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Results for “Proliferation”

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PubMed1980

[Dynamics of systems with induced cell proliferation within the framework of a branching stochastic process model. I. The number of cell generations induced to proliferate].

The probabilistic description of cell generation numbers in the populations induced to proliferate is considered on the basis of the model of branching age-dependent stochastic process. The recurrent formulas for generating functions (and moments) are derived for the following process which are of interest for the analysis of induced proliferation in closed cell populations: the number of cells in n-th generation horn up to the moment of observation, and the number of cell in n-th generation existing at a given moment.

Cell Division↗

PubMed1993

[Determination of proliferation activity of prostate cancers by means of nuclear proliferation-associated formalin resistant Ki-S5 antigens].

In order to evaluate the growth fraction in normal, hyperplastic and neoplastic prostatic tissue, we examined paraffin sections of 55 cases of prostatic cancer containing areas of benign (BPH) and atypical hyperplasia (AH). Cellular proliferation was assessed by nuclear staining with the monoclonal antibody Ki-S5 directed against a formalin-resistant epitope of the Ki67 antigen. The proliferation rate was minimal in normal glands and BPH (mean 0.35%), rather low in AH and grade I carcinoma (0.5 to 15% compared to grade II carcinoma (1 to 40%) and peaking to near 80% labeled cells in grade III carcinoma. In the majority of the tumors, foci of increased cell growth could be detected by this method. Ki-S5 labeling indices correlated significantly with the histopathologic grading established by Dhom. Correlation with the clinical outcome will be the subject of subsequent retrospective studies.

Antigens, Neoplasm↗

PubMedDate not supplied

Protein tyrosine kinase inhibition and cell proliferation: is the [3H]-thymidine uptake assay representative of the T-lymphocyte proliferation rate?

T-cell growth is controlled to a large degree by extracellular signals that bind to specific receptors on the surface of cells. A number of these receptors have intrinsic protein tyrosine kinase (PTK) activity. Their action on second messenger generation, and thus on cell proliferation, has been indirectly demonstrated by the decrease in [3H]-thymidine (TdR) uptake that follows co-stimulation of T-cells with mitogens and PTK inhibitors such as genistein (GEN). In this paper we report that the [3H]-TdR uptake assay is not a valid and reliable tool for investigating the proliferative activity of certain T-cell lines. In fact, a concomitant assessment of both [3H]-TdR uptake and cell cycle progression demonstrated that GEN is able to block G2/M progression of Jurkat T-lymphocytes even at doses (5 micrograms/ml) that do not influence [3H]-TdR uptake. Pretreatment with sodium o-vanadate (100 nM) could not reverse the GEN-related cell cycle perturbation, but was able to restore optimal [3H]-TdR uptake. Finally, GEN treatment was able to induce concentration-dependent apoptotic cell death of Jurkat T-cells. The control of cell activation, proliferation and programmed cell death is undoubtedly influenced by receptor-associated PTKs. The final effect on cell survival is almost entirely dependent on the activation state of the cell. The [3H]-TdR uptake assay seems to be inadequate for a correct interpretation of the expected results.

Cell Cycle↗

PubMed1995

Effect of Viscum album L. on rapidly proliferating amniotic fluid cells. Sister chromatid exchange frequency and proliferation index.

Amniotic fluid cells (AFC) from 10 women undergoing amniocentesis were investigated. The 5-bromo-2'-deoxyuridine-induced sister chromatid exchange (SCE) frequency of AFC remained stable after the addition of a therapeutical concentration of Viscum album L. preparation Iscador P but decreased significantly after administration of high drug doses. As the proliferation index remained stable, even at extremely high drug concentrations, this effect could not be ascribed to a reduction of proliferation. No indications of cytogenetic damage or effects of mutagenicity were seen after the addition of Viscum album L. preparation P.

Amniotic Fluid↗

PubMed1992

Assessment of rejection in orthotopic human heart transplantation using proliferating cell nuclear antigen (PCNA) as an index of cell proliferation.

Myocardial biopsies taken during the management of cardiac transplantation were stained for proliferating cell nuclear antigen (PCNA). Counts of PCNA-positive interstitial cells were compared, in retrospect, with the reported histological grade of rejection. Biopsies without rejection had negligible numbers of PCNA-positive cells. Ascending grades of rejection were paralleled by an increase in the number of PCNA-positive cells [grade 1, 13 +/- 35 (mean +/- SD); grade 2a, 38 +/- 40; grade 2b, 91 +/- 75; grade 3, 170 +/- 78]. While highly significant, in statistical terms, the overlap in the counts between different grades means that prediction of rejection from the PCNA count alone is not feasible. Biopsies graded as 0 or 1 and which immediately preceded more severe rejection episodes showed no increase in PCNA-positive cells. The majority of PCNA-positive cells are fibroblasts, although in grade 2b and 3 rejection a small population of PCNA-positive T lymphocytes occurs. PCNA staining is also seen in cardiac myocytes immediately after transplantation, during rejection episodes, and late after transplantation in the absence of rejection. The positive PCNA staining of cardiac myocytes probably reflects DNA synthesis that occurs with the shift toward polyploidy in hypertrophy.

