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.     

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.     

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.     

Sensitivity to Fas-mediated apoptosis in pediatric acute lymphoblastic leukemia is associated with a mutant p53 phenotype and absence of Bcl-2 expression

We investigated the antitumour effects of 1-(2,6-difluorophenyl)-1H,3H-thiazolo [3,4-a]benzimidazole (TBZ) a new anti-HIV-1 agent, on human promyelocytic HL60 leukaemia, both a parental and a multidrug resistant form (HL60R). HL60R overexpresses P-glycoprotein and, like HL60, lacks p53 protein expression. HL60 and HL60R show similar levels of Bcl-2 protein. In contrast to the conventional chemotherapeutic agents daunorubicin, etoposide and mitoxantrone, TBZ caused equal or even greater cytotoxicity in HL60R than in HL60, and this result was associated with a more marked induction of apoptosis in the drug resistant cells. The antitumour activity of TBZ occurred in the range of concentrations higher than those required to exert antiviral activity. TBZ seems to act in the presence of P-glycoprotein and Bcl-2 and in the absence of p53 and is able to circumvent the mechanisms of drug resistance and anti-apoptosis present in HL60R cells.     

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.     

bcl-2, p53 immunophenotypes and apoptosis in squamous cell carcinoma of the oesophagus

To establish baseline information on neopterin concentrations in livestock, companion and laboratory animals and identify the factors that may influence these concentrations, blood samples were taken from normal dairy cattle, horses, llamas, dogs, cats and rats of varying ages and sexes. In addition, neopterin concentrations in normal, adult equines were compared with those found in racing Thoroughbreds. There were no differences due to sex, sexual maturity, pregnancy, castration, or age. For all ages and sexes combined, mean neopterin concentrations were significantly lower in llamas (2.27+/-0.33 nmol litre(-1)) and rats (2.13+/-0.21 nmol litre(-1)) when compared with the other species tested. Racing Thoroughbreds demonstrated higher neopterin values than adult equines not in training (3.54+/-0.64 vs 3.13+/-1.02 nmol litre(-1)).     

Induction of apoptosis and cell cycle-specific change in expression of p53 in normal lymphocytes and MOLT-4 leukemic cells by nitrogen mustard

The diagnosis of pulmonary emphysema is often neither as obvious nor as easy as is generally assumed. In this review, the methodologies are discussed by which emphysema can be accurately diagnosed. The classification of emphysema is outlined, with the salient gross and microscopic features listed.     

p53 protein expression in peripheral lymphocytes from atrazine chronically intoxicated rats

The p53 expression in peripheral lymphocytes of rats chronically exposed to atrazine was investigated. The experiment was performed in female Wistar rats. Atrazine was administrated in different doses (2.7 and 5.4 mg/kg body weight), each dose once a day, 5 days per week, for 6 and 12 months. The percentage of rats peripheral lymphocytes expressing p53 protein was evaluated by immunocytochemical technique, using a monoclonal antibody (clone PAb 122) against a common epitope, both for the wild type and the mutant p53 protein. The results indicate that in the atrazine long-term administration, the serum level of atrazine is associated with: (i) Significantly increased percentage of lymphocytes expressing p53 protein for all treated animals; (ii) different p53 intracellular compartmentalization (nucleus and cytoplasm), depending on dose and time of atrazine administration. The present study suggests that atrazine modifies the p53 expression, which could confirm the clastogenicity of this herbicide, and that the detection of the p53 protein may serve as a biomarker for the long-term exposure to atrazine.     

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 and bcl-2 immunohistochemical alterations in prostate cancer treated with radiation therapy

PURPOSE: Upper urinary tract calculi that are too large to treat with extracorporeal shock wave lithotripsy are most commonly cleared with percutaneous endoscopic techniques. In a select group of patients who were poor candidates for percutaneous nephrostolithotomy we used retrograde endoscopic lithotripsy, and define the safety and efficacy of this modality in treating large, noninfectious stone burdens (2 cm. or greater). MATERIALS AND METHODS: A total of 51 patients with 66 large (2 cm. or greater) upper urinary tract stones were chosen for retrograde ureteroscopic surgery. Many of these patients had co-morbid conditions that precluded or complicated standard percutaneous treatment. Lithotripsy was based on the application of small diameter fiberoptic ureteroscopes and the holmium laser lithotriptor. Specifically, the 200 micro. laser fiber was used when lower pole renal access was required. Successful therapy was defined as total fragmentation of a stone burden with creation of fine sand and 2 mm. or smaller debris. Second look endoscopy was commonly performed in select patients with large branched calculi or stone burdens in excess of 3 cm. to rule out and treat large residual fragments. RESULTS: Of 51 patients 48 were treated solely in a retrograde ureteroscopic manner and in 3 either failure of lower pole access or infectious material encountered on initial endoscopy led to conversion to more standard percutaneous techniques. In 34 of 45 renal (76%), and 20 of 21 ureteral (95%) complete ureteroscopic fragmentation of the respective stone burden was accomplished after a single session. Second look endoscopy defined significant residual fragments requiring additional endoscopic lithotripsy in 8 of 15 large renal (53%) and 1 of 3 complex ureteral stone burdens. Success, that is complete pulverization of the stone burden to fine dust and small 2 mm. fragments, increased to 41 of 45 renal (91%) and all 21 ureteral calculi after these second look procedures. One patient required a third session to treat completely an exceptionally large (6 cm.) renal stone burden composed of pure cystine, thus increasing the overall success rate for renal calculi to 93%. Six-month followup data were available for 25 patients with large calculi treated ureteroscopically, of whom 15 (60%) had completely clear imaging, 6 (24%) had small lower pole debris that was decreasing on serial imaging and 4 (16%) had new stone growth which was, in part, related either to uncorrectable metabolic disorders or chronic renal scarring and urinary stasis. There were no intraoperative complications. Three postoperative complications included pyelonephritis in 1 patient, prostatic bleeding in 1 on anticoagulant therapy and a cerebral vascular accident 24 hours after the procedure in 1 with severe vascular disease. CONCLUSIONS: Large and complex upper urinary tract calculi can be addressed safely and efficiently with retrograde endoscopic techniques.     

