Repeat ECG and echocardiography after the successful RFCA showed normal sinus rhythm and normal opening excursion and the velocity across the aortic and mitral valves.     

Mineralocorticoid receptors regulate bcl-2 and p53 mRNA expression in hippocampus

The present study addressed the hypothesis that the neuronal mineralocorticoid receptor (MR) regulates genes associated with cell death, such as bax and p53, and cell viability, including bcl-2, BDNF, and NT-3. Rats were pretreated with either oil vehicle or the MR antagonist spironolactone (SPIRO) and subsequently injected with saline or kainic acid (KA). MR blockade significantly decreased basal mRNA expression of bcl-2 in CA1 of saline-treated animals and attenuated KA-induced increases in p53 mRNA levels in CA3. SPIRO pretreatment had no significant effect on expression of bax, NT-3, or BDNF mRNAs. The data suggest that the neuronal MR contributes to regulation of select cell survival and cell death-related genes in hippocampal pyramidal neurons.     

bcl-2 and p53 expression in resectable pancreatic adenocarcinomas: association with clinical outcome

The bcl-2 proto-oncogene and the p53 tumor suppressor gene are important determinants of tumor cell susceptibility to apoptosis. bcl-2 and mutant p53 proteins inhibit apoptosis in vitro and can provide prognostic information in certain tumor types. We analyzed bcl-2 and p53 expression in archival pancreatic (n = 35) and ampullary (n = 6) adenocarcinomas, resected for cure, and their relationship to overall survival. Patients were treated with 5-fluorouracil and irradiation either pre- (n = 21) or postoperatively (n = 15); 5 patients received surgery alone. Using specific monoclonal antibodies, cytoplasmic bcl-2 and nuclear p53 proteins were detected in 22 of 40 (55%) and 20 of 37 (54%) tumors, respectively. No relationship was found between bcl-2 and p53 expression. Neither bcl-2 nor p53 correlated with histological response to preoperative chemoradiation. Lymph node involvement predicted poor overall survival (P = 0.02). A trend toward improved survival was seen in well-differentiated (P = 0.08) tumors and in those with increased bcl-2 expression (P = 0.06). p53 expression was not related to clinical outcome. In a multivariate analysis, nodal status was the single most important predictor of overall survival. Of note, the combined variable of bcl-2 expression and histological grade was a stronger prognostic variable than nodal status alone. Unlike nodal status, these features can potentially be evaluated in preoperative biopsy specimens.     

p53 alterations are associated with improved prognosis in distal colonic carcinomas

Alterations of the p53 gene and the p53 protein are common in a wide spectrum of human malignancies. In several tumor types, p53 gene mutation and/or p53 protein overexpression correlate with a more clinically aggressive phenotype as judged by worse patient survival. This has not been clearly demonstrated to be the case in colorectal cancer. Herein, we report results of the prognostic significance of p53 protein accumulation and gene mutation in a large series of colorectal cancers (n = 541) with long patient follow-up (mean, 87 months). The large majority of patients (95%) received no postoperative systemic adjuvant therapy. The incidence of p53 accumulation detected by immunohistochemistry with the monoclonal antibody DO-7 was 30%, whereas the incidence of p53 gene mutation in exons 5-8 detected using PCR-single strand conformation polymorphism was 36%. Accumulation of p53 protein was associated with improved patient survival independent of tumor stage or grade (hazard ratio, 0.66; 95% confidence interval, 0.47-0.93; P = 0.017). A marked difference was observed depending on the location of the tumor: tumors originating in the distal colon showed a strong association between the presence of p53 accumulation and improved patient survival (P = 0.003), but this was not the case for those located in the proximal colon. Dukes' stage C tumors, but not stage B, also showed an association between p53 accumulation and better outcome (P = 0.013). Mutation of the p53 gene was associated with a trend toward improved survival, particularly in the distal tumors. Our results demonstrate that in some tumor types, the presence of p53 abnormalities can correlate with better prognosis.     

