Histology and histopathology Vol.24, nº3 (2009)
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- PublicationOpen AccessEnhanced CD24 expression in endometrial carcinoma and its expression pattern in normal and hyperplastic endometrium(Murcia : F. Hernández, 2009) Kim, Kyung Hee; Choi, Jong Sun; Choi, Yoon-La; Shin, Young Kee; Lee, Ho-chang; Seong, In Ock; Kim, Bum Kyung; Chae, Seoung Wan; Kim, Seok-Hyung; Kim, Jin ManCD24 is known to be an important diagnostic and prognostic marker of several major cancers affecting females. We aimed to determine CD24 expression in normal, hyperplastic, and carcinomatous endometrium and its correlation with estrogen and progesterone receptor expression. A total of 271 cases including 62 normal/atrophic endometrium cases (47/15), 127 endometrial hyperplasia cases (51/52/24, simple/complex/atypical hyperplasia), and 82 endometrial carcinoma cases were immunohistochemically analyzed by using anti-CD24, ER, and PR antibodies that were embedded on paraffin blocks. Next, we assessed the CD24 mRNA expression in these tissues by using RT-PCR. In the normal endometrium, cyclic expression of membranous CD24 was detected during the regular menstrual cycle, i.e., down-regulation in the proliferative phase and up-regulation in the secretory phase. CD24 expression was very infrequent and weak in the atrophic endometrium. In hyperplasias and carcinomas, the expression of both membranous and cytoplasmic CD24 was found to be sharply reduced in the hyperplastic lesions and significantly enhanced in the carcinomas. In the case of carcinomas, high CD24 expression showed significant correlation with high-grade (G2 and 3) (P<0.05). In addition, an inverse correlation was apparent between CD24 and the estrogen and progesterone receptor expressions in normal and diseased endometrium. In conclusion, we demonstrated that CD24 was expressed in a cyclic pattern in the normal endometrium, and its expression was enhanced in case of endometrial carcinoma. These results suggest that CD24 may be involved in tumor progression and can be a useful diagnostic biomarker.
- PublicationOpen AccessLymph node lymphangiogenesis, a new concept for modulating tumor metastasis and inflammatory process(Murcia : F. Hernández, 2009) Ji, R.C.The proliferation of lymphatic endothelial cells (LECs) occurs not only in tumor and inflamed tissues, but also in regional draining lymph nodes (LNs). The lymph node lymphangiogenesis (LNLG) has recently emerged as a prominent area in biomedical research, because it is involved in the pathogenesis of several human diseases. The LEC functional features and lymphatic remodeling regulated by lymphangiogenic factors actively promote tumor metastasis and the inflammation process. VEGFA/ VEGFR-2 and VEGF-C/-D/VEGFR-3 have been implicated as the prime mediators in inflammation- or tumor-induced LNLG. This knowledge may provide a foundation for further understanding of specific modification in the gene expression, cell migration, and differentiation of LECs and other cells in lymphaticassociated diseases. Importantly, it should be taken into consideration that inflammation and lymphangiogenesis are strongly linked in the formation and metastasis of cancer when designing therapeutic strategies.
- PublicationOpen AccessChondrocyte-like apoptosis in temporomandibular joint disc internal derangement as a repair-limiting mechanism. An in vivo study(Murcia : F. Hernández, 2009) Loreto, C.; Musumeci, G.; Leonardi, R.Temporomandibular joint internal derangement (TMJ ID) is characterised by disc displacement and degenerative tissue changes involving an active cellular response, with cell phenotype transformation from fibroblast-like to fibrochondrocyte and, eventually, to chondrocyte-like, possibly as a response to abnormal loading. However, only small patches of chondral tissue are detected in TMJ discs with ID. We decided to explore the reasons for such incomplete tissue change, postulating an involvement of the apoptosis process. Twenty-one discs removed from 19 patients with TMJ ID were processed for TRAIL and DR5 immunohistochemical localisation, and subjected to the TUNEL assay. Overexpression of DR5 receptor and its ligand (TRAIL) in chondrocyte-like cells suggested activation of programmed cell death, as also demonstrated by TUNEL-positive cells. The data suggest a failed adaptive response to disc displacement through chondroid metaplasia. The apoptotic death of chondrocyte-like cells, which is at least partly regulated by TRAIL and its death receptor, appears to underpin the failed disc repair, eventually leading to its perforation.
