Histology and histopathology Vol.30,nº10 (2015)
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- PublicationOpen AccesseNOS and iNOS trigger apoptosis in the brains of sheep and goats naturally infected with the border disease virus(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Cagdas Dince, Gungor; Kul, OguzIn this study, apoptotic and anti-apoptotic mechanisms and if present, which pathway to trigger the apoptosis in the brains of Border Disease Virus (BDV) infected lambs (n=10) and goat kids (n=5) were investigated. Briefly, apoptotic (caspase 3, caspase 9) and anti-apoptotic markers (Bcl-2), cytokine response (TNF-α, INF-γ), reactive gliosis and myelin loss were examined. eNOS, iNOS, caspase 9, caspase 3 and GFAP expressions were higher in BDV infected tissues compared to control animals (6 kids and 6 lambs) (p<0.05). Double immunoperoxidase test revelaed that TUNEL positive apoptotic cells showed significant association with increased eNOS-iNOS and iNOS-BDV expressions. However, no significant differences were found for TNFR1, TNF-α and INF-γ expressions in BD (p>0.05). There was a positive correlation between the intensity of myelin loss, GFAP activity and severity of infection. Inconclusion, as a novel finding, it is established that eNOS and iNOS overexpressions are coassociated with apoptosis in BDV infected neurons and neuroglia. The results also strongly suggested that BDV infected apoptotic cells mainly prefer the intrinsic pathway that might be most likely related to increased nitric oxide levels.
- PublicationOpen AccessThe distribution and time-dependent expression of MAGL during skeletal muscle wound healing in rats(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Jiang, Shu-Kun; Zhang, Miao; Tian, Zhi-Ling; Wang, Lin-Lin; Zhao, Rui; Li, Shan-shan; Liu, Min; Wang, Meng; Guan, Da-WeiMonoacylglycerol lipase (MAGL) is widely distributed in mammals and largely responsible for metabolizing 2-arachidonoylglycerol (2-AG). Little is known about its expression in skeletal muscles after trauma. A preliminary study on time-dependent expression and distribution of MAGL was performed by immunohistochemical staining, Western blotting and quantitative real-time PCR (qPCR) during skeletal muscle wound healing in rats. An animal model of skeletal muscle contusion was established in 40 Sprague-Dawley male rats. Samples were taken at 1, 3, 5, 7, 9, 13, 17 and 21 days after contusion, respectively (5 rats in each posttraumatic interval). 5 rats were employed as control. Weak immunoreactivity of MAGL was observed in the sarcoplasm of myofibers in control rats. Intensive immunoreactivties of MAGL were observed in polymorphonuclear cells (PMNs), roundshaped mononuclear cells (MNCs), spindle-shaped fibroblastic cells (FBCs) and regenerated multinucleated myotubes in the injured tissue. Subsequently, neutrophils, macrophages and myofibroblasts were identified as MAGL-positive cells by double immunofluorescent procedure. MAGL expression was remarkably up-regulated after contusion by qPCR and Western blot analysis. The results demonstrate that the expression of MAGL is distributed in certain cell types and time-dependently expressed in skeletal muscles after trauma, suggesting that MAGL may be involved in inflammatory response, fibrogenesis and muscle regeneration during skeletal muscle wound healing.
- PublicationOpen AccessEffects of metabolic syndrome on the ultrastructure of the femoral nerve in aging rats(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Rodrigues de Souza, Romeu; Gama, Eliane F.; El-Razi Neto, Semaan; Maldonado, DiogoThe aim of the present study was to characterize the morphometry of the femoral nerve in aging rats with metabolic syndrome compared to controls. Systolic blood pressure and fasting plasma glucose were measured, and myelinated and unmyelinated fibers in the femoral nerves were quantitatively assessed under electron microscopy. Aging rats exposed to a regimen of metabolic syndrome developed elevation of plasma glucose concentration, mild hypertension and polyneuropathy characterized by a decrease in myelin fiber area, axon diameter, myelin sheath thickness and myelin fiber loss in the femoral nerve. The histogram of size distribution for myelinated fibers and axons from the aging rats of the control group was bimodal. For aging MS animals, the histogram turned out to be unimodal. The ultrastructure of unmyelinated fibers and of Schwann cells in 18-monthold rats was well preserved. Granules of lipofuscin were seen in unmyelinated fiber axons of 18-month-old rats with MS. The damage percentage of the large myelinated fibers has increased significantly in 18- month-old and 18-month-old (MS) rats in relation to the controls. No significant difference was observed among the groups for the g-ratio. Comparing the three groups, the number of neurotubules and neurofilaments in myelinated fibers of 18-month-old rats with MS was significantly smaller than for the groups of 18-month-old and 14-month-old rats. The overall changes seen in the femoral nerve from aging rats seem minor compared to the changes in the aging rats with MS, suggesting that long-term MS accelerates the progressive modifications in peripheral nerves that develop in old age.
