Expression Of Proliferation Marker Ki-67 Research Articles

Ki-67 and minichromosome maintenance-7 (MCM7) expression in canine pituitary corticotroph adenomas

Pituitary-dependent hyperadrenocorticism (PDH) caused by pituitary corticotroph adenoma is a common endocrine disorder in dogs. The ratio between pituitary height and the area of the brain (P/B) has been used to evaluate the pituitary size. A P/B ratio > 0.31 indicates an enlarged pituitary, whereas a P/B ratio ≤ 0.31 indicates a nonenlarged pituitary. The aim of this study was to investigate the expression of proliferation markers Ki-67 and minichromosome maintenance-7 (MCM7) in canine corticotroph adenomas in enlarged and in nonenlarged pituitaries and to evaluate their relation with the size of canine pituitary corticotroph adenomas. Ki-67 and MCM7 expression in ACTH-positive tumor cells was determined by dual-labeling immunohistochemistry in resected corticotroph adenomas from 15 dogs with PDH. The mean ± SD Ki-67 labeling index (LI) was 0.55% ± 0.59% in corticotroph adenomas with nonenlarged pituitaries and 1.6% ± 0.6% in adenomas with enlarged pituitaries. The MCM7 LI in corticotroph adenomas with nonenlarged pituitaries and in adenomas with enlarged pituitaries was 2.9% ± 2.2% and 10.9% ± 3.7%, respectively. The Ki-67 LI and MCM7 LI were significantly greater in the adenomas with enlarged pituitaries than in the adenomas with nonenlarged pituitaries ( P < 0.01 and P < 0.01, respectively). The MCM7 LI was significantly greater than the Ki-67 LI in adenomas ( P < 0.01). The Ki-67 LI was positively correlated with the MCM7 LI ( r = 0.820, P < 0.01), and the P/B ratio was positively correlated with the Ki-67 LI ( r = 0.560, P = 0.03) and the MCM7 LI ( r = 0.854, P < 0.01). In conclusion, canine corticotroph adenomas in enlarged pituitaries show greater proliferation potential than do adenomas in nonenlarged pituitaries. MCM7 expression was significantly greater than Ki-67 expression in canine pituitary corticotroph adenomas. Thus, MCM7 may be superior to Ki-67 as a proliferation marker in pituitary tumors.

A High Proliferative Index of Recurrent Melanoma Is Associated with Worse Survival

Objective: Previous melanoma studies evaluating prognostic factors of survival at recurrence have focused on primary tumor characteristics and clinical variables at first recurrence. We examined the prognostic relevance of recurrent tumor proliferation. Methods: 114 melanoma patients with available recurrent tissues who were prospectively enrolled at New York University Medical Center were studied. Standard of care prognostic variables (e.g. stage at initial diagnosis and lactate dehydrogenase level) and recurrent tissue expression of proliferative marker Ki-67 were evaluated for their association with overall survival. Results: High Ki-67 expression was observed in 57 (50%) of the 114 recurrent melanomas. On univariate analysis, the median overall survival of patients whose recurrent tumors overexpressed Ki-67 was significantly shorter than that of patients whose recurrent tumors had low Ki-67 expression (3.6 vs. 9.5 years, p = 0.03). On multivariate analysis, a high proliferative index of the recurrent melanoma remained an independent predictor of worse overall survival, controlling for stage at initial diagnosis, disease-free survival, and stage at first recurrence [HR = 2.09 (95% CI 1.24–3.54), p = 0.006]. Conclusions: Our results demonstrate the prognostic relevance of tumor proliferation in recurrent melanoma patients. Data also support restratification of risk assessment upon recurrence that considers tumor biology in addition to clinical variables evaluated as part of the standard of care.