- PublicationOpen AccessPulmonary expression of vascular endothelial growth factor (VEGF) and alveolar septation in a newborn rat model exposed to acute hypoxia and recovered under conditions of air or hyperoxia(Murcia : F. Hernández, 2009) Remesal, Ana; Pedraz, Carmen; San Feliciano, Laura; Ludeña, DoloresVascular endothelial growth factor (VEGF) is an endothelial cell growth factor expressed in normal lung tissue. The aim of the study was to investigate the expression of VEGF and its repercussions as regards alveolarization in the developing rat lung. We studied pulmonary VEGF expression at 0 and 14 days of life in Wistar rats. Rat pups were exposed to hypoxia for two hours during the first hours of life and recovered under conditions of hyperoxia or normoxia for a further two hours, or not recovered. The animals of the control group were only exposed to conditions of normoxia. Our results showed that VEGF was increased in the lungs of the animals that were exposed to hypoxia but we did not find any correlation with the septation. The VEGF was decreased in the lungs of animals exposed to hyperoxia after neonatal hypoxia. We observed this at 0 and 14 days of life, and it was correlated with a lower degree of alveolarization at 14 days of life. Our data suggest that hyperoxia after neonatal hypoxia at birth may give rise to a decrease in the expression of VEGF, possibly permanently, together with a reduction in alveolar development.
- PublicationOpen AccessLangerhans cells in lichen sclerosus of the vulva and lichen sclerosus evolving in vulvar squamous cell carcinoma(Murcia : F. Hernández, 2009) Raspollini, María Rosaria; Baroni, Gianna; Taddei, Gian LiugiVulvar lichen sclerosus (LS) represents a benign chronic inflammatory skin lesion that carries a risk for development of vulvar squamous cell carcinoma (SCC). We aimed at determining whether premalignant changes in vulvar LS, a multifactorial disease, presenting a welter of evidence implicating the immune system in its pathogenesis, could be identified by analysing the Langerhans’ cells (LCs), the primary cell responsible for antigen recognition and presentation. The relationship existing between inflammation and cancer due to chronic infection, and demonstrated in many solid tumors, led us to study LCs in eight cases of vulvar LS, which showed an evolution to carcinoma of the vulva and in ten cases of unchanged vulvar LS in matched patients by immunohistochemistry for antibodies CD1a and S100. We did not find a statistically significantly different number of LCs counted either in S100 stained specimens, nor in CD1a stained specimens of LS epithelium in unchanged or evolving cases. The data emerging in our study do not support the hypothesis that the variation in the number of LCs may be related to the development of SCC in late stage LS cases.
- PublicationOpen AccessMesenchymal stem cells in connective tissue engineering and regenerative medicine: Applications in cartilage repair and osteoarthritis therapy(Murcia : F. Hernández, 2009) Mobasheri, A.; Csaki, C.; Clutterbuck, A.L.; Rahmanzadeh, M.; Shakibaei, M.Defects of load-bearing connective tissues such as articular cartilage, often result from trauma, degenerative or age-related disease. Osteoarthritis (OA) presents a major clinical challenge to clinicians due to the limited inherent repair capacity of articular cartilage. Articular cartilage defects are increasingly common among the elderly population causing pain, reduced joint function and significant disability among affected patients. The poor capacity for self-repair of chondral defects has resulted in the development of a large variety of treatment approaches including Autologous Chondrocyte Transplantation (ACT), microfracture and mosaicplasty methods. In ACT, a cartilage biopsy is taken from the patient and articular chondrocytes are isolated. The cells are then expanded after several passages in vitro and used to fill the cartilage defect. Since its introduction, ACT has become a widely applied surgical method with good to excellent clinical outcomes. More recently, classical ACT has been combined with tissue engineering and implantable scaffolds for improved results. However, there are still major problems associated with the ACT technique which relate mainly to chondrocyte de-differentiation during the expansion phase in monolayer culture and the poor integration of the implants into the surrounding cartilage tissue. Novel approaches using mesenchymal stem cells (MSCs) as an alternative cell source to patient derived chondrocytes are currently on trial. MSCs have shown significant potential for chondrogenesis in animal models. This review article discusses the potential of MSCs in tissue engineering and regenerative medicine and highlights their potential for cartilage repair and cell-based therapies for osteoarthritis and a range of related osteoarticular disorders.
