SECMF - Serviço de Estomatologia e Cirurgia Maxilo Facial
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- Activation of ERK1/2 MAP kinases in familial amyloidotic polyneuropathyPublication . MONTEIRO, F.A.; SOUSA, M.M.; CARDOSO, I.; Barbas-Amaral, J.; GUIMARAES, A.; SARAIVA, M.J.J Neurochem. 2006 Apr;97(1):151-61. Epub 2006 Mar 3. Activation of ERK1/2 MAP kinases in familial amyloidotic polyneuropathy. Monteiro FA, Sousa MM, Cardoso I, do Amaral JB, Guimarães A, Saraiva MJ. Molecular Neurobiology, Instituto de Biologia Celular e Molecular, ICBAS, University of Porto, and Estomatology, Maxillofacial Surgery, Hospital Geral de Santo António, Portugal. Abstract Familial amyloidotic polyneuropathy (FAP) is a neurodegenerative disorder characterized by the extracellular deposition of transthyretin (TTR), especially in the PNS. Given the invasiveness of nerve biopsy, salivary glands (SG) from FAP patients were used previously in microarray analysis; mitogen-activated protein (MAP) kinase phosphatase 1 (MKP-1) was down-regulated in FAP. Results were validated by RT-PCR and immunohistochemistry both in SG and in nerve biopsies of different stages of disease progression. MKP-3 was also down-regulated in FAP SG biopsies. Given the relationship between MKPs and MAPKs, the latter were investigated. Only extracellular signal-regulated kinases 1/2 (ERK1/2) displayed increased activation in FAP SG and nerves. ERK1/2 kinase (MEK1/2) activation was also up-regulated in FAP nerves. In addition, an FAP transgenic mouse model revealed increased ERK1/2 activation in peripheral nerve affected with TTR deposition when compared to control animals. Cultured rat Schwannoma cell line treatment with TTR aggregates stimulated ERK1/2 activation, which was partially mediated by the receptor for advanced glycation end-products (RAGE). Moreover, caspase-3 activation triggered by TTR aggregates was abrogated by U0126, a MEK1/2 inhibitor, indicating that ERK1/2 activation is essential for TTR aggregates-induced cytotoxicity. Taken together, these data suggest that abnormally sustained activation of ERK in FAP may represent an early signaling cascade leading to neurodegeneration. PMID: 16515552 [PubMed - indexed for MEDLINE]
- Biomarkers in the assessment of therapies for familial amyloidotic polyneuropathyPublication . MACEDO, B.; BATISTA, A.R.; Barbas-Amaral, J.; SARAIVA, M.J.Mol Med. 2007 Nov-Dec;13(11-12):584-91. Biomarkers in the assessment of therapies for familial amyloidotic polyneuropathy. Macedo B, Batista AR, do Amaral JB, Saraiva MJ. SourceMolecular Neurobiology, Instituto de Biologia Molecular e Celular, Porto, Portugal. Abstract The identification of specific biomarkers provides opportunities to develop early diagnostic parameters, monitor disease progression, and test drug efficiency in clinical trials. We previously demonstrated that in familial amyloidotic polyneuropathy (FAP) related to the abnormal extracellular tissue deposition of mutant transthyretin (TTR), inflammatory and apoptotic pathways are triggered in the presymptomatic stages of the disease, when nonfibrillar TTR deposits are present. In the present work, to better define biomarkers for future assessment of prophylactic and therapeutic drugs in the treatment of FAP, we extended the search for oxidative stress and apoptotic biomarkers to clinical samples and animal models presenting nonfibrillar and fibrillar TTR. We found that lipid peroxidation measured by hydroxynonenal, oxidative DNA damage measured by 8-hydroxy-2'-deoxyguanosine, and cellular redox homeostasis measured by glutaredoxin 1 were consistently increased in biopsy specimens from FAP patients and in tissues from transgenic mouse models presenting nonfibrillar TTR deposition. Death-receptor Fas, caspase-8, and Bax were also found to be increased, indicative of the involvement of death receptors in the observed apoptosis process. Removal of TTR deposition by an immunization protocol resulted in significant decreases of the selected markers we describe, corroborating the relationship between TTR deposition, oxidative stress, and apoptosis. Taken together, our results provide a robust biomarker profile for initial experimental animal studies and clinical trials to assess the application of the selected markers in therapies aimed at removal and/or inhibition of TTR polymerization. PMID: 17932549 [PubMed - indexed for MEDLINE] PMCID: PMC2017105Free PMC Article Images from this publication.See all images (5) Free text Figure 1 (A) Top panels: Representative 4-hydroxy-2-nonenal (HNE) staining of salivary glands from healthy individuals (left, n = 6) and FAP patients (right, n = 6). Middle panels: Representative HNE staining in stomach tissue of hTTR Met30 mice without TTR deposition (−/−, left, n = 5) and with TTR deposition (+/−, right, n = 5) ... Biomarkers in the Assessment of Therapies for Familial Amyloidotic Polyneuropathy Mol Med. ;13(11-12):584-591.Figure 2 Top 2 panels: Representative Grx1 and Trx1 staining of salivary glands from healthy individuals (left, n = 6) and FAP patients (right, n = 6); nuclear staining is indicated by the arrow. Middle panel: Representative Grx1 staining in stomach tissue of hTTR Met30/(+/−)hsf mice without TTR deposition (−/−, left, n = 5) and wi... Biomarkers in the Assessment of Therapies for Familial Amyloidotic Polyneuropathy Mol Med. ;13(11-12):584-591.Figure 3 Representative FasL, Fas, active caspase-8, active caspase-3, and Bax staining of salivary glands from healthy individuals (left, n = 6) and FAP patients (right, n = 6). 