Minichromosome maintenance proteins 2 and 5 in non-benign epithelial ovarian tumours: relationship with cell cycle regulators and prognostic implications

Minichromosome maintenance proteins (MCM) have recently emerged as novel proliferation markers with prognostic implications in several tumour types. This is the first study investigating MCM-2 and MCM-5 immunohistochemical expression in a series of ovarian adenocarcinomas and low malignant potential (LMP) tumours aiming to determine possible associations with clinicopathological parameters, the conventional proliferation index Ki-67, cell cycle regulators (p53, p27Kip1, p21WAF1 and pRb) and patients' outcome. Immunohistochemistry was applied in a series of 43 cases of ovarian LMP tumours and 85 cases of adenocarcinomas. Survival analysis was restricted to adenocarcinomas. The median MCM-2 and MCM-5 labelling indices (LIs) were significantly higher in adenocarcinomas compared to LMP tumours (P<0.0001 for both associations). In adenocarcinomas, the levels of MCM-2 and MCM-5 increased significantly with advancing tumour stage (P=0.0052 and P=0.0180, respectively), whereas both MCM-2 and MCM-5 increased significantly with increasing tumour grade (P=0.0002 and P=0.0006, respectively) and the presence of bulky residual disease (P<0.0001 in both relationships). A strong positive correlation was established between MCM-2 or MCM-5 expression level and Ki-67 LI (P<0.0001) as well as p53 protein (P=0.0038 and P=0.0500, respectively). Moreover, MCM-2 LI was inversely correlated with p27Kip−1 LI (P=0.0068). Finally, both MCM-2 and MCM-5 were associated significantly with adverse patients' outcome in both univariate (⩾20 vs >20%, P=0.0011 and ⩾25 vs <25%, P=0.0100, respectively) and multivariate (P=0.0001 and 0.0090, respectively) analysis. An adequately powered independent group of 45 patients was used in order to validate our results in univariate survival analysis. In this group, MCM-2 and MCM-5 expression retained their prognostic significance (P<0.0001 in both relationships). In conclusion, MCM-2 and MCM-5 proteins appear to be promising as prognostic markers in patients with ovarian adenocarcinomas

Expression of Ser729 phosphorylated PKCepsilon in experimental crescentic glomerulonephritis: an immunohistochemical study

Normal 0 false false false EL X-NONE X-NONE MicrosoftInternetExplorer4 PKCε, a DAG-dependent, Ca2+- independent kinase attenuates extent of fibrosis following tissue injury, suppresses apoptosis and promotes cell quiescence. In crescentic glomerulonephritis (CGN), glomerular epithelial cells (GEC) contribute to fibro-cellular crescent formation while they also transdifferentiate to a mesenchymal phenotype. The aim of this study was to assess PKCε expression in CGN. Using an antibody against PKC-ε phosphorylated at Ser729, we assessed its localization in rat model of immune-mediated rapidly progressive CGN. In glomeruli of control animals, pPKCε was undetectable. In animals with CGN, pPKCε was expressed exclusively in glomerular epithelial cells (GEC) and in GEC comprising fibrocellular crescents that had acquired a myofibroblast-type phenotype. In non-immune GEC injury induced by puromycin aminonucleoside and resulting in proteinuria of similar magnitude as in CGN, pPKCε expression was absent. There was constitutive pPKCε expression in distal convoluted tubules, collecting ducts and thick segments of Henley’s loops in both control and experimental animals. We propose that pPKCε expression occurring in GEC and in fibrocellular crescentic lesions in CGN may facilitate PKCε dependent pathologic processes. st1\:*{behavior:url(#ieooui) }st2\:*{behavior:url(#ieooui) } /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Κανονικός πίνακας"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;} <![endif]--

Understanding the complement-mediated glomerular diseases: focus on membranoproliferative glomerulonephritis and C3 glomerulopathies

An enhanced understanding of the role of complement in the pathogenesis of membranoproliferative glomerulonephritis has led to reclassification of the latter into immunoglobulin-mediated and non-immunoglobulin-mediated disease. The new classification schema resulted in improved diagnostic clinical algorithms, while it brought into light again the diseases, which are characterized by the presence of glomerular deposits, composed predominantly by C3, in the absence of significant amounts of immunoglobulins in renal biopsy, namely, C3 glomerulopathies (dense deposit disease and C3 glomerulonephritis). Despite the lack of randomized controlled trials following the advances in the understanding of the pathogenetic pathways involved in membranoproliferative glomerulonephritis, it is important that the new mechanistic approach has opened new roads for the exploration and discovery of targeted therapies. © 2016 APMIS. Published by John Wiley &amp; Sons Lt

Histone Deacetylase (HDAC) Inhibitors: A Promising Weapon to Tackle Therapy Resistance in Melanoma