Autoantigens↗

PubMed1994

Proliferation in malignant mesothelioma as determined by mitosis counts and immunoreactivity for proliferating cell nuclear antigen (PCNA).

In order to assess its discriminating and prognostic value, we studied immunoreactivity for proliferating nuclear cell antigen (PCNA) in human malignant mesothelioma (31 cases) and in human non-neoplastic mesothelium (33 cases with reactive mesothelium and 20 cases of normal mesothelium) using the murine monoclonal antibody PC10. We also compared it with mitosis counts expressed as the mitotic volume index (MV index). There were differences between malignant mesothelioma, reactive mesothelium, and normal mesothelium for percentage of PCNA immunoreactive cells (mean +/- SD; 27 +/- 9, 9.5 +/- 5.1, and 3.6 +/- 1.6, respectively) and for their MV index (20.3 +/- 4.5, 9.4 +/- 2.1, and 3.6 +/- 0.6, respectively). The median actuarial survival was 10.1 months for patients with less than 25 per cent PCNA immunoreactive cells, 9.4 months for patients with less than 20 mitoses per mm2 of tumoural tissue, 5.9 months for patients with more than 25 per cent PCNA immunoreactive cells, and 5.3 months for patients with more than 20 mitoses per mm2 of tumoural tissue. Our results suggest that PCNA immunoreactivity is useful in discriminating between neoplastic and non-neoplastic mesothelium and that it may have prognostic value in malignant mesothelioma.

Adult↗

PubMed1994

Proliferating cell nuclear antigen counts as markers of cell proliferation in head and neck cancer.

Proliferating cell nuclear antigen (PCNA) expression was investigated immunhistochemically in 53 squamous cell carcinomas of the head and neck. PCNA is a 36-kDa nuclear protein associated with the cell cycle. Results were compared with Ki67 counts, with this latter marker used to demonstrate proliferative compartments. Overall, the PCNA and Ki67 labelling index showed a similar distribution pattern in normal and tumor tissue. A strong correlation was found to histological differentiation. There was no significant difference between PCNA and Ki67 counts (r = 0.8), and PCNA immunostaining allowed assessment of proliferative activity in the head and neck cancers studied. The application of formalin-fixed, paraffin-embedded tumor material demonstrated the advantage of this method and showed that it is an excellent alternative to Ki67 counts.

Antibodies, Monoclonal↗

PubMed1994

Changes of colon epithelium proliferation due to individual aging with cyclin proliferating cell nuclear antigen (PCNA/cyclin) immunostaining compared to [3H]-thymidine radioautography.

We report a change in the proliferative activity of mouse colonic epithelium due to development and aging. In order to measure the proliferative activity, colonic epithelium was immunostained for cyclin proliferating cell nuclear antigen (PCNA/cyclin), which appears from the Gl to the S phase of the cell cycle, and compared with labeling obtained by [3H]-thymidine radioautography. Litter mice of six age groups from the fetal period (embryonic day 19), newborn period (postnatal day 1), suckling period (postnatal day 5), weaning period (postnatal dy 21), adult period (2 month old) to the senescent period (11 month old) were examined by immunohistochemistry. The descending colons were fixed in methacarn (method-Carnoy) and embedded in paraffin. Sections were stained for PCNA/cyclin activity using 19A2 monoclonal antibody and the avidin-biotin peroxidase complex (ABC) technique. For radioautography, litter mice of nine age groups using in vivo intraperitoneal administration of [3H]-thymidine. The labeling indices of colonic epithelial cells in the proliferative zone were then analyzed and compared between the two investigative methods. Our results show that the proliferative activity of mice colon was high in the fetal and newborn periods and almost constant from the suckling period to senescence, as demonstrated by both PCNA/cyclin immunohistochemistry and [3H]-thymidine radioautography. The labeling index seen by PCNA/cyclin immunohistochemistry was, however, higher than that seen by [3H]-thymidine radioautography.

Aging↗

PubMed1993

Proliferating-cell nuclear antigen (PC10) immunolabelling and other proliferation indices as prognostic factors in breast cancer.

