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Hospital de Órbigo, Spain

Ochoa-Callejero L.,Center for Biomedical Research of La Rioja | Perez-Martinez L.,Center for Biomedical Research of La Rioja | Rubio-Mediavilla S.,Pathology Service | Oteo J.A.,Center for Biomedical Research of La Rioja | And 2 more authors.

Chronic liver disease may result in a sequential progression through fibrosis, cirrhosis and lead, eventually, to hepatocellular carcinoma (HCC). Hepatic stellate cells (HSC) seem to be responsible for the fibrogenic response through the activation of an autocrine loop involving the chemokine receptor, CCR5. However, the role of CCR5 in HCC remains poorly understood. Since this receptor is also one of the main ports of entry for the human immunodeficiency virus (HIV), several CCR5 inhibitors are being used in the clinic to reduce viral load. We used one of these inhibitors, maraviroc (MVC), in a mouse model of diet-induced HCC to investigate whether this intervention would reduce disease progression. Animals treated with MVC on top of a normal control diet did not present any evidence of toxicity or any morphological change when compared with non-treated mice. Animals treated with MVC presented higher survival, less liver fibrosis, lower levels of liver injury markers and chemokines, less apoptosis, lower proliferation index, and lower tumor burden than their counterparts receiving only the hepatotoxic diet. In addition, MVC inhibits HSC activation markers such as phosphorylation of p38 and ERK, and increases hepatocyte survival. This study suggests that MVC, a well tolerated and clinically characterized drug, may be used as a preventative treatment for HCC. Clinical studies are needed to demonstrate the efficacy of this drug, or other CCR5 inhibitors, in patients with high risk of developing HCC. © 2013 Ochoa-Callejero et al. Source

Noguera R.,University of Valencia | Nieto O.A.,University of Quindio | Tadeo I.,University of Valencia | Farinas F.,Pathology and Infectious Diseases Institute | Alvaro T.,Pathology Service
Histology and Histopathology

The extracellular matrix (ECM) constitutes a three-dimensional network that surrounds all cells, organs and tissues in the body. It forms a biophysical filter for protection, nutrition and cell innervation, as well as the medium for facilitating immune response, angiogenesis, fibrosis and tissue regeneration. It is the mechanism by which mechanical forces are transmitted to the basement membrane which, through the integrins, supports the tensegrity system and activates the epigenetic mechanisms of the cell. A review and update on current knowledge on this topic reveals how disturbance of the ECM leads to a loss of efficient filtering, nutrition, elimination, and cell denervation functions, in addition to loss of regeneration capacity and disorders in mechanotransduction. Furthermore, such disturbance results in a loss of substrate, and with it the ability to provide a proper immune response against tumor, toxic and infectious agents. Reciprocal communication between ECM stromal and parenchymatous cells directs gene expression. The oncogenic capacity of the stroma derives from the associated cells as well as from the tumor cells, the angiogenic microenvironment and from an alteration in tensegrity; all of which are dependent on the ECM. It has been shown that the malignant phenotype is reversible by correction of the altered cues of the ECM. Source

Viti A.,Thoracic Surgery Unit | Bertolaccini L.,Thoracic Surgery Unit | Cavallo A.,Thoracic Surgery Unit | Fortunato M.,Pathology Service | And 2 more authors.
European Journal of Cardio-thoracic Surgery

Objectives: To investigate the usefulness of 18-fluorine fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET-CT) in the pretreatment evaluation of thymic epithelial neoplasms (TENs). We previously demonstrated that the ratio between standardized uptake value of the tumour and aortic arch (SUV T/M) correlates with World Health Organization (WHO) classification. We now focused our evaluation on thymomas only, excluding carcinomas. We also searched for the expression of a pathological biomarker, Ki-67, that gained both diagnostic and prognostic relevance for various solid tumours. Its correlation with SUV T/M and WHO classification was evaluated. Methods: We performed a retrospective dynamic cohort study of data from January 2006 to December 2012, on 23 consecutive patients with pathologically proven TEN, excluding thymic carcinomas, evaluated with PET-CT. For each patient, SUV T/M was calculated. The patients were then categorized, according to WHO classification, into two groups (low-risk: 3 A, 9 AB, 5 B1; high-risk: 5 B2, 1 B3) and Ki-67 labelling index (LI) was defined. We employed the Spearman rank non-linear correlation coefficient (ρ) to estimate the correlations between variables. Results: SUV T/M proved to be significantly higher for high-positive Ki-67 samples, indicating a strong correlation between SUV T/M and Ki-67 LI (ρ = 0.8). Furthermore, high Ki-67 LI samples correlate with the higher-risk WHO subgroup (ρ = 0.9). Conclusions: FDG PET-CT can provide a useful tool in the preoperative work-up of TEN, reflecting its proliferation capacity, as described also by the Ki-67 expression. In particular, SUV T/M could provide a 'metabolic biopsy' to divide TEN into high-risk and low-risk neoplasms. © The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. Source