Fas-mediated apoptosis with normal expression of bcl-2 and p53 in lymphocytes from aplastic anaemia

The p53 tumor suppressor gene is critical in regulating cell proliferation following DNA damage, and disruption of p53 protein function by mutation has been implicated as a factor responsible for resistance of tumor cells to chemotherapeutic agents. Our studies were initiated by asking whether the translational product of the p53 gene is associated with cisplatin resistance in the 2780CP human ovarian tumor model. We have demonstrated by single-strand conformation polymorphism analysis and sequencing that p53 in parental cisplatin-sensitive A2780 cells was wild type. In 2780CP cells, however, a mutation was found in exon 5 at codon 172 (Val to Phe). Interestingly, exposure to X-rays resulted in p53 induction in both A2780 and 2780CP tumor models. The p53 increases by the ionizing radiation were accompanied by concomitant increases in levels of the p53-regulated p21Waf1/Cip1 protein and led to arrest of cells in G1 phase of the cell cycle. A yeast functional assay confirmed that p53 in A2780 was wild type, but, more importantly, it provided evidence that the p53 mutation in 2780CP cells was temperature sensitive and heterozygous. These experiments demonstrate that sensitive and resistant cells have normal p53 functions, despite the presence of p53 mutation in the 2780CP model. In parallel investigations using the Western technique, exposure of A2780 cells to clinically relevant concentrations of cisplatin (1-20 microM) resulted in time- and dose-dependent increases in p53, together with coordinate increases in p21Waf1/Cip1. In contrast, cisplatin did not induce these proteins in 2780CP cells to any significant degree. The results indicate that a defect exists in the signal transduction pathway for p53 induction following cisplatin-induced DNA damage in 2780CP cells, and this may represent a significant mechanism of cisplatin resistance. Furthermore, induction of p53 in 2780CP cells by X-rays, but not cisplatin, strongly suggests that independent pathways are involved in p53 regulation for the two DNA-damaging agents.     

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.     

Analysis of bcl-2 expression in normal, inflamed, dysplastic nasopharyngeal epithelia, and nasopharyngeal carcinoma: association with p53 expression

Differentiation between benign and malignant adrenocortical neoplasms is made using a combination of clinical and pathologic parameters. Despite these parameters, it is still difficult to predict the biologic potential of some tumors. Forty adrenocortical lesions, including 10 hyperplasias, 10 adenomas, 12 carcinomas and eight metastatic/recurrent adrenocortical carcinomas were studied for the expression of MiB-1, p53, and the retinoblastoma gene product (RB) utilizing immunohistochemical techniques. The mean tumor proliferating fraction (TPF), expressed as the number of MiB-1-positive nuclei per 1,000 tumor cells, was 14.9 in adenomas, 31.5 in hyperplasias, 208.1 in carcinomas and 166.1 in recurrent or metastatic disease. None of the 20 benign lesions had a TPF of > 80, and only one of the 20 malignancies had a TPF of < 80. Nine of the 20 carcinomas were positive for p53. None of the benign lesions were p53 positive. Thirty-nine cases, including benign and malignant ones, were RB positive, and one was uninterpretable. We conclude that prognostic markers can be of great assistance in recognizing adrenocortical carcinomas. High TPF (> 80), as measured by staining with MiB-1, and positive p53 strongly correlate with malignant behavior and therefore may be useful in distinguishing benign from malignant adrenal lesions. Staining for RB does not appear to be a helpful technique.     

Bcl-2 protein expression: association with p53 and prognosis in colorectal cancer