Inhibition of aldose reductase prevents angiogenesis in vitro and in vivo

We have recently shown that aldose reductase (AR, EC 1.1.1.21) a nicotinamide adenine dinucleotide phosphate-dependent aldo-keto reductase, known to be involved in oxidative stress-signaling, prevents human colon cancer cell growth in culture as well as in nude mice xenografts. Inhibition of AR also prevents azoxymethane-induced aberrant crypt foci formation in mice. In order to understand the chemopreventive mechanism(s) of AR inhibition in colon cancer, we have investigated the role of AR in the mediation of angiogenic signals in vitro and in vivo models. Our results show that inhibition of AR significantly prevented the VEGF- and FGF -induced proliferation and expression of proliferative marker Ki67 in the human umbilical vein endothelial cells (HUVEC). Further, AR inhibition or ablation with siRNA prevented the VEGF- and FGF -induced invasion and migration in HUVEC. AR inhibition also prevented the VEGF- and FGF- induced secretion/expression of IL-6, MMP2, MMP9, ICAM, and VCAM. The anti-angiogenic feature of AR inhibition in HUVEC was associated with inactivation of PI3K/AKT and NF-κB (p65) and suppression of VEGF receptor 2 protein levels. Most importantly, matrigel plug model of angiogenesis in rats showed that inhibition of AR prevented infiltration of blood cells, invasion, migration and formation of capillary like structures, and expression of blood vessels markers CD31 and vWF. Thus, our results demonstrate that AR inhibitors could be novel agents to prevent angiogenesis.

Hepatic Expression of the Proliferative Marker Ki-67 and cell cycle p53 Protein in chronic hepatitis C (A histopathological and immunohistochemical study)

Aim and background: To evaluate hepatic expression of the nuclear proliferative marker Ki-67 and the cell cycle marker p53 oncoprotein in chronic hepatitis C in relation to the advanced stages of liver fibrosis in HCV positive Egyptian patients. Material & Methods: Paraffin-embedded liver biopsy specimens were studied from 21 untreated patients with chronic HCV infection. All patients were HCV antibody positive, as determined by a commercially available enzyme-linked immunosorbent assay kit. Patients having other etiologies for chronic liver disease including HBV infection were not included in this study. Liver biopsies were obtained percutaneous. All biopsies were fixed in formalin, embedded in paraffin, and sectioned by microtome with a thickness of 5 µm. Routine specimen processing involved staining slides with hematoxylin and eosin (5 levels), Masson's trichrome stain (5 levels), for a total of 10 levels per specimen All levels were screened. All specimens were examined by two pathologists, and classified by consensus for all abnormal histological findings. The histological activity index (or histological grade) was determined using Ishak grading scheme22 expressed as a semiquantitative score for portal inflammation (0-4), lobular activity sporadic lytic foci (0-4) and parenchymal confluent necrosis (0-6), and piecemeal necrosis(0-4). The extent of fibrosis (or histological stage) was determined using Ishak score (0-6). Steatosis was scored according to Keliner et al 2005, from grade 0 to 3; where S0 = no steatosis or less than 5% (low or medium power evaluation) of parenchymal involvement by fatty changes, S1 (mild) = 5%-33%, S2 (moderate) = >33%-66% and S3 (severe) > 66% of the hepatocytes are involved by fatty changes. Expression of p53 and Ki67 were determined by immunohistochemistry, using avidin-biotin-peroxidase. Results: Liver histology: The studied group (n = 21) involved 16 males and 5 females (male to female ratio 3.3:1). The histopathological findings of HCV infection, including portal lymphoid infiltration, periportal piecemeal necrosis, lymphocyte infiltration of the lobules, hepatocellular necrosis, steatosis and fibrosis, were studies. The age ranged from 31 to 59 years old with mean of 44.86 ± 8.74, males 76.2%, females 23.8% .P53 expression was positive in 52.4% and negative in 47.6%. cytoplasmic localization dominated over nuclear expression. Ki 67 was negative in 81% of cases and positive in19% of cases, all cases in stage 6 were positive for p53 while there were no difference in the other stages of fibrosis, and this relation was statistically significant. There was no relation between the grade of necro-inflammation and the expression of p53, and this result was statistically non significant.There was a relation between the percent of steatosis and the expression of p53 as percent of positivity increases with the increase of the percent of steatosis, and this result was statistically significant using independent sample t test and regression test.All negative cases for P53 have negative Ki67 but this rule is not applied on positive cases for P53, and this relation was not statistically significant There was no relation between the grade of necro-inflammation and the expression of Ki67, and this result was statistically non significant. Conclusion: Hepatic expression of the nuclear proliferative marker Ki-67 and the cell cycle marker p53 oncoprotein in chronic hepatitis C in relation to advanced stages of liver fibrosis in HCV positive patients are expressed in a considerable present of cases which should be cansdidates for follow up for early detection of hepatocellular carcinoma.