- PublicationOpen AccessMolecular mechanisms in dental follicle precursor cells during the osteogenic differentiation(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Morsczeck, Christian
- PublicationOpen AccessE-cadherin, β-catenin, and α2β1 and α3β1 integrin expression in primary oral squamous cell carcinoma and its regional metastasi(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Quirino Silveira Soares, Mariana; Andrade Mendonça, Juliana; Oliveira Morais, Marília; Rodrigues Leles, Claudio; Carvalho Batista, Aline; Mendonça, Elismauro Francisco. To investigate E-cadherin, β-catenin, and α2β1 and α3β1 integrins in 40 samples of nonmetastatic and metastatic oral squamous cell carcinoma (OSCC) with positive cervical lymph nodes (LN). Immunohistochemistry was used to evaluate expression in the lesion center (LC) and invasive tumor front (ITF) of non-metastatic (n=18) and metastatic (n=22) OSCC and in the LN on the metastatic neoplastic cells (MNC; n=22). In metastatic OSCC, E-cadherin and β-catenin presented significantly lower cytoplasmic membrane expression in the ITF and MNC when compared to the LC and lower cytoplasmic expression in MNC when compared to the LC and ITF (p<0.05). Integrins α2β1 and α3β1 showed high cytoplasmic expression in the LC, ITF and MNC (p>0.05). A positive correlation was observed between E-cadherin cytoplasmic expression and α2β1 (ρ=0.860) and α3β1 (ρ=0.975) expression. When comparing the primary sites of metastatic and non-metastatic disease, β-catenin presented lower cytoplasmic membrane (p=0.013) expression in metastatic OSCC. E-cadherin presented low expression and the integrins high expression in both groups. Abnormal expression of β-catenin and E-cadherin associated with high expression of α2β1 and α3β1 integrins contribute to LN metastasis in OSCC.
- PublicationOpen AccessInter- and intra-tumoral relationships between vasculature characteristics, GLUT1 and budding in colorectal carcinoma(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Mezheyeuski, Artur; Nerovnya, Alexander; Bich, Tatjana; Tur, Gennadiy; Ostman, Arne; Portyanko, AnnaVascular characteristics, hypoxia and tumor budding are features that have been implied in the biology and prognosis of colorectal cancer. Internal relationships and the inter- and intra-tumoral variation of these tumor properties remain to be determined. In the current study we have characterized blood vessel status in different areas of CRC and in the peritumoral fibroblastic stroma. Analyses of these characteristics have been supplemented by characterization of budding and hypoxia. Analyses revealed significantly lower values of vessel perimeter (VP) and vessel lumen area (VL) at the invasive front and surrounding stroma as compared to the tumor center. Also, the number of vessels (VN) in the peritumoral stroma was higher than in the center. Thus, tumor center displays larger and fewer vessels as compared to the tumor periphery. GLUT1 expression was correlated directly with VN (r=0.351, p=0.028) and inversely with VL and VP (r=- 0.432, p=0.006 and r=-0.484, p=0.002) at the invasive front. Moreover, GLUT1 expression, VP at the invasive front, and VN in the surrounding peritumoral stroma, were associated with budding score (r=0.574, p<0.000, r=-0.340, p=0,034 and r=-0,389, p=0.025 respectively). Furthermore, GLUT1, budding score, vessel number in peritumoral stroma, and vessel size in the invasive front, were significantly different in tumors with or without lymph node metastasis. This study reports previously unrecognized relationships between localization-specific vascular characteristics, hypoxia and tumor budding. The findings suggest potential functional relationships, which should be further explored, and also highlight the inter-tumoral variations in vasculature, which is highly relevant for ongoing efforts to identify vessel-based biomarkers.
- PublicationOpen AccessMolecular markers predicting lymph node metastasis in early esophageal cancer(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Plum, Patrick S.; Warnecke-Eberz, Ute; Dhaouadi, Oulfa; Alakus, Hakan; Drebber, Uta; Metzger, Ralf; Prenze, Klaus L.; Hölscher, Arnulf H.; Bollschweiler, Elfriedey. AIMS: The aim of this study was to identify molecular markers predicting depth of tumor infiltration and presence of lymph node metastasis in early esophageal cancer. METHODS: Between 1996 and 2004, 67 patients with pT1 esophagus cancer underwent esophagectomy. Resected tumors and lymph nodes were analyzed by immunohistochemistry for tissue infiltration, lymph node metastasis (LNM), micrometastasis and extracapsular lymph node infiltration (ELNI). We focused on MMP-2 (matrix-metalloproteinase-2), TIMP2 (tissue inhibitor of metalloproteinase-2), PIM-1 and survivin as the most promising marker candidates. The data was correlated with the patients’ long term followup (median follow-up time 11.4 years). RESULTS: We found 22 pT1a and 45 pT1b carcinomas. None of the mucosal carcinomas, but 58% (26 patients) of the submucosal carcinomas showed lymph node metastasis or micrometastasis. The rate of LNM positively correlated with the depth of tumor infiltration (23% LNM in sm1 tumors and 82% LNM in sm3 tumors). Low grade PIM-1 expression (<30%) was significantly associated with occurrence of LNM (p=0.034) while high expression TIMP-2 (>70%) were detected in submucosal tumors. Logistic regression analysis revealed PIM-1 and Grading G3 as independent risk factors for LNM (p<0.001). Survival of patients with micrometastasis was comparable to those with LNM (median survival: 5.05 years versus 5.52 years). Patients with ELNI had the worst prognosis (median survival: 1.7 years). CONCLUSIONS: PIM-1 is a promising marker for prediction of lymph node metastasis in early esophagus cancer. Extracapsular lymph node infiltration has an independent worse prognostic impact.
