Early Stages Of Progression Research Articles

Early progression stage of malignancy of uterine cervical dysplasia as revealed by immunohistochemical demonstration of increased DNA-instability.

The degree of DNA-instability as revealed by the immunohistochemical staining with anti-single-stranded DNA antibody after acid hydrolysis (DNA-instability test) was used as a marker of malignancy. This was applied to mild dysplasia (42 cases), moderate dysplasia (43 cases), severe dysplasia (27 cases), squamous cell carcinoma in situ (CIS) (21 cases), invasive squamous cell carcinoma (SCC) (31 cases) and normal (7 cases) human uterine cervix. The expression of tumour suppressor gene p53 and oncogene bcl-2 was detected immunohistochemically. Proliferative activity was evaluated by PCNA immumohistochemistry and the quantitative analysis of the number, mean area, the largest area and maximum shape irregularities of AgNOR in a nucleus were performed for all these cases. The distribution of numeric chromosomal aberrations of chromosome 17 was also investigated in some of these cases. The results showed that 31 SCC (100%), 21 CIS (100%), 21 severe dysplasia (77.77%), 28 moderate dysplasia (65.11%), and 14 mild dysplasia (33.33%) were positively stained by the DNA-instability test diffusely or sporadically, indicating their malignancy. Reflecting the malignant character, these cases showed a remarkable increase in the PCNA-index with the loss of polarity of PCNA positive cell distribution and also an increase in number, mean and largest sizes and maximum shape irregularity of AgNOR dots. The mean chromosome index for chromosome 17, p53 and bcl-2 immunostaining positivity were also found to be significantly increased in moderate and severe dysplasia and in cancerous cases in comparison to normal and mild dysplasia cases. Moreover, the DNA-instability-test positive dysplasia cases showed statistically significant increased values of PCNA-index, AgNOR parameters, mean chromosome index, p53 and bcl-2 expression in comparison to those of DNA-instability-test negative dysplasia cases. In conclusion, some mild dysplasia (33.33%) and most of the moderate (65.11%) and severe dysplasia (77.77%) were regarded as malignant in nature, existing at an early stage of progression of malignancy.

Contrasting roles for nitric oxide and peroxynitrite in the peroxidation of myelin lipids

Peroxynitrite is formed by the reaction of nitric oxide (NO) and superoxide. Since widespread peroxynitrite activity was observed during experimental allergic encephalomyelitis (EAE), the effect of this strong lipid-peroxidizing agent on myelin integrity was examined. Incubation of myelin suspensions with the peroxynitrite donor 3-morpholinosydnonimine (SIN-1) resulted in the formation of the lipid peroxidation product, malondialdehyde (MDA). MDA formation was inhibited in the presence of butylated hydroxytoluene, which interrupts the progression of the lipid peroxidation chain reaction. Superoxide dismutase inhibited the effect of SIN-1, which indicates a role for superoxide, and contradicts a role for its dismutation product, hydrogen peroxide. The latter was confirmed by the failure of the catalase to inhibit MDA formation. Neither NO nor superoxide alone induced significant MDA formation in myelin, indicating that peroxynitrite formation is required for myelin-lipid peroxidation. Interestingly, NO actually inhibited lipid peroxidation in myelin, as demonstrated using simple NO donors. On the other hand, the simultaneous production of superoxide, as achieved with the NO-donor SIN-1, negated the inhibitory effect of NO. Finally, the production of isoprostanes, novel products generated during lipid peroxidation, was examined. Peroxynitrite-induced peroxidation of myelin resulted in isoprostane formation. Furthermore, increased levels of F 2-isoprostanes and neuroprostanes were observed in spinal cords of mice during early progressive stages of autoimmune encephalomyelitis.

Pulmonary surfactant composition early in development of acute lung injury after cardiopulmonary bypass: prophylactic use of surfactant therapy.