Hepatic Expression of the Proliferative Marker Ki-67 and cell cycle p53 Protein in chronic hepatitis C (A histopathological and immunohistochemical study)

Aim and background: To evaluate hepatic expression of the nuclear proliferative marker Ki-67 and the cell cycle marker p53 oncoprotein in chronic hepatitis C in relation to the advanced stages of liver fibrosis in HCV positive Egyptian patients. Material & Methods: Paraffin-embedded liver biopsy specimens were studied from 21 untreated patients with chronic HCV infection. All patients were HCV antibody positive, as determined by a commercially available enzyme-linked immunosorbent assay kit. Patients having other etiologies for chronic liver disease including HBV infection were not included in this study. Liver biopsies were obtained percutaneous. All biopsies were fixed in formalin, embedded in paraffin, and sectioned by microtome with a thickness of 5 µm. Routine specimen processing involved staining slides with hematoxylin and eosin (5 levels), Masson's trichrome stain (5 levels), for a total of 10 levels per specimen All levels were screened. All specimens were examined by two pathologists, and classified by consensus for all abnormal histological findings. The histological activity index (or histological grade) was determined using Ishak grading scheme22 expressed as a semiquantitative score for portal inflammation (0-4), lobular activity sporadic lytic foci (0-4) and parenchymal confluent necrosis (0-6), and piecemeal necrosis(0-4). The extent of fibrosis (or histological stage) was determined using Ishak score (0-6). Steatosis was scored according to Keliner et al 2005, from grade 0 to 3; where S0 = no steatosis or less than 5% (low or medium power evaluation) of parenchymal involvement by fatty changes, S1 (mild) = 5%-33%, S2 (moderate) = >33%-66% and S3 (severe) > 66% of the hepatocytes are involved by fatty changes. Expression of p53 and Ki67 were determined by immunohistochemistry, using avidin-biotin-peroxidase. Results: Liver histology: The studied group (n = 21) involved 16 males and 5 females (male to female ratio 3.3:1). The histopathological findings of HCV infection, including portal lymphoid infiltration, periportal piecemeal necrosis, lymphocyte infiltration of the lobules, hepatocellular necrosis, steatosis and fibrosis, were studies. The age ranged from 31 to 59 years old with mean of 44.86 ± 8.74, males 76.2%, females 23.8% .P53 expression was positive in 52.4% and negative in 47.6%. cytoplasmic localization dominated over nuclear expression. Ki 67 was negative in 81% of cases and positive in19% of cases, all cases in stage 6 were positive for p53 while there were no difference in the other stages of fibrosis, and this relation was statistically significant. There was no relation between the grade of necro-inflammation and the expression of p53, and this result was statistically non significant.There was a relation between the percent of steatosis and the expression of p53 as percent of positivity increases with the increase of the percent of steatosis, and this result was statistically significant using independent sample t test and regression test.All negative cases for P53 have negative Ki67 but this rule is not applied on positive cases for P53, and this relation was not statistically significant There was no relation between the grade of necro-inflammation and the expression of Ki67, and this result was statistically non significant. Conclusion: Hepatic expression of the nuclear proliferative marker Ki-67 and the cell cycle marker p53 oncoprotein in chronic hepatitis C in relation to advanced stages of liver fibrosis in HCV positive patients are expressed in a considerable present of cases which should be cansdidates for follow up for early detection of hepatocellular carcinoma.