Proliferating cell nuclear antigen, PCNA (PC10), immunolabelling was determined in 175 women with breast carcinomas and related to other established prognostic factors: flow-cytometric data, volume-corrected mitotic index, sex steroid receptor content and clinical outcome during the mean follow-up of 9 years. The maximum fraction of PCNA-positive nuclei (PCNAmax), the average fraction of positive nuclei (PCNAtot) and the number of intensely stained nuclei per microscope field (PCNAcount) were significantly related to histological grade (P < 0.001), DNA ploidy ((P < 0.001), S-phase fraction (P < 0.001), mitotic index (P < 0.001) and sex steroid receptor content (P = 0.002). PCNAmax (P = 0.015) predicted survival in univariate analysis; PCNAtot (P = 0.025), PCNAmax (P = 0.007) and PCNAcount (P = 0.019) predicted the recurrence-free survival. In axillary-lymph-node-negative tumours, PCNAtot (P = 0.092), PCNAmax (P = 0.036) and PCNAcount (P = 0.006) predicted survival and recurrence-free survival (P = 0.011), (P = 0.012) and (P = 0.006) respectively. In multivariate analysis including clinical, histological, flow-cytometric and biochemical variables, PCNAtot (P = 0.004) predicted the recurrence-free survival independently. In axillary-lymph-node-negative breast cancers, PCNAtot predicted accurately the patient survival (P = 0.002) and the recurrence-free survival (P = 0.002). The results indicate that PCNA immunolabelling has independent prognostic value particularly in local breast cancer.

Adult↗

PubMed2002

Peroxisome proliferators activate growth regulatory pathways largely via peroxisome proliferator-activated receptor alpha-independent mechanisms.

Peroxisome proliferators (PPs) induce liver tumors in rodents through an unknown mechanism requiring PP-activated receptor (PPAR) alpha. Since PPs possess growth modulatory activities that may be important to their hepatocarcinogenicity, we aimed at dissociating the activation of growth signaling pathways from the PPARalpha-mediated response induced by PPs in cultured rat primary hepatocytes. Pretreatment with the differentiation-promoting agent dimethylsulfoxide (DMSO) increased PPARalpha mRNA/protein and enhanced the expression of PPARalpha-regulated genes [fatty acyl Co-A oxidase (FACO), cytochrome P450 4A1 (CYP4A1)] induced by PPs. In contrast, DMSO reduced the expression of immediate early genes (IEG) expression (c-myc, c-jun, c-fos, junB, egr-1) and inhibited mitogen-activated protein kinase (MEK) kinase/extracellular signal-regulated kinases (ERKs) and p38 phosphorylation. Furthermore, the inhibitors Tyrphostin and PD98059 dowregulated IEG/ERKs induction and slightly enhanced the FACO/CYP4A1 response induced by the PP WY-14,643. The stimulation of signal transduction pathways by PPs can be dissociated from PPARalpha activation, thus suggesting that PPs could activate growth regulatory pathways largely via PPARalpha-independent mechanisms.

Animals↗

PubMed1999

The prognostic value of cell proliferation in colorectal adenomas assessed with tritiated thymidine and anti-proliferating cell nuclear antigen.

We analyze the cell kinetics of colorectal adenomas by tritiated thymidine (3HTdR) autoradiographic method and anti-proliferating cell nuclear antigen (PCNA) antibodies. A total of 46 patients who underwent prior endoscopic polypectomy for colorectal adenomas were reevaluated by colonoscopy for 4 years. Thymidine labeling index (T-LI) in index adenomas ranged from 1.40 to 38.0% (median value: 10. 75%); PCNA labeling index (PCNA-LI) in index adenomas ranged from 0 to 27.0% (median value: 1.95%). Among the 46 patients studied, 16 developed recurrent adenomas (Group A) and 30 were free of recurrent adenomas (Group B). The T-LI and PCNA-LI comparisons between Groups A and B were statistically significant (p < 0.0001, chi2 test). These results demonstrate that T-LI and PCNA-LI in colorectal adenomas might be helpful to predict the development of metachronous adenomas and hence to plan the follow-up of patients with adenomatous polyps after polypectomy.

Adenomatous Polyps↗

PubMed1998

The proliferation of spermatogonia in normal and pathological human seminiferous epithelium: an immunohistochemical study using monoclonal antibodies against Ki-67 protein and proliferating cell nuclear antigen.

