Histology and histopathology Vol.24, nº4 (2009)
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- PublicationOpen AccessImmunohistochemical expression of glycodelin in breast cancer correlates with estrogen-receptor α and progesterone-receptor A positivity(Murcia : F. Hernández, 2009) Scholz, Christoph; Toth, Bettina; Barthell, Elisabeth; Mylonas, I.; Weissenbacher, Tobias; Friese, Klaus; Jeschke, UdoGlycodelin (Gd), previously known as placental protein 14 (PP 14), acts as an immunosuppressive glycoprotein by suppressing the cytolytic capacity of human natural killer (NK) cells and T-cells in vitro. Glycodelin is expressed in normal glandular epithelium of the endometrium as well as in normal and malignant glandular cells in and outside of the reproductive tract. Recently, Gd expression was demonstrated in normal and cancerous human breast tissue. Paraffin-embedded breast cancer tissue blocks (n=121) were examined for Gd expression. No part of the specimens contained carcinoma in situ. Gd expression was present in lobular and ductal breast carcinoma. We observed expression of Gd in breast cancer independent of grading. With regard to nodal status, no significant differences in the expression of Gd between cancer tissue from patients with or without axillary lymph node metastases were present. However, Gd expression was found to be significantly higher in breast cancer tissue when the staining reaction for steroid receptors was also positive. These results implicate that Gd might be an additional marker for the differentiation of breast cancer tissue. To which extent Gd could serve as an additional indicator for breast cancer survival is part of our ongoing research.
- PublicationOpen AccessBiomarkers for novel targeted therapies of hepatocellular carcinoma(Murcia : F. Hernández, 2009) Okamoto, Kinya; Neureiter, DanielIncreasing insights into molecular alterations of signalling pathways have led to the development of specific targeted therapies for cancer. Due to the high specificity of monoclonal antibodies or small molecule inhibitors, identification of patients who will benefit from these therapeutics is crucial for treatment success. Furthermore, as classical endpoints of clinical trials are not fully applicable to targeted therapies, biomarkers for monitoring treatment response have to be identified. The recent introduction of a multi-kinase inhibitor for the treatment of liver cancer has accelerated efforts in the field of biomarker research. As further novel targeted therapies are on the horizon for liver cancer therapy, we will here review candidate markers for new hepatocellular carcinoma therapies, with a focus on EGF- and VEGF-receptor related pathways.
- PublicationOpen AccessLiver growth factor antifibrotic activity in vivo is associated with a decrease in activation of hepatic stellate cells(Murcia : F. Hernández, 2009) Díaz-Gil, Juan J.; García-Monzón, Carmelo; Rúa, Carmen; Martín Sanz, Paloma; Cereceda, Rosa M.; Miquilena-Colina, María E.; Machín, Celia; Fernández Martínez, Amalia; García Cañero, RafaelThe antifibrotic activity of Liver Growth Factor (LGF), a liver mitogen, was previously demonstrated in several models of rat liver fibrosis and even in extrahepatic sites, such as carotid artery in hypertensive rats and rat CdCl2-induced lung fibrosis. In the present study, we have attempted to examine in depth its mechanism of antifibrotic action in bile duct-ligated (BDL) rats, with special emphasis on its activity in fibrogenic liver cells. BDL rats received either LGF 9 μg/week for 2 or 3 weeks (BDL+LGF, n=20/group) or saline (BDL+S, n=20/group), at times 0, week 2, or week 5 after operation. Groups were compared in terms of liver a- smooth muscle actin (SMA) content (western blotting and immunohistochemistry), hepatic apoptosis, liver desmin content (western blotting), and serum endothelin-1 (ELISA). LGF produced a marked decrease in liver a-SMA content compared with saline-injected rats, especially evident at longer times (5w and 8w; p<0.05), accompanied by a decrease in hepatic a-SMA+ cells. This decrease was not due to the killing of activated hepatic stellate cells (HSC) or myofibroblasts by LGF, since there was a slight decrease in hepatic apoptosis that was more evident at 2w (p<0.05). Moreover, LGF did not seem to influence HSC proliferation, as shown by measuring liver desmin content. The antifibrotic activity exerted by LGF seems to be closely related to a modulation of the activation state of fibrogenic liver cells (activated HSC and myofibroblasts) in BDL rats.
- PublicationOpen AccessMGMT analysis at DNA, RNA and protein levels in glioblastoma tissue(Murcia : F. Hernández, 2009) Preusser, MatthiasEvidence from several studies supports that the epigenetic, transcriptional and translational regulation and expression of O6-methylguaninemethyltransferase (MGMT) is relevant for prognostic and predictive considerations in glioblastoma patients. MGMT status is being used as a stratifying factor or eligibility criterion in ongoing and accruing clinical glioblastoma trials. In some cases, there is also interest in MGMT assessment of glioblastoma tissue in the dayto- day clinical setting. However, a number of different methods and protocols have been used for MGMT analysis and it is unclear which methods harbour the greatest potential for translation into routine clinical use. This article reviews methods that have been used for MGMT assessment at DNA-, RNA- and protein-level in glioblastoma with a focus on their potential clinical utility. Conclusions. (1) DNA-based methods for MGMT analysis seem more promising for translation into the clinical setting than RNA- or protein-based methods. However, at present there is lack of data to base recommendations for a specific method or protocol for MGMT testing on. There is a strong need for systematic comparisons and validation of intra- and interlaboratory reproducibility and clinical performance of different methods for MGMT assessment to identify the best method for clinical MGMT testing. (2) The current practice of formalin-fixation of neurosurgical specimens considerably limits the spectrum of methods that can be applied for molecular diagnosis in clinical neurooncology. Further studies may be helpful to establish more appropriate protocols for tumour tissue preservation (e.g. identification of alternative fixatives that do not deteriorate DNA and RNA quality).
- PublicationOpen AccessThe interactomics of sortilin: an ancient lysosomal receptor evolving new functions(Murcia : F. Hernández, 2009) Canuel, Maryssa; Libin, Yuan; Morales, Carlos R.The delivery of soluble lysosomal proteins to the lysosomes is dependent primarily on the mannose 6- phosphate receptor (MPR). The MPR has been demonstrated to attain the early endosomes via a process that requires the interaction of its cytosolic domain with the GGA and AP-1 adaptor proteins. Additionally, the MPR can be recycled back to the trans-Golgi network (TGN) through its interaction with the retromer complex. Interestingly, in I-cell disease (ICD), in which the MPR pathway is non-functional, many soluble lysosomal proteins continue to traffic to the lysosomes. This observation led to the discovery that sortilin is responsible for the MPR-independent targeting of the sphingolipid activator proteins (SAPs) and acid sphingomyelinase (ASM). More recently, our laboratory has tested the hypothesis that sortilin is also capable of sorting a variety of cathepsins that exhibit varying degrees of MPR-independent transport. We have demonstrated that the transport of cathepsin D is partially dependent upon sortilin, that cathepsin H requires sortilin, and that cathepsins K and L attain the lysosomes in a sortilin-independent fashion. As a type-1 receptor, sortilin also has numerous cytosolic binding partners. It has been observed that like the MPR, the anterograde trafficking of sortilin and its cargo require both GGAs and AP-1. Similarly, the retrograde recycling pathway of sortilin also involves an interaction with retromer through a YXXf site in the cytosolic tail of sortilin. In conclusion, the cytosolic domains of sortilin and MPR possess a high degree of functional homology and both receptors share a conserved trafficking mechanism.
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