Dysregulation of bcl-2, c-myc, and Fas expression during tricyclic antidepressant-induced apoptosis in human peripheral lymphocytes

Tricyclic antidepressants (TCAs) have been shown to induce apoptosis in human lymphocytes. In the present report, we investigated in parallel the regulation of the three oncogenes bcl-2, c-myc, and Fas. A reduction in c-myc and bcl-2 levels of 35-40% and 22-27%, respectively, was observed. On the other hand, Fas expression on the outer surface of the plasma membrane was increased up to 31%. In conclusion, bcl-2, c-myc, and Fas are undergoing dysregulation due to TCA-induced apoptosis.     

p53 and apoptosis

Loss of function of the p53 tumour suppressor gene is a frequent and important event in the genesis or progression of many human malignancies. Loss of p53 dependent apoptosis is believed to be critical to carcinogenesis in many of these cases, suggesting the possibility to therapeutically restore this pathway and directly eliminate malignant cells or increase or restore their sensitivity to chemotherapeutic agents. The regulation of p53-dependent responses is complex and variable between cell types, and whether a cell undergoes apoptosis after activation of p53 is highly sensitive to signal context, including environmental and cell intrinsic influences. This article focuses upon p53-dependent apoptosis, considering current understanding of the biochemical steps involved, the factors determining selection of apoptosis over other p53-dependent responses, the significance of p53-dependent apoptosis for the genesis, progression and drug resistance of human cancers, and finally the prospects for clinical manipulation of this pathway in cancer therapy.     

Decreased expression of bcl-2 (p26) in CD8(+) lymphocytes of patients with T-cell lymphoproliferative disorders of large granular lymphocytes

The objective of the present study was to identify the polychlorinated biphenyl congeners of Aroclor 1254 that are responsible for the induction of the cytosolic bioactivation of aromatic amines. Various chlorobiphenyls, ranging from di- to hexa-substituted, were administered to rats and the ability of the hepatic cytosol to bioactivate 2-aminoanthracene and 2-aminofluorene was investigated. These studies revealed that the induction of the cytosolic activation of aromatic amines increased with the increasing extent of chlorination; moreover, planar congeners were more effective inducers of this activity compared to their non-planar isomers. This observation prompted us to investigate whether the cytosolic activation of aromatic amines is associated with the Ah receptor. Treatment of mice with Aroclor 1254 stimulated the cytosolic activation of aromatic amines in C57BL6 mice, an Ah-responsive strain, whereas it had no effect in DBA2 mice, a non-responsive strain. These findings indicate that the bioactivation of aromatic amines by the liver cytosol is linked to the Ah receptor.     

Growth hormone prevents human monocytic cells from Fas-mediated apoptosis by up-regulating Bcl-2 expression

Voltage-sensitive dyes NK 2761 and RH 155 were employed (in conjunction with a 12 x 12 photodiode array) to study membrane potential transients in optic lobe neuropils in the eye stalk of the crayfish Procambarus clarkii. By this means we investigated a pathway linking deutocerebral projection neurons, via hemiellipsoid body local interneurons, to an unidentified target (most likely neurons processing visual information) in the medulla terminalis. Rapid (10- to 20-ms duration), transient changes in absorption with the characteristics of action potentials were recorded from the optic nerve and the region occupied by deutocerebral projection neurons after stimulation of the olfactory globular tract in the optic nerve and were blocked by 1 microM tetrodotoxin. Action potentials appeared to propagate to the glomerular layer of the hemiellipsoid body where synaptic responses were recorded from a restricted region of the hemiellipsoid body occupied by dendrites of hemiellipsoid body neurons. Action potentials were also recorded from processes of hemiellipsoid body neurons located in the medulla terminalis. Synaptic responses in the hemiellipsoid body and medulla terminalis were eliminated by addition to the saline of 500 microM Cd2+ or 20 mM Co2+, whereas the action potential attributed to branches of deutocerebral projection neurons in the hemiellipsoid body remained unaffected. Action potentials of hemiellipsoid body neurons in the medulla terminalis evoked postsynaptic potentials (50- to 200-ms duration) with an unidentified target in the medulla terminalis. Transient absorption signals were not detected in either the internal or external medulla nor were they recorded from other parts of the optic lobes in response to electrical stimulation of axons of the deutocerebral projection neurons. Functional maps of optical activity, together with electrophysiological and pharmacological findings, suggest that gamma-aminobutyric acid affects synaptic transmission in glomeruli of the hemiellipsoid body. Synapses of the olfactory pathway located in the medulla terminalis may act as a "filter," modifying visual information processing during olfactory stimulation.     