- PublicationOpen AccessAnalysis of pRb, p16INK4A proteins and proliferating antigens, PCNA, Ki-67 and MCM5 expression in aggressive fibromatosis (desmoid tumor)(Murcia : F. Hernández, 2009) Stalinska, Lilliana; Turant, María; Tosik, Dariusz; Sygut, Jacek; Kulig, Andrzej; Kopczynski, Janusz; Dziki, Adam; Ferenc, TomascAggressive fibromatosis (desmoid tumor) is a mesenchymal lesion originating from fascial, aponeurotic and muscular connective tissue. It rarely becomes histologically malignant. In this study we analyzed the cell cycle regulation proteins: pRb, p16, and proliferating antigens: Ki-67, PCNA, MCM5 with immunohistochemical method in archival material derived from 27 extra-abdominal (E-AD), 18 abdominal (AD) and 5 intra-abdominal (I-AD) cases of desmoid tumor. None of the examined cases (n=50) of aggressive fibromatosis was pRb-immunonegative. Heterogeneous expression of pRb was observed in 51.85% (14/27) of Group AD cases and in 5.56% (1/18) of Group E-AD cases; positive expression in 48,15% (13/27) of Group AD cases, in 94.44% (17/18) of Group E-AD cases, and in 100% (5/5) of Group I-AD cases. There were no negative cases for p16 staining in any of the examined groups. The number of heterogeneous cases in individual groups was: 33.33% (9/27) in Group AD, 50% (9/18) in Group E-AD and 40% (2/5) in Group I-AD, and positive cases: 66.67% (18/27), 50% (9/18) and 60% (3/5), respectively. Overexpression of PCNA was noted in 98% (49/50) of cases. The positive staining for Ki-67 protein was noted in 25.93% (7/27) in Group AD, in 16.67% (3/18) in Group E-AD and in 60% (3/5) in Group I-AD. None of the examined cases was immunopositive for MCM5 protein. The noted levels of pRb and p16 expression in desmoid cells reflect their function in cell cycle regulation. Probably the unsettled cell cycle progression, especially in G1 phase, is not the cause of aggressive fibromatosis pathogenesis.
- PublicationOpen AccessIntestinal uptake of amyloid B protein through columnar epithelial cells in suckling mice(Murcia : F. Hernández, 2009) Ano, Yasuhisa; Nakayama, Hiroyuki; Sakudo, Akikazu; Sawano, Yoriko; Tanokura, Masaru; Itohara, Shigeyoshi; Onodera, TakashiThe mechanism of transmission of amyloid protein, especially the dynamics in the intestine, is still largely unknown. In the present study, a fusion protein (Aß-EGFP) that combined enhanced green fluorescent protein with amyloid-ß protein (Aß) was orally administered to mice before and after weaning, and the uptake and kinetics of amyloid protein within the intestine were elucidated through histopathology. Aß- EGFP was incorporated into the cytoplasm of columnar epithelial cells, rather than M cells, at 3 h after administration and thereafter. Aß-EGFP then accumulated in the crypt, Peyer's patch, and even the spleen. However, this uptake was not observed in weaned mice. These results suggest that a specific tolerant mechanism for incorporation of Aß escaped from the digestion exists during suckling periods. This age-dependent uptake is important for estimating the risk of transmission.
- PublicationOpen AccessTime-course changes in neural cell apoptosis in the rat fetal brain from dams treated with 6-mercaptopurine (6-MP)(Murcia : F. Hernández, 2009) Kanemitsu, H.; Yamauchi, Hirofumi; Komatsu, M.; Yamamoto, S.; Okazaki, S.; Nakayama, Hiroyuki6-Mercaptopurine (6-MP), one of the major drugs for the therapy of acute lymphoblastic leukemia and autoimmune diseases, is incorporated as thioguanine in nucleic acid and it induces cytotoxicity and fetotoxicity. In the present study, pregnant rats were treated with 50 mg/kg of 6-MP on 13 embryonic days (E), and fetuses were collected from 12 to 96 h after the treatment to examine the mechanism and time-course changes in neural cell death in the developing brain. The weights of fetal telencephalon and the thickness of the dorsal telencephalic wall of the fetuses were significantly reduced at 96 h. The number of pyknotic neural cells in the fetal telencephalon began to increase at 24 h, peaked at 36 h, and then gradually decreased toward 72 h. The nuclei of most of these pyknotic cells were stained positively by TUNEL method, which detects DNA fragmentation. Moreover, pyknotic cells were immunohistochemically positive for cleaved caspase-3, one of the key executioners of apoptosis, and the increased expression of the protein from 30 to 48 h was confirmed by using Western blot analysis. Also, electron microscopical features of the pyknotic cells showed ultrastructural characteristics of apoptosis. On the other hand, the number of mitotic and BrdU-positive neural cells in the telencephalon decreased from 30 to 72 h. These results suggest that 6-MP induced apoptotic cell death in neural cells in the rat fetal brain is probably due to cytotoxic action of 6-MP.