Cardiopulmonary bypass surgery (CPB) causes lung injury and at least 2% of adult patients and more children develop the most severe from acute respiratory distress syndrome (ARDS). Pulmonary surfactant deficiency contributes to the pathogenesis of ARDS. It has been proposed that surfactant therapy immediately after CPB might arrest progression to ARDS. However, many patients develop only mild lung injury after CPB. Thus early markers are needed to identify those patients at highest risk to guide selection for treatment. The aim of this study was to determine whether changes in surfactant phospholipids occur, and reflect severity of lung injury within the first few hours after bypass. Because of the relatively low incidence of ARDS in adult patients, this study was conducted using young pigs highly susceptible to bypass-induced lung injury. Eight pigs were given 2 hours bypass. Six controls underwent 'sham' bypass. At 3 h after bypass pulmonary vascular endothelial permeability was assessed by transcapillary leakage of radiolabelled transferrin. A 4 hour broncho-alveolar lavage (BAL) was used to assess intra-alveolar levels of surfactant, inflammatory cells and oedema protein. Bypass caused falls in arterial oxygenation and lung compliance (P < 0.01), but at this early stage in progression of lung injury BAL surfactant phospholipid and albumin levels were within the control range indicating that the alveolar epithelium had not yet suffered major damage. The main abnormalities were increases in vascular endothelial permeability (P < 0.01), BAL neutrophils (P < 0.01), total protein and sphingomyelin (SM) (P < 0.05). Lung histology showed that the main damage was interstitial oedema located around the bronchioles and their associated vessels. A single instilled dose of surfactant phospholipids in 5 animals caused excess in vivo supplementation and did not reduce the early pathophysiologic changes. Our findings suggest that surfactant phospholipid deficiency does not make a major contribution in the initial stages of lung injury after CPB, and that excessive phospholipid supplementation at this stage can be deleterious.

How insecure is Pacific Asia?

This article rejects extreme views on the Pacific Asian security situation that posit either smooth progress towards a prosperous and secure peace or accelerating tensions and arms races. It identifies four key conditions essential for the construction of durable regional security: pluralist political systems; growing interdependence; the creation of regional society; and a robust balance of power. None of these conditions is sufficient on its own: the tensions that can arise from economic interdependence and the dangers of the early stages of progress towards a pluralist polity are emphasized. Nevertheless, despite the limited effectiveness hitherto of formal pan-regional security organizations, there are positive signs of an emerging regional balance of power.

Gene competition and the possible evolutionary role of tumours

The evolutionary role of tumours might consist of providing the conditions for the expression of evolutionary new genes and thus in providing the material for the origin of new cell types. To approach this concept the principle of gene competition is essential. With an increase in gene number in the genomes of the evolving multicellular organisms the enforcement of gene competition should take place. Therefore, the pre-existing cell types possess limited possibilities for the expression of evolutionary new genes. Like evolutionary new genes originated from extra copies (duplicates) of old genes, evolutionary new cell types had to originate from extra cells which were not functionally necessary to the organism. Tumours could have supplied the evolving multicellular organisms with extra cells for the expression of originating evolutionary new genes. Of course, on the basis of this proposal only tumours at the earlier stages of progression are considered to be meaningful, or some kind of tumour-like processes, but not malignant tumours at late stages of progression. The evolutionary new genes originate in the DNA of germ line cells but not in DNA of tumour cells. Until the moment of their expression in the tumour cells these genes could stay silent. After the expression of these genes tumour cells should acquire the function in the organism, differentiate and lose their previous autonomy. The organisms with a new cell type should then be selected against their fitness and competitive abilities.

The quantitation of altered hepatic foci during multistage hepatocarcinogenesis in the rat: Transforming growth factor α expression as a marker for the stage of progression

The experimental three-stage hepatocarcinogenesis protocol of initiation, promotion, and progression, coupled with the analytical technique of stereology, permits quantitative analysis of the carcinogenic process, including the derivation of biologically based risk assessment models. The aberrant expression of the placental isozyme of glutathione S-transferase (PGST) is an efficient marker for initiated, preneoplastic, and neoplastic hepatocytes. Putatively initiated cells and their clonal progeny can be identified, enumerated, and their growth characteristics determined on the basis of their aberrant expression of this protein. A lack of suitable markers has made the identification and quantitation of hepatocytes in the early stage of progression more difficult. One characteristic of cells in the stage of progression is the evolution of relatively autonomous growth. The alteration of growth factor signalling pathways may provide one mechanism for this observation. The expression of transforming growth factor α (TGFα) is seen in many malignancies. The initiation-promotion-progression protocol has been used to induce progression in the rat liver. The focal expression of TGFα was found to correlate with areas of progression in rats subjected to this protocol. The ability to identify and quantitate cells in the stage of progression should facilitate application of the Moolgavkar-VenzonKnudson model for assessing human risk from carcinogens active at each of these three stages. Validation of this model will require determination of the number and growth characteristics of hepatocytes in the stage of progression.