Increased Turnover of FoxP3high Regulatory T Cells Is Associated With Hyperactivation and Disease Progression of Chronic HIV-1 Infection

To characterize the homeostasis of CD4FoxP3 regulatory T cells (Treg) and its association with immune hyperactivation in the disease progression of chronic HIV-1 infection. Treg proliferation and apoptosis markers were determined and the relation to disease progression and Treg activation was analyzed. Fifty-six HIV-1-infected highly active antiretroviral therapy (HAART)-naive subjects and 17 HAART-treated subjects were enrolled. Proliferation and apoptosis of Treg from peripheral blood were evaluated by intracellular Ki-67 and active caspase-3 or surface Annexin-V staining. T-cell activation markers, CD38 and HLA-DR, were simultaneously monitored. The effects of in vitro TCR (T cell receptor) stimulation on proliferation, apoptosis, and activation of Treg were determined from both HIV-1-infected subjects and healthy controls. HIV-1-infected patients displayed increased Treg turnover status indicated by higher expression of proliferation marker Ki-67 and apoptosis marker active caspase-3 and Annexin-V. Turnover level of Treg was positively associated with disease progression and immune hyperactivation. In vitro TCR stimulation increased the turnover level of Treg. The HAART treatment decreased the turnover and activation levels of Treg in complete responders. Turnover level of Treg was increased in HIV-1-infected subjects, which is associated with immune hyperactivation and the disease progression, and may serve as a surrogate marker to predict HIV-1 disease progression.

Cyclic Morphological Changes in the Beagle Mammary Gland

Interpretation of chemical-induced effects on the female beagle mammary gland can be difficult owing to the wide variation of normal glandular morphology. In this retrospective study, morphological features of the gland in four (proestrus, estrus, diestrus, and anestrus) phases of the cycle are described. The gland was quiescent (inactive) in proestrus and estrus. In diestrus, with the rise of progesterone, four (I-IV) distinct morphological changes were evident. In phase I, there was exuberant stromal and ductal proliferation. In phase II, there was early lobular development with branching ducts and alveolar proliferation. In phase III, there was an abundance of glandular tissue with large lobules containing secretory material, whereas phase IV had features of early regression, increased interlobular connective tissue, and eosinophilic secretions in distended ducts and acini. In early anestrus, ducts were distended, with eosinophilic secretions with alveolar regression, whereas regression was complete in late anestrus. Glandular morphology was slightly variable in the mammary chain within the same dog. Progesterone receptor expression was prominent in estrus and early diestrus, and peak estrogen receptor expression was noted in diestrus II. Expression of proliferation marker ki-67 was highest in diestrus I, followed by diestrus II. There was excellent concordance between the estrous stage and the glandular morphology.

Proliferation and motility of HaCaT keratinocyte derivatives is enhanced by fibroblast nemosis

The role of paracrine tumor-stroma regulation in the progression of cancer is under intense investigation. Activated fibroblasts are key components of the tumor microenvironment providing the soluble factors mediating the regulation. Nemosis is an experimental model to study these parameters: formation of a multicellular spheroid activates fibroblasts and leads to increased production of soluble factors involved in the promotion of growth and motility. Role of nemosis was investigated in the tumorigenesis of HaCaT derivatives representing skin carcinoma progression. Conditioned medium from fibroblast spheroids increased proliferation rate of HaCaT derivatives. Expression of proliferation marker Ki-67 increased significantly in benign A5 and low-grade malignant II-4 cells, but did not further increase in the metastatic RT3 cells. Expression of p63, keratinocyte stem cell marker linked to cancer progression, was augmented by medium from nemotic fibroblasts; this increase was also seen in RT3 cells. Scratch-wound healing of the keratinocytes was enhanced in response to fibroblast nemosis. Neutralizing antibodies against growth factors inhibited wound healing to some extent; the response varied between benign and malignant keratinocytes. Migration and invasion were enhanced by conditioned medium from nemotic fibroblasts in benign and low-grade malignant cells. RT3 keratinocyte migration was further augmented, but invasion was not, indicating their intrinsic capacity to invade. Our data demonstrate that fibroblast nemosis increases proliferation and motility of HaCaT keratinocyte derivatives, and thus nemosis can be used as a model to study the role of soluble factors secreted by fibroblasts in tumor progression.