- PublicationOpen AccessRole of isocitrate dehydrogenase 1/2 (IDH 1/2) gene mutations in human tumors(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Liu, Xiang; Ling, Zhi-QiangIn recent years, frequent isocitrate dehydrogenase 1/2 (IDH1/IDH2) gene mutations were found in a variety of tumors, which specifically alter arginine residues of catalytic active site in IDH1/IDH2 and confer new enzymatic function of directly catalyzing alpha-ketoglutarate (α-KG) to R-2-hydroxyglutarate (2- HG). 2-HG could competitively inhibit α-KG–dependent enzymes and might therefore contribute to tumorigenesis. In addition, mutation status of IDH1/IDH2 is closely related to the progress and prognosis of certain tumors. Thus IDH1/IDH2 is considered to be a promising biomarker for early diagnosis and prognosis and targeted therapy. In this study, the current research on IDH1/IDH2 mutation, especially the mechanisms and clinical characteristics related to tumor, are reviewed.
- PublicationOpen AccessThe clinical translational potential of p53-related alterations as cancer biomarkers(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Xiao, Meng; Wang, Xu; Chen, WantaoWe aimed to analyse and summarise the potential value of the clinical use of p53-related alterations as cancer biomarkers. A systematic search and collection of the published meta-analyses on p53- related alterations and cancers in the past 5 years was conducted through appropriate queries in the PubMed database. We then composed “grey-scale” tables to show the significant levels for each variant, and the potential heterogeneity was subsequently discussed. The data show that p53-related alterations are extremely complex biomarkers in terms of their clinical translation. Together with the experimental studies on p53-related alterations, a gold-standard approach is still in need of development, with more evidence from clinical studies with large, prospectively planned cohorts, to fully understand its potential as a cancer biomarker.
- PublicationOpen AccessImmunolocalization of thymidylate synthase as a favorable prognostic marker in estrogen receptor-positive breast carcinoma(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Takagi, Kiyoshi; Miki, Yasuhiro; Nakamura, Yasuhiro; Hirakawa, Hisashi; Kakugawa, Yoichiro; Amano, Goro; Watanabe, Mika; Ishida, Takanori; Sasano, Hironobu; Suzuki, TakashiBackground: Thymidylate synthase (TS) is an enzyme involved in DNA synthesis, and it is a target for 5-fluorouracil. Previous studies have demonstrated that TS is a potent estrogen-induced gene in breast carcinoma cells, suggesting the importance of TS in estrogen-receptor (ER)-positive breast carcinoma. TS immunolocalization has been reported previously, but the clinicopathological significance of TS in ER-positive breast carcinoma still remains unclear. Patients and methods: We immunolocalized TS in 178 breast carcinoma tissues in total, and examined its significance according to the ER-status. Results: TS status was positive in 58% of ERpositive ductal carcinoma in situ (DCIS) cases, and it was significantly associated with the Ki-67 and progesterone receptor (PR). Moreover, in ER-positive DCIS patients who received aromatase inhibitor (AI) before surgery, TS immunoreactivity was significantly decreased after AI treatment. In ER-positive invasive ductal carcinoma (IDC) cases, TS status was significantly associated with PR, and it turned out an independent favorable prognostic factor for recurrence of the patients by multivariate analysis. On the other hand, TS status was positively correlated with pathological T factor in ER-negative IDC cases, and tended to have a worse prognosis for disease-free survival of the patients. Conclusion: These results suggest that TS expression is mainly regulated by estrogen in ERpositive breast carcinoma and is associated with estrogen-mediated proliferation. TS status is a favorable prognostic factor in ER-positive IDC patients, which is different from the ER-negative cases.
- PublicationOpen AccessAnticancer properties of carotenoids in prostate cancer. A review(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) da Costa Pereira Soares, Nathalia; Junger Teodoro, Anderson; Falagan Lotsch, Priscila; Mauro Granjeiro, José; Borojevic, RadovanProstate cancer is the most common noncutaneous cancer of men in the world. Several epidemiological studies have linked increased carotenoids consumption with decreased prostate cancer risk. These findings are supported by in vitro and in vivo experiments showing that carotenoids not only enhance the antioxidant response of prostate cells, but that they are able to inhibit proliferation, induce apoptosis and decrease the metastatic capacity of prostate cancer cells. However, clear clinical evidence supporting the use of carotenoids in prevention or treatment of prostate cancer is not available, due to the limited number of published randomized clinical trials, and the varying protocols used in the existing studies. The scope of the present review is to discuss the potential impact of carotenoids on prostate cancer by giving an overview of the molecular mechanisms and in vitro / in vivo effects.