Tissue and cell—cell interactions in prostate cancer progression

Prostate cancer is unique among human cancers in the wide discrepancy between the high prevalence of histologic changes recognizable as cancer (latent cancer) and the much lower prevalence of clinically recognizable disease (clinical cancer). Latent or incidental prostate cancer is often found at autopsy, affecting nearly 33% of all men older than 50 years, yet the number of new cases of clinically manifest prostate cancer represents only a small fraction of this latent disease. This discrepancy indicates that life-threatening prostate cancer results from progression of only a subset of the latent and clinically insignificant lesions and not the progression of all small tumors. Therefore, we must understand the underlying molecular and cellular determinants of prostate cancer progression. The role of tissue and cell-cell interactions in prostate cancer progression is complex. During early stages of progression, relatively normally organized stroma can suppress discrete steps in carcinogenesis. This phenomenon is exemplified by studies using the mouse prostate reconstitution (MPR) model system, where investigators showed that intrinsic properties of the mesenchyme can modulate the conversion of oncogene-initiated benign hyperplastic prostatic epithelium to the malignant phenotype. When the ras and myc oncogenes were introduced into both the mesenchymal and epithelial compartments of the microdissected urogenital sinus, poorly differentiated prostate cancer was produced at a high frequency (more than 90%) in inbred C57BL/6 mice. In contrast, benign prostatic hyperplasia converted to cancer at a low frequency (less than 10%) in BALB/c MPR mice under similar conditions. Heterologous MPR composed of BALB/c mesenchyme and C57BL/6 epithelium or vice versa showed that intrinsic properties of BALB/c mesenchyme can arrest the progression of ras + myc-initiated C57BL/6 epithelium from benign hyperplasia to cancer. Further progression of prostate cancer beyond its earliest forms of the malignant phenotype leads to increasingly disorganized stroma, where inappropriate stromal cell-cancer cell interactions can occur. Such interactions may include endothelial cell-cancer cell, lymphocyte-cancer cell, and neuron-cancer cell interactions. In addition to stromal cell-cancer cell interactions, the direct interaction of cancer cells with other cancer cells may lead to the establishment of important selection criteria whereby subsets of prostate cancer cells progress to metastatic disease. Understanding these various cell-cell interactions requires additional experimental studies that address the molecular and cellular basis of prostate cancer progression using appropriate model systems that contain the critical cell types. Recently we modified the MPR model system to involve the use of p53 knock-out urogenital sinus tissue as a target for oncogene-initiated prostate cancer. Using this protocol, we produced metastatic prostate cancer from normal cells in vivo. Importantly, the organ specificity of the metastatic disease closely resembles that in humans, and thus we can study genetic and phenotypic variability throughout the course of progression. In addition, because we use recombinant retroviruses to transduce the initiating oncogenes, we can track clonal progression and determine common progenitors of organ-specific metastatic disease.

Expression of p53 mutant nuclear phosphoprotein in oral carcinoma and potentially malignant oral lesions.

An immunohistochemical study of primary oral squamous cell carcinomas (n = 37) with a monoclonal antibody (PAb 1801) specific to p53 antioncogene product demonstrated nuclear overexpression of the mutant protein in 35% of cases. Those positive included carcinomas without deep invasion suggesting that p53 mutation may occur in the early stages of progression of a malignancy. This is supported by the observation that mutant protein was detectable in limited amounts in 2 cases of oral mucosal dysplasia (n = 12). None of the normal or reactive oral mucosal tissues (n = 17) were positive for p53. The presence or absence of p53 was not correlated with the site of the lesion or its degree of differentiation. Our data suggest that p53 gene mutations are commonly involved in oral cancer but are neither sufficient nor necessary for the development of malignancy. Nevertheless, as this mutation is the commonest genetic change described so far in cancers in white caucasoids, it is possible that its presence can be used as a marker of risk in a high proportion of malignant and potentially malignant oral lesions.