- PublicationOpen AccessExpression of enzymes involved in synthesis and metabolism of estradiol in human breast as studied by immunocytochemistry and in situ hybridization(Murcia : F. Hernández, 2009) Li, Zhuo; Luu-The, Van; Poisson-Paré, David; Ouellet, Johanne; Li, Songyun; Labrie, Fernand; Pelletier, GeorgesIt is well documented that human breast is actively involved in the local formation of estrogens. To determine the site(s) of action of enzymes involved in synthesis and metabolism of the most potent estrogen estradiol (E2), we have studied the expression of the following enzymes: 3ß-hydroxysteroid dehydrogenase (3-HSD), 17ß-HSD types 1, 2, 5, 7 and 12, aromatase, steroid sulfatase (STS) and estrogen sulfotransferase (EST) 1E1 at the cellular level in breast. Both in situ hybridization and immunocytochemistry were used for enzyme localization in normal breast tissues. For immunocytochemistry, we used rabbit antibodies, while in situ hybridization studies were performed using (35S)- labeled cRNA probes. Similar results were obtained with both approaches. All the enzymes (3ß-HSD; 17ß-HSD types 1, 5, 7 and 12; aromatase) involved in the conversion of circulating dehydroepiandrosterone (DHEA) to E2 as well as STS which converts estradiol sulfate (E2-S) to E2 have been found to be expressed in epithelial cells of acini and/or ducts as well as the stromal cells. Moreover, 17ß-HSD type 2 and EST1E1, two enzymes which inactivate E2, have been also localized in the same cell types. The present results indicate the enzymes which play a role in the synthesis and metabolism of E2 are expressed in both epithelial and stromal cells in human breast.
- PublicationOpen AccessCanonical and non-canonical pathways of osteoclast formation(Murcia : F. Hernández, 2009) Knowles, H.J.; Athanasou, N.A.Physiological and pathological bone resorption is mediated by osteoclasts, multinucleated cells which are formed by the fusion of monocyte / macrophage precursors. The canonical pathway of osteoclast formation requires the presence of the receptor activator for NFkB ligand (RANKL) and macrophage colony stimulating factor (M-CSF). Noncanonical pathways of osteoclast formation have been described in which cytokines / growth factors can substitute for RANKL or M-CSF to induce osteoclast formation. Substitutes for RANKL include LIGHT, TNFa and interleukins 6, 11 and 8. M-CSF substitutes include vascular endothelial growth factor (VEGF), placental growth factor (PlGF), FLt-3 ligand and hepatocyte growth factor (HGF). These growth factors can also influence canonical (RANKL / M-CSFinduced) osteoclast formation. Both canonical and noncanonical pathways of osteoclast formation play a role in the formation of osteolytic lesions where there is increased osteoclast formation and activity, such as in giant cell tumour of bone.
- PublicationOpen AccessDysregulation of Hedgehog, Wnt and Notch signalling pathways in breast cancer(Murcia : F. Hernández, 2009) Zardawi, Sarah J.; O’Toole, Sandra A.; Sutherland, Robert L.; Musgrove, Elizabeth A.There has been a significant decrease in mortality from breast cancer in the last two decades. This has been attributed to the introduction of mammographic screening and to the development of specialised therapies, notably anti-estrogens such as tamoxifen in estrogen receptor (ER) positive tumours, and adjuvant chemotherapy. More recently monoclonal antibodies such as trastuzumab directed against Her2- overexpressing tumours show significant promise in improving outcome from this aggressive subtype. While there have been significant advances, a number of clinical challenges still remain, particularly development of targeted therapies for other forms of breast cancer lacking ER or Her2, such as the aggressive basal-like carcinomas. Identification of new therapeutic targets in poor prognosis groups will be critical to further improvements in breast cancer treatment. Proper functioning of the Hedgehog, Notch and Wnt signalling pathways is required for normal development during early life and these pathways also play a key role in regulation and maintenance of stem cells. Increasing evidence implicates dysregulation of these pathways in the development and progression of a number of malignancies, including breast cancer. This review presents the current evidence for aberrations in these pathways in breast cancer and proposes that the Hedgehog, Notch and Wnt signalling pathways may represent novel therapeutic targets.
- PublicationOpen AccessAn overview of the pale and clear cells of the nipple epidermis(Murcia : F. Hernández, 2009) Garijo, M.F.; Val, D.; Val-Bernal, José FernandoThe stratified squamous epithelium of the nipple-areola complex may contain pale or clear cells including: Paget’s disease cells (PDCs), Toker cells (TCs), and so-called clear cells (CCs). Paget’s disease is an uncommon presentation of breast carcinoma. PDCs are large, atypical, have abundant, pale-staining cytoplasm that may contain mucin secretion vacuoles and bulky heterochromatic nuclei. They are commonly concentrated along the basal layer and stain for EMA, CAM5.2, cytokeratin 7, and HER2/neu oncoprotein. TCs are bland cells with roundish and scant chromatin nuclei. They are found incidentally and are reactive for EMA, CAM5.2, and cytokeratin 7, but show negativity for HER2/neu oncoprotein. So-called CCs show varied morphology, are found incidentally, and have been variably interpreted by different authors. The majority of cells that have been called epidermal CCs fit the features of pagetoid dyskeratosis. These cells are reactive for high molecular weight cytokeratin. Other CCs showing signet-ring morphology present negativity for mucins and correspond to a fixation artefact.