Melanoma is an aggressive malignant tumor, arising more commonly on the skin, while it can also occur on mucosal surfaces and the uveal tract of the eye. In the context of the unresectable and metastatic cases that account for the vast majority of melanoma-related deaths, the currently available therapeutic options are of limited value. The exponentially increasing knowledge in the field of molecular biology has identified epigenetic reprogramming and more specifically histone deacetylation (HDAC), as a crucial regulator of melanoma progression and as a key driver in the emergence of drug resistance. A variety of HDAC inhibitors (HDACi) have been developed and evaluated in multiple solid and hematologic malignancies, showing promising results. In melanoma, various experimental models have elucidated a critical role of histone deacetylases in disease patho-genesis. They could, therefore, represent a promising novel therapeutic approach for advanced disease. A number of clinical trials assessing the efficacy of HDACi have already been completed, while a few more are in progress. Despite some early promising signs, a lot of work is required in the field of clinical studies, and larger patient cohorts are needed in order for more valid conclusions to be extracted, regarding the potential of HDACi as mainstream treatment options for melanoma. © 2022 by the authors. Licensee MDPI, Basel, Switzerland

Expression of Ser(729) phosphorylated PKCepsilon in experimental crescentic glomerulonephritis: an immunohistochemical study

PKCe, a DAG-dependent, Ca2+- independent kinase attenuates extent of fibrosis following tissue injury, suppresses apoptosis and promotes cell quiescence. In crescentic glomerulonephritis (CGN), glomerular epithelial cells (GEC) contribute to fibro-cellular crescent formation while they also transdifferentiate to a mesenchymal phenotype. The aim of this study was to assess PKCe expression in CGN. Using an antibody against PKC-epsilon phosphorylated at Ser(729), we assessed its localization in rat model of immune-mediated rapidly progressive CGN. In glomeruli of control animals, pPKC epsilon was undetectable. In animals with CGN, pPKC epsilon was expressed exclusively in glomerular epithelial cells (GEC) and in GEC comprising fibrocellular crescents that had acquired a myofibroblasttype phenotype. In non-immune GEC injury induced by puromycin aminonucleoside and resulting in proteinuria of similar magnitude as in CGN, pPKCe expression was absent. There was constitutive pPKC epsilon expression in distal convoluted tubules, collecting ducts and thick segments of Henley’s loops in both control and experimental animals. We propose that pPKCe expression occurring in GEC and in fibrocellular crescentic lesions in CGN may facilitate PKCe dependent pathologic processes

Differential immunohistochemical expression of CD44s, E-cadherin and β-catenin among hyperplastic and neoplastic lesions of the prostate gland

Introduction: CD44s, E-cadherin and β-catenin are cell adhesion molecules (CAMs) and appear to influence organ development, inflammation, cancer invasion and metastasis. We studied the expression of these CAMs in prostate cancer (PCa), high-grade prostatic intraepithelial neoplasia (HGPIN) and nodular adenomatous hyperplasia (NH). Materials and Methods: 135 paraffin blocks of radical prostatectomy specimens were assessed. CAMs were determined by immunohistochemistry. All sections included PCa, HGPIN and NH. The expression was semiquantitatively evaluated in three scores (1+, 2+, 3+). The markers&apos; immunopositivity was statistically investigated with Gleason score and TNM stage. Results and Conclusions: CD44s had score 3+ in 41.5, 46.7 and 37.8% of areas with NH, HGPIN and PCa, respectively. E-cadherin immunostaining was highly detected in 71.1, 78.5 and 63.0% of NH, HGPIN and PCa areas while β-catenin score 3+ was exclusively membranous in 80.7% of NH and nuclear/cytoplasmic in 70.4 and 48.9% of HGPIN and PCa areas. No marker related to the Gleason score (p = 0.352). CD44s and E-cadherin expression was inversely associated with TNM stage (p = 0.021 and p = 0.042, respectively); no such association was observed for β-catenin (p = 0.556). The decreased expression of CD44s and E-cadherin is probably associated with the invasive potential of PCa. The β-catenin staining pattern in neoplastic lesions, either preinvasive or invasive, differs from that in non-neoplastic prostate lesions. Copyright © 2012 S. Karger AG, Basel

Matrix metalloproteinase-1 and -3 in breast cancer: Correlation with progesterone receptors and other clinicopathologic features