P53 point mutations in primary human gastric carcinomas.

p53 point mutations in primary gastric carcinomas were analyzed by performing cDNA deoxynucleotide sequencing of the gene. Out of 16, 9 (56.3%) primary gastric carcinoma cases, including early cancer, showed one or more p53 point mutations in their open-reading frame, and 4 out of 9 cases had a p53 point mutation within highly conserved domains. The characteristics of the p53 mutation spectrum observed in primary tumors were (a) frequent mutation at an A:T pair (50%, 7 out of 14 mutations), (b) high transversion incidence (29%, 4 out of 14 mutations), (c) no transition at CpG, and (d) no G:C to T:A transversion. Our results suggest that p53 mutation is a common event in gastric carcinoma occurring from the early stage of progression with its specific mutation spectrum.

Ras Transfection and expression does not induce progression from tumorigenicity to metastatic ability in mouse LTA cells

Studies testing the ability of a transfected ras oncogene to confer metastatic properties on non-metastatic cells have yielded conflicting results. Most of these studies have used recipient cells at early stages of progression (primary or immortalized, non-tumorigenic lines). In this study we tested the ability of the T24-H-ras oncogene to induce progression of tumorigenic, non-metastatic, murine LTA cells to a metastatic phenotype. Metastatic ability was assessed in complementary assays in two immune-deficient hosts, nude mice (after s.c. injection) and chick embryos (after i.v. injection), to determine if ras transfection affected metastatic properties in hosts lacking an intact immune system. Even with greatly elevated levels of ras p21 protein, pools of ras-transfected cells as well as individual clonal populations remained non-metastatic in both hosts. Serial in vivo passaging did not consistently enhance for either ras expression or metastatic ability. We conclude that expression of an activated ras oncogene in LTA cells does not induce progression from a tumorigenic to a metastatic phenotype. These results are in marked contrast to those obtained for ras expression in most other types. High levels of expression of an activated ras oncogene thus do not always promote progression from tumorigenicity to metastatic ability.

Cytoplasmic suppression of tumor progression in reconstituted cells

This report details studies of whether mouse NIH/3T3 TGr karyoplasts that are exposed to benzo[a]pyrene epoxide(trans) (BPDE) can progress to tumorigenicity when they are rescued with either mouse B10mtJ CAPr tumorigenic (experiment 1) or nontumorigenic (experiment 2) cytoplasts. The mitochondrial DNA of the B10mtJ cells has restriction fragment length differences that allow distinction from the mitochondrial DNA of the NIH/3T3 cells. The reconstructed clones in experiment 1 were all tumorigenic, while those from experiment 2 were all nontumorigenic. The clones in both experiments were passaged for an equivalent time. These findings reflect the presence of factors in mouse cytoplasm capable of suppressing the tumor phenotype of NIH/3T3-BPDE treated karyoplasts when rescued at an early stage of progression.

Detection and natural progression of early oesophageal carcinoma: preliminary communication.

Twenty-three cases of untreated early carcinoma of the oesophagus are described. The detection and observation on the natural progression of these early carcinomas were performed by means of abrasive cytology, barium oesophagography, and/or fibreoptic oesophagoscopy. Eleven cases had developed late carcinoma in a mean of 55.5 +/- 29.0 months after the initial detection of the disease, while in the remaining 12 cases the disease had maintained its early stage of progression for 74.4 +/- 27.3 months without developing into late carcinoma. Further, of the 23 patients, 18 had lived beyond 5 years, making a natural 5-year survival rate of 78.3%. The relatively long period of dormancy at the early stage of oesophageal carcinoma might thus influence the 5-year survival rate of this disease currently treated by surgery.

Results of use of corticotropin (ACTH) in treatment of retrolental fibroplasia.

IN RECENT reports 1 we stated that our experience with the use of corticotropin (ACTH) in the early progressive stages of retrolental fibroplasia gave us some hope that it might prove effective. This hope has not been realized. The present paper covers infants born between Dec. 15, 1949, and July 25, 1951. The treatment of infants born during this time was begun between February, 1950, and August, 1951, a 19-month experience. MATERIAL Source of Material Studied. —Cases of retrolental fibroplasia considered in this report occurred in two New York hospitals—Babies Hospital and Lincoln Hospital. Selection of Cases for Treatment. —In selecting the cases for treatment, it was important to make the decision before irreversible fundus changes occurred and, at the same time, not to choose cases in which there was a reasonable chance of spontaneous regression. The only chance of salvaging a useful eye was to arrest the disease before