In myocardial SPECT perfusion imaging, reorientation algorithms from transaxial image planes are used to generate short- and long-axis views of myocardial tracer uptake. We performed phantom experiments with 201Tl to delineate how image reorientation affects the results of quantitative image analysis. METHODS: Thirty consecutive patient studies were analyzed to characterize the distribution of the angle of reorientation in a clinical setting. Short-axis SPECT images of a cardiac phantom with and without a 180 degrees cold-spot insert were reconstructed with three different backprojection filters (ramp, Metz and Butterworth) and reoriented through different angles ranging from 45 degrees to 89 degrees. Four interpolation algorithms were used to calculate from the transaxial images the pixel values of the reoriented images: (a) a simple interpolator that averages the pixel values of the eight neighboring pixels of the transaxial image; (b) a three-dimensional linear interpolator; (c) a hybrid interpolator that combines a two-dimensional linear in-plane with a one-dimensional cubic across-plane interpolation; and (d) a three-dimensional cubic convolution interpolator. Images were reoriented twice with opposite angles so that the original and the reoriented images could be directly compared. Circumferential profile analysis was applied to determine the root mean square error of corresponding profiles and the difference of the extent and the severity of perfusion defects. Single and multivariate analyses of variance (ANOVA) were used to compare the effects of the reorientation angle, the backprojection filter and the interpolation algorithm. RESULTS: In the clinical studies, the angle between the transaxial and reoriented images was 75 degrees +/- 10 degrees (s.d.). In 48 phantom experiments, multivariate ANOVA demonstrated that the backprojection filter and the interpolation algorithm significantly affect the circumferential profiles and the extent and severity of a perfusion defect (p < 0.05). In contrast, the angle of reorientation was not a significant factor (p = ns). By univariate analysis, the three-dimensional cubic interpolator was associated with significantly (p < 0.05) less error than the simple and three-dimensional linear algorithms. Relative computation times (simple interpolator = 100%) were 119% for the three-dimensional linear, 136% for the hybrid and 243% for the three-dimensional cubic interpolator. CONCLUSION: For quantitative analysis of myocardial SPECT perfusion images, a Metz filter for filtered backprojection in combination with a three-dimensional cubic convolution interpolation for image reorientation appears to offer improved accuracy.     

Increased proliferative activity and p53 expression in normal glandular breast tissue after radiation therapy

Macrophage colony-stimulating factor (M-CSF), initially described as a growth factor of the mononuclear phagocytic lineage, also participates in immunological and inflammatory reactions, bone metabolism and pregnancy. All its biological activities are mediated by a tyrosine kinase receptor (M-CSF-R) that is encoded by the c-fms protooncogene. After a brief overview on the synthesis, structure, metabolism and signalling of M-CSF and its receptor, we present with more details the major in vitro and/or in vivo biological activities of this cytokine. A particular attention has been devoted to the results suggesting that the various M-CSF isoforms (i.e. soluble, cell-associated and matrix anchored forms) play different specific roles on target cells bearing M-CSF-R at their surface. Infectious, inflammatory and neoplastic diseases in which M-CSF is involved and could participate to their physiopathology are mentioned. Finally, the role that the various isoforms of M-CSF could play in the regulation of "physiological and pathological cytokine networks" during inflammatory and immune responses is discussed.     

Frequent expression of Bcl-2 in renal-cell carcinomas carrying wild-type p53

Lunate excision alone is seldom utilized in the management of Kienbock's disease due to concerns about progressive carpal collapse following removal of this central carpal bone. We report a 32-year follow-up of a patient who underwent lunate excision only for treatment of Kienbock's disease with a successful outcome. Although lunate excision is thought to be associated with a high failure rate, a review of the literature suggests that success rates following lunate excision are comparable to those reported for other more conventional techniques such as radial shortening, ulnar lengthening, limited carpal fusions, and proximal row carpectomy. The current perception that lunate excision is associated with a high failure rate is not supported in the literature. As such, it may not be appropriate to assign this operation to the category of "historical interest only."     

The prevalence of bcl-2, p53, and Ki-67 immunoreactivity in transitional cell bladder carcinomas and their clinicopathologic correlates

The aim of this study was to investigate the expression of bcl-2, p53 oncoproteins, and Ki-67 antigen in a series of transitional cell bladder carcinomas and its relation to the traditional prognostic indicators and patient's survival. One hundred six cases with transitional cell carcinoma (TCC) were examined for detection of bcl-2, p53 proteins, and Ki-67 antigen (MIB1 antibody). Bcl-2 immunohistochemical positivity was observed in 52% of TCCs and in 57% of low-grade and 44% of high-grade TCCs. Bcl-2 was also detected in normal urothelium and dysplastic lesions with basal cell expression, and negative staining was observed in carcinomas in situ. Tumor stage showed a significant inverse correlation with overall bcl-2 positivity. The loss of bcl-2 protein expression in higher-stage TCCs was statistically significant (Pt = .01). p53 protein was overexpressed in 50% of TCCs and more frequently in invasive and in carcinomas in situ than in superficial TCCs (Pt = .03). In contrast, detection of p53 was not observed in normal and dysplastic urothelium. p53 positivity was related to the degree of differentiation and to the stage of the disease (Pf = .01 and Pt = .03, respectively). Concerning Ki-67 antigen, its expression was found in 57.5% of TCCs. There was a strong overall correlation of Ki-67 with tumor stage (Pt = .002) and grade (Pf = .002). Univariate statistical analysis showed that the expression of p53 and Ki-67 was significantly correlated to poor prognosis (P = .02, P = .02, respectively). On multivariate analysis, none of these markers but only stage and grade were significantly correlated to prognosis (P = .02, P = .02, respectively). These findings suggest that overexpression of bcl-2 protein may be an early event in tumorigenesis. Tumors with loss of bcl-2 positivity and overexpression of p53 and Ki-67 had an unfavorable prognosis; however, in multivariate analysis, they had no independent prognostic value.     