Although matrix metalloproteinases (MMPs) are implicated in breast cancer progression, the contribution of MMP-1 and MMP-3 to this process, has not been thoroughly investigated. Matrix metalloproteinases (MMPs) are important at several points during multistage neoplastic progression. Immunohistochemistry (Strept-ABC-HRP method) and in situ hybridization were performed to detect MMP-1, MMM-3 proteins, and MMP-3 mRNA, respectively, in 77 infiltrative breast carcinomas. MMP-1, MMP-3 protein, and MMP-3 mRNA detection were analyzed in parallel with clinicopathologic features (menopausal status, histological type, nuclear and histological grade, stage) and the immunohistochemical reactivity of estrogen (ER), progesterone (PR) receptors, and c-erbB-2 oncoprotein in breast carcinomas. Statistical analysis was performed using the multiple linear regression test.. Immunoreactivity for MMP-1 and MMP-3 was observed in 59 of 77 (77%) and 22 of 77 (28.5%) breast carcinomas and was evaluated separately in cancer cells and in stromal fibroblasts. MMP-3 mRNA was detected in 72 of 77 (93.5%) carcinomas exclusively in stromal cells within the tumors or in the marginal portion, of tumors. MMP-1 protein immunoreactivity in stromal fibroblasts but not in cancer cells showed a statistically significant correlation with tumor stage (P = .04). MMP-1 reactivity either in stromal or in cancer cells showed a statistically significant inverse correlation with PR expression (P = .04 and P = .04, respectively). MMP-3 protein immunoreactivity in cancer or stromal cells and MMP-3 mRNA expression was not associated with the clinicopathologic features studied. MMP-3 mRNA was detected more often in ductal carcinomas. These results indicate that MMP-1 may contribute to breast cancer invasiveness. Furthermore, they suggest differential functions for MMP-1 and MMP-3 in breast cancer progression. Copyright (C) 1999 by W.B. Saunders Company

The role of the VEGF-C/-D/flt-4 autocrine loop in the pathogenesis of salivary neoplasms

Salivary gland cells produce and secrete VEGF under normal conditions, but this property has not been studied in salivary gland neoplasms. The aim of this study was to evaluate the expression of VEGF-C/VEGF-D/flt-4 in salivary gland tumors.Thirty-one salivary gland tumors (19 with and 12 without myoepithelial differentiation) were examined. Immunostaining for VEGF-C/VEGF-D/flt-4, p63 and SMA was carried out. The chi-square distribution and the Pearson correlation were applied.A statistically significant relationship (p&lt;0.05) was found in the group of tumors with myoepithelial differentiation regarding simultaneous positive staining for VEGF-C/VEGF-D and flt-4. All pleomorphic adenomas (PA) exhibited a statistically significant coexpression of the three antibodies. p63 and SMA were strongly expressed in the same areas as VEGF-C, VEGF-D and flt-4.The cells responsible for the strong expression of VEGF-C, VEGF-D and flt-4 in PAs are myoepithelial cells. Coexpression of flt-4 and its ligands in all PAs suggests the presence of a dominant VEGF-C/VEGF-D/flt-4 axis in this tumor. © 2012 Elsevier GmbH

Phenotypic characterization of a novel HO-1 depletion model in the rat

Although the protective role of HO-1 induction in various forms of kidney disease is well established, mechanisms other than heme catabolism to biliverdin, bilirubin and carbon monoxide have recently been identified. Unraveling these mechanisms requires the generation of appropriate animal models. The present study describes the generation of a HO-1 deficient Hmox1−/− rat model and characterizes its renal and extrarenal phenotype. Hmox1−/− rats had growth retardation and splenomegaly compared to their Hmox1+/+ littermates. Focal segmental glomerulosclerosis-type lesions and interstitial inflammatory infiltrates were prominent morphologic findings and were associated with increased blood urea nitrogen, serum creatinine and albuminuria. There was no increase in iron deposition in glomeruli, tubules or interstitium. Iron deposition in spleen and liver was reduced. Electron microscopic examination of glomeruli revealed edematous podocytes with scant areas of foot process effacement but otherwise well preserved processes and slit-diaphragms. Of the filtration barrier proteins examined, β-catenin expression was markedly reduced both in glomeruli and extrarenal tissues. Since the rat is the preferred laboratory animal in experimental physiology and pathophysiology, the rat model of HO-1 deficiency may provide a novel tool for investigation of the role of this enzyme in renal function and disease. © 2016, Springer International Publishing Switzerland

Acute interstitial nephritis and membranous nephropathy in the context of IgG4-related disease

We present the case of a patient with IgG4-related disease, which manifested in an asynchronous manner as vitiligo, cholecystitis, sialadenitis, lymphadenopathy, facial palsy and kidney dysfunction. The patient underwent a renal biopsy, and a presumptive diagnosis of lupus nephritis was made due to compatible clinical and immunological findings. The biopsy revealed IgG4-related kidney disease with severe interstitial nephritis and membranous nephropathy. Corticosteroids treatment restored all disease manifestations. We bring this case to the attention of the nephrologists because of the protean, asynchronous, multisys-temic nature of the disease that necessitates a multidisciplinary approach, a low threshold for kidney biopsy and a high index of suspicion for making the correct diagnosis and treatment. © 2014 S. Karger AG, Basel