Reduced or absent cyclin H expression is an independent prognostic marker for poor outcome in diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults, accounting for nearly 40% of all non-Hodgkin's lymphomas. As cell proliferation is essential for tumor growth, analysis of the cell cycle might give additional information on tumor progression. Although markers distinctive for cell-cycle regulation in DLBCL have been addressed, less attention has been paid to cyclin H in DLBCL with respect to its prognostic and potential therapeutic implications. Cyclin H occurs as a component of the cyclin H/Cdk 7/Mat 1 complex. Cyclin H is also a substrate of protein kinase 2, a ubiquitously expressed serine/threonine protein kinase required for cell viability and cell-cycle progression. We evaluated the expression of cyclin H by immunohistochemistry in 301 DLBCLs in a tissue microarray format. Validation was done by performing quantitative real-time polymerase chain reaction and Western blotting experiments for cyclin H. We studied the relationship between cyclin H expression in comparison to other cyclins (A, B1, D1, D3, and E) and the proliferation marker Ki-67. Reduced or absent cyclin H expression was seen in 14.5% of the DLBCL cases. Interestingly, reduced or absent cyclin H expression was correlated with lower expression of proliferation marker Ki-67 (P < .0001), cyclin B1 (P = .0001), cyclin D3 (P = .0007), and cyclin E (P < .0001). Reduced or absent cyclin H expression was significantly associated with poor overall survival, in both the univariate (P = .0286) and multivariate analysis with International Prognostic Index (P = .0180). Our study demonstrates the independent prognostic value of cyclin H expression in DLBCL and proposes its use as a prognostic marker.

Comparative effects of 17β-estradiol and phytoestrogens in the regulation of endometrial functions in the rodent uterus

The present study aimed at improving our understanding of the effects of 17beta-estradiol and phytoestrogens on the uterine tissue, by evaluating tissue-specific modulation of molecules related to cell-cycle control and angiogenesis. Specifically, the uterine expression of Ki67, peroxisome proliferator-activated receptor gamma (PPARgamma), and vascular endothelial growth factor receptor-2 (VEGFR-2), was examined by immunohistochemical analysis. Ovariectomized (OVX) rats were treated with either the vehicle, a phytoestrogen- containing soy extract (SSE) (100 mg/kg/day pos), or 17beta-estradiol (0.5 mg/kg/day pos); a sham control group (SHAM) was also included in the study. At necropsy, uteri were weighed, collected, and subsequently processed for histopathology or immunohistochemistry. SSE-treated rats did not show any significant change either in the weight or in histological features of the uterus when compared to OVX controls; the epithelial expression of proliferation marker Ki67 was seen to be significantly reduced, in comparison to both SHAM and OVX rats. Conversely, 17beta-estradiol significantly increased uterine weight, induced hyperplasia in the majority of rats, and enhanced Ki67 epithelial expression. The regulation of PPARgamma expression, reduced after ovariectomy, was similar in SSE- and 17beta-estradiol-treated rats, showing a further significant decrease in stromal immunostaining, in comparison to OVX controls. VEGFR-2 epithelial immunostaining, slightly reduced following ovariectomy, was highly increased on 17beta-estradiol treatment, while following SSE, the pattern of staining observed was similar to that of OVX controls. Data from this study show that PPARgamma and VEGFR-2 represent additional targets by which sex steroid estrogen and plant-derived phytoestrogens may, at certain doses, differentially regulate endometrial functions.

Expression of proliferation marker Ki67 correlates to occurrence of metastasis and prognosis, histological subtypes and HPV DNA detection in penile carcinomas.