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.     

Detection of p53 protein overexpression and DNA ploidy analysis in colon cancer

BACKGROUND/AIMS: This study was designed to demonstrate the accumulation of the mutant p53 protein in human neoplasms. The correlation of flow cytometric DNA ploidy pattern with p53 expression using the immunoblotting technique was also investigated. METHODOLOGY: In this study, the occurrence of p53 overexpression was analyzed in 34 cases of adenocarcinoma of the colon by western immunoblotting technique, using an anti-human p53 monoclonal antibody (Do-7). The nuclear protein extract from human colon tumor specimens was immunoblotted relative to protein standards of known molecular weight. Flow cytometric analysis was used to study the DNA ploidy pattern of the tumor cells. RESULTS: Monoclonal antibody p53-Do 7 detected a single band of 53 KDa in 70.5% (24 of 34) of the tumor specimens examined. Whereas, no bands were detected in the normal colon mucosa. The relation between p53 overexpression and the clinicopathological variable (Dukes' staging) was studied and no significant difference in p53 overexpression between Dukes' stages B and C was found. Flow cytometric analysis revealed a higher incidence of DNA aneuploidy in 75% (15 of 20) of p53 positive cases compared with 64.3% (9 of 14) in the diploid tumors. CONCLUSION: The immunoblotting technique can successfully detect the mutant p53 and is therefore expected to provide valuable information on the role of p53 in the process of carcinogenesis.     

bcl-2 but not p53 expression is associated with resistance to chemotherapy in advanced breast cancer

Programmed cell death is an important determinant of the response to chemotherapy. Among the factors controlling this process, a significant role is played by bcl-2 and p53, the expression of which, together with estrogen receptor content and tumor proliferative activity, was investigated by means of immunohistochemistry in 55 advanced breast cancer patients (median age, 60 years; range, 25-71 years). Analysis of bcl-2 expression identified two groups of patients with a significant difference in response rate. A total of 17 patients (31%) responded to chemotherapy (5 had a complete response and 12 had a partial response): 14 of 32 (44%) bcl-2-negative patients (< 40% stained cells) and only 3 of 23 (13%) bcl-2-positive patients (> or = 40% of stained cells; P = 0.019 by Fisher's exact test). The two groups were well balanced in terms of age, performance status, disease-free survival, menopausal status, and type of chemotherapy. bcl-2-negative tumors showed a tendency toward a higher p53 expression and proliferation rate, whereas an excess of bone as the dominant disease site was evident among the bcl-2-positive ones. However, the only variable to result significantly different between the two groups was estrogen receptor expression (P = 0.004). A multivariate logistic regression model showed that bcl-2 maintained its power of discriminating two groups with a different probability of responding to chemotherapy, although the greatest contribution was given by dominant disease site and type of chemotherapy. In conclusion, the results of this study suggest a possible role for bcl-2 in predicting resistance to chemotherapy.     

p53 expression in ovarian carcinoma with regard to second-look findings

The coefficient of relationship by isonymy is Ri=sigma(n(n-1)/2(N(N-1)) in which n is the number of persons of each surname and N=sigma n. Dividing Ri into two components, one for the contribution of co-residence (family size) and the other for diversity of surnames among residences is achieved by letting a1 represent sigma n(n-1) for all residents, a2 represent sigma n(n-1) after eliminating all but one individual of any name at any residence, and b1 represent 2N(N-1) for all residents. Then the component for inter-residence diversity is a2/b1 and the component for relationship by co-residence (including the interaction) is (a1-a2)/b1. By the same logic it is possible to calculate separately the interaction component, but the additional information seems of limited importance.     