Bcl-2, p53 and MIB-1 expression in normal and neoplastic parathyroid tissues

A marine bacterium, identified as a pseudomonad, isolated from Suberea creba Bergquist, 1995 (Porifera, Dictyoceratida, Verongida, Aplysinellidae) collected along the eastern coast of New Caledonia, gave in culture phenazine-alpha-carboxamide, 2-n-heptylquinol-4-one, 2-n-nonylquinol-4-one, 2-n-(1'E-nonenyl)quinol-4-one, 3-n-heptyl-3-hydroxyquinolin-2,4-dione, a N-oxide-2-n-heptylquinoline derivative, and a benzyldiketopiperazine. None of these products could be detected, at the HPLC-UV sensitivity level, in the sponge extracts, which contained instead (+)-aerothionin, homoaerothionin, (+)-aeroplysinin-1, dibromo-, bromochloro-, and dichloroverongiaquinol. 2-n-Heptylquinol-4-one, (+)-aeroplysinin-1, and dibromoverongiaquinol showed strong antibacterial activity in vitro. The latter also proved promising for mariculture, rivaling chloramphenicol as an antibacterial agent in cultures of Pecten maximus larvae, while being nontoxic according to the Artemia salina test.     

Basal cell adenocarcinoma of the salivary glands: comparison with basal cell adenoma through assessment of cell proliferation, apoptosis, and expression of p53 and bcl-2

Local anesthetics, particularly bupivacaine, are known to be myotoxic to skeletal muscle. Injury is followed by satellite cell mediated regeneration. The eyelid is a common site for the injection of local anesthetics. Due to the complex anatomy of this region and the unique properties of facial musculature compared to limb skeletal muscle, the response of the orbicularis oculi to local injection of bupivacaine was examined to determine the time course of maximum satellite cell activation and division. The lower eyelids of rabbits were injected with two doses of a combination of bupivacaine and hyaluronidase, spaced 18 h apart. To assess the time course of satellite cell division, bromodeoxyuridine (BrdU) was injected immediately or, 1, 2, 3, 6 or 13 days after the second bupivacaine injury. The rabbits were sacrificed 24 h later. The eyelids were prepared for immunohistological examination and morphometric analysis of the presence of CD11-positive monocytes, neutrophils and macrophages, MyoD expression in satellite cells and/or myoblasts, and co-expression of BrdU and the developmental myosin heavy chain isoform. One day after bupivacaine injury of the orbicularis oculi, there was a large influx of CD11-positive cells which gradually decreased over time. Maximum activation of satellite cells, as defined by MyoD expression, occurred 2 and 3 days after the injury. Using double labeling techniques, the peak of BrdU incorporation occurred on day 3 and was identified in developmental myosin co-labeled cells 4 days after injury. The peak of satellite cell activation and division occurred 3 days after bupivacaine induced injury, as demonstrated by both MyoD expression and after pulse labeling with BrdU as identified in double labeled cells positive for BrdU and the developmental myosin heavy chain isoform. The process of regeneration in this muscle extended beyond the duration of this study. Muscle fibers remained small in cross-sectional area and positive for developmental myosin 2 weeks after injury, at a time when the fiber number had reached control, uninjured levels.     

Enhanced expression of bcl-2 inhibits apoptosis in cultured human keratinocytes

Intravenous heparin followed by oral warfarin sodium is effective for preventing recurrent thromboembolism in patients who have pulmonary embolism or proximal vein thrombosis. The effectiveness of intravenous heparin depends on obtaining an adequate anticoagulant response early during therapy. A validated heparin protocol should be used to ensure that an adequate anticoagulant response is obtained as soon as possible. Low molecular weight heparin has the practical advantage that it does not require monitoring and dose finding. If thrombolytic therapy is indicated, it is safer for many patients to base management on the noninvasive diagnosis rather than performing pulmonary angiography. In patients suspected to have pulmonary embolism who have nondiagnostic lung scan and adequate cardiorespiratory reserve, serial noninvasive leg testing is a practical approach that avoids pulmonary angiography, identifies patients who have proximal vein thrombosis requiring treatment, and avoids the risks of anticoagulant treatment in the majority of patients.