Clinical outcome of penile squamous cell carcinoma (PSCC) largely depends on the presence of lymph node metastasis. In search of a valuable marker predicting the risk for metastasis, the expression of Ki67 was investigated immunohistochemically in primary tumors and compared to presence of inguinal lymph node metastasis. As human papilloma virus (HPV) is thought to affect Ki67 expression, we evaluated whether occurrence of HPV DNA correlates to Ki67 score or metastatic potential. Samples originated from patients subjected to resection of invasive SCC of penis. Immunohistochemistry was done on paraffin-embedded sections using a monoclonal antibody against Ki67. After DNA isolation from paraffin embedded tissue the presence of HPV 6/11, HPV 16 and HPV 18 DNA was analyzed by PCR. Statistical analysis was done using two tail unpaired t test and Chi-square test. Four of 28 patients showed a weak Ki67 expression, without displaying lymph node metastasis. Among 17 patients showing an intermediate Ki67 index, eight exhibited metastases while in all seven patients with a strong expression of Ki67 lymph node metastases were found. The median Ki67 expression in metastastic lesions was significantly different (50.3%) from tumors without lymph node metastasis (31.8%) (p=0.024). Furthermore, a correlation between presence of HPV DNA and strong Ki67 expression was determined (p=0.009). Since our study demonstrated a strong Ki67 labeling index significantly associated to positive lymph nodes, we suggest Ki67 expression as a prognostic marker for lymph node metastasis in penile squamous carcinoma.

Immunohistochemical Characterization and Evaluation of Prognostic Factors in Canine Oral Melanomas with Osteocartilaginous Differentiation

Melanomas are the most common malignant oral neoplasm in dogs. Osteocartilaginous differentiation in oral melanomas is a rare feature described both in veterinary and human medicine. Here, 10 cases of this type of neoplasm were used to study their immunohistochemical, biological, and clinical characteristics. Reactivity for S100 and melan A antigen was evaluated, and 4 prognosis factors (mitotic index, invasiveness of epithelium, nuclear atypia, and proliferation index) were analyzed and correlated with the clinical course of the neoplasms after diagnosis. Immunohistochemical analysis of the studied neoplasms, including the osteocartilaginous areas, showed positive immunoreaction for S100 and melan A, except in one dog, which was negative for melan A. Analysis of the results showed that oral melamonas with osteocartilaginous differentiation have a clinical course similar to that of other melanomas in the oral cavity. Analysis of the mitotic index and the expression of proliferation marker Ki-67 could be useful tools for predicting the biological behavior of these neoplasms.

Immunohistochemical detection of cdc2 is useful in predicting survival in patients with mantle cell lymphoma

Recent cDNA microarray studies have reported the prognostic value of several genes in mantle cell lymphoma patients. We aimed to validate the prognostic significance of three of these genes: α-tubulin, cdc2, and CENP-F. The protein expression of α-tubulin, cdc2, and CENP-F was assessed using immunohistochemistry. Their immunoreactivity in 48 formalin-fixed/paraffin-embedded mantle cell lymphoma tumors was determined by estimating the percentage of positive cells. These results were correlated with the expression of proliferation marker Ki67 and survival. Of these 48 mantle cell lymphoma patients, 41 were men and seven were women. The median age at time of diagnosis was 64.5 years, and the overall median survival was 40 months. In benign lymph nodes, the expression of cdc2 and α-tubulin was restricted to the germinal centers; mantle zones were negative. Expression of CENP-F was more uniformly distributed. In mantle cell lymphoma, Ki67 significantly correlated with all three markers (P<0.05, Spearman), but only Ki67 (>50%) and cdc2 (>25%) significantly correlated with shorter survival (P<0.0006, Spearman). Of several clinical parameters examined, international prognostic index of ≥2 correlated with worse clinical outcome, and high clinical stage (ie 4 vs ≤3) showed a trend for shorter survival. The prognostic significance of cdc2 and Ki67 was independent of international prognostic index and clinical stage. We have validated the prognostic value of cdc2, and confirmed that of Ki67, in a cohort of mantle cell lymphoma patients. Immunohistochemical detection of cdc2 and Ki67 may be a useful and simple method in evaluating the prognosis of mantle cell lymphoma patients.