Expression of bcl-2, p53 and Ki-67 in arsenical skin cancers

To investigate the regulation of apoptosis and proliferation in arsenic-induced skin cancers, we examined the expression of bcl-2, p53, and Ki-67 using immunohistochemical staining. Thirty patients with Bowen's disease (BD), ten with basal cell carcinoma (BCC), eight with squamous cell carcinoma (SCC) and eleven of perilesional normal skin (PLN) of the non-sun exposure sites from endemic area were examined. The results showed that: 1) bcl-2 was expressed in all of the BCC homogeneously, in none of the SCC, and in 12/30 of the BD focally or homogeneously; 2) p53 was expressed in all of the arsenical skin cancers with a labelling index of 75 +/- 14% of BD, 50 +/- 17% of BCC, 61 +/- 15% of SCC, and also in all of the perilesional normal skin with a labelling index of 55 +/- 24%; 3) Ki-67 was expressed in all of the skin cancers with labelling index of 58 +/- 17% of BD, 12 +/- 7% of BCC, 47 +/- 21% of SCC, and in 9/11 of PLN with a labelling index of 41 +/- 24%. Expression of bcl-2 in BCC or BD is related to the phenotype of germinative basal cell. The constant expression of bcl-2 i early dysplastic cells of BD and the earliest expression of P53 in the basal cells of perilesional normal skin indicate that the initial step of arsenic-induced carcinogenesis is from the basal germinative cells. There is no mutual relationship between bcl-2, p53 or Ki-67 expression in any type of the arsenical skin cancers, but there is a positive correlation between p53 and Ki-67 expression identified in perilesional normal skin. BD had the highest labelling index of p53 and Ki-67.     

Circulating antibodies against p53 protein in patients with ovarian carcinoma. Correlation with clinicopathologic features and survival

BACKGROUND: Genetic alterations of the p53 tumor suppressor protein are the most frequent molecular events in human carcinogenesis. For as yet unknown reasons, mutant p53 often acts as an immunogen for autoantibody generation. These autoantibodies can be detected in the serum of cancer patients. The presence of such antibodies has been identified in a subset of patients with ovarian carcinoma, but their clinical significance has not been investigated. METHODS: Serum samples from patients with ovarian carcinoma were quantitatively analyzed for the presence of p53 autoantibodies with a time-resolved immunofluorometric procedure. Tumor p53 overexpression was assessed by immunohistochemical analysis of tissue sections. Kaplan-Meier survival curves were calculated for p53 antibody positive and negative patients, and the Cox model was used to evaluate the strength of the associations between the presence of serum p53 antibodies and cancer relapse or death, and also between the presence of such antibodies and other clinicopathologic features. RESULTS: p53 antibodies were detected in the serum of 41 of 174 patients with ovarian carcinoma (24%). Antibody levels ranged from a few hundred to 9 x 10(6) arbitrary Units/L, and fluctuated during the course of the disease. p53 antibody positive patients tended to have tumors overexpressing p53, but the association between the two parameters was not statistically significant (P = 0.13). There was also no association between the presence of p53 antibodies and clinical stage, tumor histologic type, or overall patient survival. However, these antibodies were more frequently present in patients older than 50 years (P = 0.001), in patients with moderately or poorly differentiated tumors (P = 0.001), and in patients who received chemotherapy (P = 0.015), and who suffered relapse after surgery (P = 0.018). In univariate analysis, p53 antibody positive patients were at an increased risk for relapse but not death. In multivariate analysis, the differences in disease free and overall survival between patients who were p53 antibody positive or negative were not statistically significant. CONCLUSIONS: p53 autoantibodies are found frequently in the serum of patients with ovarian carcinoma. The presence of such autoantibodies was associated with older patient age, more aggressive tumors, and reduced patient disease free survival. In multivariate analysis the prognostic value of p53 autoantibodies was not statistically significant.