Perez-Martinez L.,Center for Biomedical Research of La Rioja | Perez-Matute P.,Center for Biomedical Research of La Rioja | Aguilera-Lizarraga J.,Center for Biomedical Research of La Rioja | Rubio-Mediavilla S.,Pathology Service | And 5 more authors.
Journal of Antimicrobial Chemotherapy

Objectives: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the general population. The NAFLD spectrum ranges from simple steatosis to cirrhosis. The chemokine CCL5/RANTES plays an important role in the progression of hepatic inflammation and fibrosis. The objective of this study was to examine the effects of maraviroc, a CCR5 antagonist, on liver pathology in a NAFLD mouse model. Methods: A total of 32 male C57BL/6 mice were randomly assigned to one of four groups: (i) control group (chow diet plus tap water); (ii) maraviroc group (chow diet plus maraviroc in drinking water); (iii) high-fat diet (HFD) group (HFD plus tap water); and (iv) maraviroc/HFD group (HFD plus maraviroc). All mice were sacrificed 16 weeks after the beginning of the experiment. Biochemical analyses and liver examinations were performed. Results: Mice in the HFD group showed a tendency towards increased body mass gain and liver damage compared with the maraviroc/HFD group. Moreover, liver weight in the HFD group was significantly higher than in the maraviroc/HFD group. Hepatic triglyceride concentration in the maraviroc/HFD group was significantly lower than in the HFD group. Interestingly, the maraviroc/HFD group exhibited a lower degree of steatosis. Furthermore, hepatic CCL5/RANTES expression was significantly lower in the maraviroc/HFD group than in the HFD group. Overall, no differences were observed between the control group and the maraviroc group. Conclusions: Maraviroc ameliorates hepatic steatosis in an experimental model of NAFLD. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. Source

Roa I.,Creative Bioscience | de Toro G.,Pathology Service | Schalper K.,Yale University | Churi C.,University of Texas M. D. Anderson Cancer Center | Javle M.,University of Texas M. D. Anderson Cancer Center
Gastrointestinal Cancer Research

Background: The HER2/neu gene is a proto-oncogene that can predict the response to treatment with trastuzumab, pertuzumab, and lapatinib. This study was conducted to determine the frequency of HER2/neu overexpression and to identify a subgroup of patients with gallbladder cancer who would benefit from targeted therapy. Methods: Patients with gallbladder cancer (n = 187; 165 women and 22 men) with a recorded follow-up of at least 5 years were included, along with control subjects (n = 75). An automated immunohistochemical technique was used with an anti-ErbB2 antibody. Scoring was conducted according to the CAP/ASCO (College of American Pathologists/ American Society of Clinical Oncology) criteria for breast cancer. Results: Overexpression of HER2/neu was observed in 12.8% of the cases. Of those, 0% were mucosal, 14.3% muscular, 12.8% subserosal, and 10.6% serosal. In 20% of the cases, equivocal staining was observed. Overexpression was more frequent in the advanced cancers and in the better differentiated tumors (13.8% and 17.4%, respectively), but the difference was nonsignificant. The patients with overexpression of HER2/neu had a worse overall survival, when compared with those who had no expression at 5 years (34% vs. 41%). Conclusion: This is the single largest study of HER2/neu expression in gallbladder cancer to use commonly accepted scoring criteria. The results indicate that HER2/neu overexpression occurred in 14% of the advanced gallbladder cancer cases. This subgroup may benefit from inhibitors of the HER2/neu pathway. © 2014 by International Society of Gastrointestinal Oncology. Source

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