The quantitative distribution pattern of Ki-67 protein and proliferating cell nuclear antigen (PCNA) immunoreactivity was studied in human testis biopsies. In normal seminiferous epithelium Ki-67 is expressed in nuclei of spermatogonia, while PCNA additionally occurs in nuclei of primary spermatocytes. The staining pattern of spermatogonia is as follows (Ki-67-positive/PCNA-positive): 26.6 +/- 12.4%/46.3 +/- 9.5%. No stage-dependent differences were found. Biopsies with mixed atrophy (score < or =7) showed a significant (P < 0.05) decrease of immunopositive spermatogonia to 19.9 +/- 3.0%/31.4 +/- 5.7% (score 1) with minimal variation between different samples (score 7 to 1). Associated with defined histological defects such as hypospermatogenesis (hyp), spermatogenic arrest at the level of spermatids (sda), spermatocytes (sca) or spermatogonia (sga), however, there was a significant (P < 0.05) decrease of Ki-67 staining in tubules showing hyp (28.6 +/- 8.8%), sda (25.6 +/- 9.3%), sca (23.7 +/- 9.3%) and sga (16.2 +/- 6.0%) and of PCNA staining in sca (32.2 +/- 11.8%) and sga (20.0 +/- 9.5%), respectively. The decrease of immunoreactive spermatogonia did not correspond to elevation of follicle stimulating hormone (FSH). These data demonstrate that the low spermatogenic efficiency in infertile men is not only due to postmeiotic events, but also to a decrease in the meiotic activity of spermatogonia, and is not related to serum FSH.

Antibodies, Monoclonal↗

PubMed2005

p21 loss compromises the relative quiescence of forebrain stem cell proliferation leading to exhaustion of their proliferation capacity.

Adult stem cells in various tissues are relatively quiescent. The cell cycle inhibitor p21cip1/waf1 (p21) has been shown to be important for maintaining hematopoietic stem cell quiescence and self-renewal. We examined the role of p21 in the regulation of adult mammalian forebrain neural stem cells (NSCs). We found that p21-/- mice between post-natal age 60-240 d have more NSCs than wild-type (+/+) controls due to higher proliferation rates of p21-/- NSCs. Thereafter, NSCs in p21-/- mice decline and are reduced in number at 16 mo relative to p21+/+ mice. Similarly, both p21-/- and p21+/+ NSCs display self-renewal in vitro; however, p21-/- NSCs display limited in vitro self-renewal (surviving a few passages, then exhausting). Thus, p21 contributes to adult NSC relative quiescence, which we propose is necessary for the life-long maintenance of NSC self-renewal because NSCs may be limited to a finite number of divisions.

Analysis of Variance↗

PubMed1995

Assessment of cellular proliferation of eccrine acrospiromas and eccrine sweat gland carcinomas by AgNOR counting and immunohistochemical demonstration of proliferating cell nuclear antigen (PCNA) and Ki-67.

Argyrophil nucleolar organizer regions (AgNORs) were counted and immunostaining using antibodies raised against proliferating cell nuclear antigen (PCNA) and Ki-67 was carried out on eccrine acrospiroma and eccrine sweat gland carcinoma, to determine the malignant potential and prognosis of these tumours. Formalin-fixed and paraffin-embedded tissue specimens surgically excised from 25 patients with eccrine sweat gland carcinoma (20 cases of eccrine porocarcinoma, four cases of ductal sweat gland carcinoma and one case of malignant clear cell hidradenoma) and 25 patients with eccrine acrospiroma (16 cases of eccrine poroma, four cases of poroid hidradenoma and five cases of clear cell hidradenoma) were used. PCNA and Ki-67 labelling indices were categorized semiquantitatively into four grades. Significant differences were noted between eccrine sweat gland carcinoma and eccrine acrospiroma with these three methods (P < 0.01). When a cut-off of 5 was chosen, the AgNOR value distinguished eccrine sweat gland carcinoma from eccrine acrospiroma with high specificity and sensitivity. Moreover, we compared the results of these three methods between stages 1 or 2 (17 cases) and stage 3 (eight cases) eccrine sweat gland carcinomas, and no significant differences were observed. From these findings, these three methods are useful in discriminating malignant from benign lesions of eccrine tumours, but have no value in estimating the aggressiveness of eccrine sweat gland carcinomas.

Acrospiroma↗

PubMed1995

Use of bromodeoxyuridine, proliferating cell nuclear antigen, and nucleolar organizer regions in the multiparametric assessment of proliferating potency in cervical intraepithelial neoplasia.