The role of p-STAT3 (ser727) revealed by its association with Ki-67 in cervical intraepithelial neoplasia

Objectives. Constitutive activation of signal transducer and activator of transcription 3 (STAT3) has been described in many types of cancers. However, the role of phospho-STAT3 (p-STAT3) at serine residue 727 is in large part undetermined. Our purposes of this study were to evaluate the expression patterns of p-STAT3 (ser727) in cervical intraepithelial neoplasia (CIN) and to explore its possible role in the progression of cervical cancer. Methods. Paraffin-embedded sections from 56 patients including 20 CIN 1, 10 CIN 2, and 26 CIN 3 were collected in this study. Immunohistochemical analysis was performed, and the expression patterns of p-STAT3 (ser727) were categorized by semiquantitative method and further correlated with the CIN histopathologic grade using the χ 2 test with Bonferroni adjustment for multiple comparisons and with the proliferation marker Ki-67 expression using Fisher's Exact Test. Results. The categorized high p-STAT3 (ser727) expression group in nuclei of dysplastic cells was significantly higher in CIN 3 (76.92%), in comparison with CIN 1/2 (13.33%, P < 0.001). Moreover, both the nuclear and cytoplasmic p-STAT3 (ser727) expressions were correlated with Ki-67 nuclear staining ( P < 0.001 and < 0.001, respectively). Conclusions. Our result revealed that aberrant expression levels of p-STAT3 (ser727) were significantly correlated with CIN lesion grade and cell proliferation. Evaluation of p-STAT3 (ser727) expression may provide additional prognostic information for the clinical course of the disease and therefore to be developed as a prognostic indicator for cervical cancer.

Expression of cyclin-dependent kinase inhibitors, p21cip1 and p27kip1, during wound healing in rats.

Wound healing is a physiological process in which growth of cells is stringently regulated. Cell growth is controlled by cell cycle-related proteins in which the cyclin kinase inhibitors cause cell cycle arrest and inhibit proliferation. However, little is known about the expression and the role of cyclin kinase inhibitors during wound healing in vivo. This study was mainly designed to examine the expression of p21cip1 and p27kip1 in excisional wounds of full-thickness skin in rats. Concomitant expression of proliferation marker Ki67 was also examined. Proliferation predominantly occurred in the first week after injury, peaking at postwounding day 5. Expression of both p21cip1 and p27kip1 at the gene and protein levels did occur during wound healing and showed an inverse gradient to that of Ki67. Constitutive p27kip1 was expressed throughout wound healing with low levels during the proliferating period of days 3 and 5 and increased levels during post-mitotic and remodeling stages. In contrast, p21cip1 was expressed transiently with detectable levels only between days 7 and 14 by Western blot analysis. Immunohistochemically, epithelial cells, endothelial cells and fibroblasts all could express both p21cip1 and p27kip1. In conclusion, the overall results suggested that p21cip1 and p27kip1 may play a key role in supervising the growth resulting from cell proliferation in tissue repair.

Expression of the proliferation markers Ki67 and transferrin receptor by human trophoblast populations

Immunohistochemical techniques were used to investigate the expression of proliferation markers (Ki67 and transferrin receptor) by fetal trophoblast in normal human pregnancy. In placental villous tissue, transferrin receptor was detected not only on the apical syncytiotrophoblastic membrane but also on the proximal portion of cytotrophoblast columns, an area of high cellular proliferative activity. The majority of cells in cytotrophoblast columns and shell showed nuclear reactivity with Ki67. Villous syncytiotrophoblast was uniformly unreactive with Ki67 but a proportion of the underlying cytotrophoblast was Ki67-positive throughout pregnancy. Occasional Ki67-positive trophoblast cells were identified within chorion laeve at term. In contrast, interstitial and endovascular extravillous trophoblast in maternal uterine decidual tissue failed to label with either proliferation marker. Thus, chorionic villous cytotrophoblast and extravillous trophoblast in the chorion laeve appear to retain their proliferative capacity into late pregnancy. Cytotrophoblast columns represent a zone of cellular proliferation which may be dependent on transferrin.