20× magnification. Quantitation of IHC images of FasL, Fas, active caspase-8, active caspase-3, and Bax staining are represented a... Biomarkers in the Assessment of Therapies for Familial Amyloidotic Polyneuropathy Mol Med. ;13(11-12):584-591.Figure 4 Representative Fas (upper panels) and Bax (bottom panels) staining in stomach and DRG tissue of TTR transgenic mice. Upper panels: Stomach tissue of hTTR Met30 mice without TTR deposition (−/−, left, n = 5) and with TTR deposition (+/−, right, n = 5), of hTTR Met30/(+/−)HSF1-KO, without TTR deposition (−/−, left, n = 6) and with TTR de... Biomarkers in the Assessment of Therapies for Familial Amyloidotic Polyneuropathy Mol Med. ;13(11-12):584-591.Figure 5 Representative immunohistochemistry of TTR, BiP, Fas, Bax, 8-OHdG and Grx1 in stomach tissue of TTR Y78F immunized transgenic mice 9–10 months old (right; n = 6) and nonimmunized age-matched controls (left; n = 6). 20× magnification; Quantification of IHC images of TTR, BiP, Fas, Bax, 8-OHdG, and Gr... Biomarkers in the Assessment of Therapies for Familial Amyloidotic Polyneuropathy Mol Med. ;13(11-12):584-591.Publication Types, MeSH Terms, SubstancesPublication Types Research Support, Non-U.S. Gov't MeSH Terms Amyloidosis, Familial/metabolism Amyloidosis, Familial/therapy* Animals Animals, Genetically Modified Apoptosis Biological Markers/metabolism* DNA Damage Immunohistochemistry Mice Oxidative Stress Polyneuropathies/metabolism Polyneuropathies/therapy* Prealbumin/metabolism Substances Biological Markers Prealbumin
- A clinical-pathological and survival study of oral squamous cell carcinomas from a population of the North of PortugalPublication . Monteiro, L.; Barbas-Amaral, J.; Vizcaíno, J.; Lopes, C.; Torres, F.OBJECTIVES: Our aim was to analyze the clinical, pathological, and outcome characteristics of oral squamous cell carcinomas (OSCC) from a population of the North of Portugal. MATERIAL AND METHODS: We conducted a descriptive study of 128 OSCC diagnosed between the years of 2000 and 2010 in the Centro Hospitalar do Porto. Through of the review of the clinical records we studied several clinical, pathological, and outcome variables. The overall survival (OS) and disease-free survival (DFS) were analyzed by Kaplan-Meier method and log-rank test. Cox regression method was used for multivariate analysis. RESULTS: Of 128 patients with OSCC, 83 (64.8%) were male and 45 (35.2%) were female, (mean age of 62.13±15.57 years). The most affected location was the tongue (n=52; 40.6%). The most common cause of reference was a non-healing ulcer (n=35; 28.9%) followed by oral pain (n=27; 22.3%). Sixty (60.6%) patients were tobacco consumers and 55 (57.3%) alcohol consumers. The cumulative 3-years OS rate was 58.6% and DFS was 55.4%. In multivariable analysis for OS, we found an adverse independent prognostic value for advanced tumour size (p<0.001) and for the presence of perineural permeation (p=0.012). For DFS, advanced stage tumours presented adverse independent prognostic value (p<0.001). CONCLUSION: OSCC occurred most frequently in males, in older patients, and in patients with tobacco and/or alcohol habits. TNM and tumour stage additionally to the perineural permeation were the most important prognostic factor for the survival of these patients, contributing to identify high-risk subgroups and to guide therapy.
- EMMPRIN expression in oral squamous cell carcinomas: correlation with tumor proliferation and patient survivalPublication . Monteiro, L.; Delgado, M.; Ricardo, S.; Garcez, F.; Barbas-Amaral, J.; Pacheco, J.; Lopes, C.; Bousbaa, H.The aim of our study was to explore the clinicopathological and prognostic significance of extracellular matrix metalloproteinase inducer (EMMPRIN) expression in oral squamous cell carcinomas (OSCC), and its relation with the proliferative tumor status of OSCC. We examined EMMPRIN and Ki-67 proteins expression by immunohistochemistry in 74 cases with OSCC. Statistical analysis was conducted to examine their clinicopathological and prognostic significance in OSCC. EMMPRIN membrane expression was observed in all cases, with both membrane and cytoplasmic tumor expression in 61 cases (82.4%). EMMPRIN overexpression was observed in 56 cases (75.7%). Moderately or poorly differentiated tumors showed EMMPRIN overexpression more frequently than well-differentiated tumors (P = 0.002). Overexpression of EMMPRIN was correlated with high Ki-67 expression (P = 0.004). In the multivariate analysis, EMMPRIN overexpression reveals an adverse independent prognostic value for cancer-specific survival (CSS) (P = 0.034). Our results reveal that EMMPRIN protein is overexpressed in more than two-thirds of OSCC cases, especially in high proliferative and less differentiated tumors. The independent value of EMMPRIN overexpression in CSS suggests that this protein could be used as an important biological prognostic marker for patients with OSCC. Moreover, the high expression of EMMPRIN makes it a possible therapeutic target in OSCC patients.