The authors analysed of the proliferative activity of intraepithelial neoplasia of the cervix utilizing the labeling index of monoclonal antibody to Bromodeoxyuridine (BrdU) or proliferating cell nuclear antigen (PCNA), and the number of Nucleolar organizer regions (Ag-NOR). The BrdU labeling index (B.L.I.) for normal squamous epithelium, mild dysplasia, and moderate dysplasia were significantly lower than for severe dysplasia or carcinoma in situ. The PCNA labeling index (P.L.I.) for normal squamous epithelium, mild dysplasia, and moderate dysplasia were significantly lower than for severe dysplasia or carcinoma in situ. The number of Ag-NOR dots of normal squamous epithelium and mild dysplasia were lower than those of severe dysplasia or carcinoma in situ. There are significantly positive correlations of the B.L.I., P.L.I., and the number of Ag-NORs in cervical intraepithelial neoplasia.

Bromodeoxyuridine↗

PubMed1992

Detection of proliferating hepatocytes by immunohistochemical staining for proliferating cell nuclear antigen (PCNA) in patients with acute hepatic failure.

This study evaluated whether liver regeneration could take place after massive or submassive necrosis of liver cells in 25 patients with several kinds of hepatic failure by immunohistochemical staining for proliferating cell nuclear antigen (PCNA). PCNA positivity was significantly higher (P less than 0.01) in the patients who survived than in the patients who died. Furthermore, PCNA-positive hepatocytes were recognized diffusely in the lobule of the liver in survivors. There was positive correlation between PCNA positivity and plasma concentration of AFP (alpha-fetoprotein), (r = 0.77, P less than 0.01). These results show that liver regeneration could take place after massive necrosis of liver cells in survivors from acute hepatic failure and that immunohistochemical staining for PCNA is useful for prognostic evaluation.

Antibodies, Monoclonal↗

PubMed2006

Thiazolidinediones and rexinoids induce peroxisome proliferator-activated receptor-coactivator (PGC)-1alpha gene transcription: an autoregulatory loop controls PGC-1alpha expression in adipocytes via peroxisome proliferator-activated receptor-gamma coactivation.

Thiazolidinediones (TZDs) are insulin-sensitizing drugs currently used to treat type 2 diabetes. They are activators of peroxisome proliferator-activated receptor (PPAR)-gamma, and adipose tissue constitutes a major site for their biological effects. PPAR coactivator (PGC)-1alpha is a transcriptional coactivator of PPARgamma and other transcription factors. It is involved in the control of mitochondrial biogenesis, and its activity has been linked to insulin sensitization. Here we report that PGC-1alpha gene expression in brown and white adipocytes is a direct target of TZDs via PPARgamma activation. Activators of the retinoid X receptor also induce PGC-1alpha gene expression. This is due to the presence of a PPARgamma-responsive element in the distal region of the PGC-1alpha gene promoter that binds PPARgamma/retinoid X receptor heterodimers. Moreover, there is a positive autoregulatory loop of control of the PGC-1alpha gene through coactivation of PPARgamma responsiveness to TZDs by PGC-1alpha itself. These data indicate that some of the effects of TZDs, especially promotion of mitochondrial biogenesis and oxidative pathways in adipose depots, entail PGC-1alpha up-regulation via enhanced transcription of the PGC-1alpha gene.

3T3-L1 Cells↗

PubMed2002

Effect of peroxisome proliferators on Leydig cell peripheral-type benzodiazepine receptor gene expression, hormone-stimulated cholesterol transport, and steroidogenesis: role of the peroxisome proliferator-activator receptor alpha.

In this study, we hypothesized that many of the reported effects of phthalate esters and other peroxisome proliferators (PPs) in the testis are mediated by members of the PP- activated receptor (PPAR) family of transcription factors through alterations in proteins involved in steroidogenesis. Exposure of Leydig cells to PPs prevented cholesterol transport into the mitochondria after hormonal stimulation and inhibited steroid synthesis, without altering total cell protein synthesis or mitochondrial and DNA integrity. PPs also reduced the levels of the cholesterol-binding protein peripheral-type benzodiazepine receptor (PBR) because of a direct transcriptional inhibition of PBR gene expression in MA-10 Leydig cells. MA-10 cells contain mRNAs for PPARalpha and PPARbeta/delta, but not for PPARgamma. In vivo treatment of mice with PPs resulted in the reduction of both testis PBR mRNA and circulating testosterone levels, in agreement with the proposed role of PBR in steroidogenesis. By contrast, liver PBR mRNA levels were increased, in agreement with the proposed role of PBR in cell growth/tumor formation in nonsteroidogenic tissues. However, PPs did not inhibit testosterone production and testis PBR expression in PPARalpha-null mice. These results suggest that the antiandrogenic effect of PPs is mediated by a PPARalpha-dependent inhibition of Leydig cell PBR gene expression.

Androgen Antagonists↗