12 results on '"Soledad Urra"'
Search Results
2. The Combination of RET, BRAF and Demographic Data Identifies Subsets of Patients with Aggressive Papillary Thyroid Cancer
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Sergio Vargas-Salas, Antonieta Solar, Augusto León, Nicolás Droppelmann, José R Martínez, Hernán E. González, Estefanía Muñoz, Soledad Urra Gamboa, Mark Zafereo, F. Christopher Holsinger, and José Carlos de Miguel Domínguez
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Adult ,Male ,Proto-Oncogene Proteins B-raf ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,DNA Mutational Analysis ,Lymph node metastasis ,Demographic data ,medicine.disease_cause ,Papillary thyroid cancer ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Mutational status ,In patient ,Prospective Studies ,Thyroid Neoplasms ,Lymph node ,Mutation ,Endocrine and Autonomic Systems ,business.industry ,Proto-Oncogene Proteins c-ret ,Middle Aged ,Prognosis ,medicine.disease ,Treatment Outcome ,030104 developmental biology ,medicine.anatomical_structure ,Thyroid Cancer, Papillary ,Lymphatic Metastasis ,030220 oncology & carcinogenesis ,Cohort ,Female ,Lymph Nodes ,business - Abstract
The use of BRAFV600E and RET/PTC1 as biomarkers to guide the extent of surgery in patients with papillary thyroid cancer (PTC) remains controversial. We assessed the combined use of demographic data (sex and age) with mRNA expression levels and/or mutational status (BRAFV600E and RET/PTC1) to identify potential subsets of patients with aggressive histopathological features (lymph node metastases and extrathyroidal extension). In a cohort of 126 consecutive patients, BRAFV600E and RET/PTC1 mutations were found in 52 and 18%, respectively. By conditional bivariate analysis (CBVA), a 'high activity' profile of BRAF (BRAFV600E positive or high expression) and 'low activity' profile of RET (RET/PTC1 negative or low expression) was associated with extrathyroidal extension (ETE) (OR 4.48). Alternatively, a 'high activity' profile of RET (RET/PTC1 positive or high expression) and 'low activity' profile of BRAF (BRAFV600E negative or low expression) were associated with lymph node metastasis (LNM) (OR 12.80). Furthermore, in patients younger than 55 years, a low expression of BRAF was associated with LNM (OR 17.65) and the presence of BRAFV600E mutation was associated with ETE (OR 2.76). Our results suggest that the analysis of demographic and molecular variables by CBVA could contribute to identify subsets of patients with aggressive histopathologic features, providing a potential guide to personalised surgical management of PTC.
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- 2019
3. Genetic testing for indeterminate thyroid cytology: review and meta-analysis
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Thomas Uslar, Soledad Urra, Natalia Mena, José Carlos de Miguel Domínguez, José R Martínez, Marcela Henríquez, Sergio Vargas-Salas, Hernán E. González, and Marcela Lagos
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Thyroid nodules ,Cancer Research ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,media_common.quotation_subject ,Thyroid Gland ,030209 endocrinology & metabolism ,Review ,molecular diagnostics ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,medicine ,Humans ,Quality (business) ,Genetic Testing ,Thyroid Neoplasms ,Intensive care medicine ,Thyroid cancer ,indeterminate thyroid cytology ,Genetic testing ,media_common ,medicine.diagnostic_test ,accuracy ,business.industry ,Molecular diagnostics ,medicine.disease ,Precision medicine ,meta-analysis ,Oncology ,030220 oncology & carcinogenesis ,Meta-analysis ,Indeterminate ,business - Abstract
Thyroid cancer is the most frequent endocrine malignancy, and its incidence is increasing. A current limitation of cytological evaluation of thyroid nodules is that 20–25% are reported as indeterminate. Therefore, an important challenge for clinicians is to determine whether an indeterminate nodule is malignant, and should undergo surgery, or benign, and should be recommended to follow-up. The emergence of precision medicine has offered a valuable solution for this problem, with four tests currently available for the molecular diagnosis of indeterminate cytologies. However, efforts to critically analyze the quality of the accumulated evidence are scarce. This systematic review and meta-analysis is aimed to contribute to a better knowledge about the four available molecular tests, their technical characteristics, clinical performance, and ultimately to help clinicians to make better decisions to provide the best care options possible. For this purpose, we address three critical topics: (i) the proper theoretical accuracy, considering the intended clinical use of the test (rule-in vs rule-out) and the impact on clinical decisions; (ii) the quality of the evidence reported for each test (iii) and how accurate and effective have the tests proved to be after their clinical use. Together with the upcoming evidence, this work provides significant and useful information for healthcare system decision-makers to consider the use of molecular testing as a public health need, avoiding unnecessary surgical risks and costs.
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- 2017
4. Differential expression profile of CXCR3 splicing variants is associated with thyroid neoplasia. Potential role in papillary thyroid carcinoma oncogenesis?
- Author
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Juan Carlos Roa, Antonieta Solar, Paulina Orellana, Loreto P. Véliz, Alexis M. Kalergis, Marcelo López-Lastra, José R Martínez, Soledad Urra, C. Joaquín Cáceres, Claudia A. Riedel, Karen Bohmwald, Augusto León, Alejandro H. Corvalan, Rodrigo A. Fuentealba, Martin C. Fischer, Nicolás Droppelmann, and Hernán E. González
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0301 basic medicine ,endocrine system diseases ,Papillary thyroid cancer ,Inflammation ,chemokine receptors ,CXCR3 ,medicine.disease_cause ,Thyroiditis ,Thyroid carcinoma ,03 medical and health sciences ,0302 clinical medicine ,medicine ,CXCL10 ,papillary thyroid cancer ,business.industry ,Chemokine receptors ,Thyroid ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,inflammation ,030220 oncology & carcinogenesis ,Cancer research ,medicine.symptom ,business ,Carcinogenesis ,Research Paper - Abstract
Indexación: Scopus. Papillary thyroid cancer (PTC) is the most prevalent endocrine neoplasia. The increased incidence of PTC in patients with thyroiditis and the frequent immune infiltrate found in PTC suggest that inflammation might be a risk factor for PTC development. The CXCR3-ligand system is involved in thyroid inflammation and CXCR3 has been found upregulated in many tumors, suggesting its pro-tumorigenic role under the inflammatory microenvironment. CXCR3 ligands (CXCL4, CXCL9, CXCL10 and CXCL11) trigger antagonistic responses partly due to the presence of two splice variants, CXCR3A and CXCR3B. Whereas CXCR3A promotes cell proliferation, CXCR3B induces apoptosis. However, the relation between CXCR3 variant expression with chronic inflammation and PTC development remains unknown. Here, we characterized the expression pattern of CXCR3 variants and their ligands in benign tumors and PTC. We found that CXCR3A and CXCL10 mRNA levels were increased in non-metastatic PTC when compared to non-neoplastic tissue. This increment was also observed in a PTC epithelial cell line (TPC-1). Although elevated protein levels of both isoforms were detected in benign and malignant tumors, the CXCR3A expression remained greater than CXCR3B and promoted proliferation in Nthy-ori-3-1 cells. In non-metastatic PTC, inflammation was conditioning for the CXCR3 ligands increased availability. Consistently, CXCL10 was strongly induced by interferon gamma in normal and tumor thyrocytes. Our results suggest that persistent inflammation upregulates CXCL10 expression favoring tumor development via enhanced CXCR3A-CXCL10 signaling. These findings may help to further understand the contribution of inflammation as a risk factor in PTC development and set the basis for potential therapeutic studies. http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=23502&path[]=74025
- Published
- 2017
5. A 10-Gene Classifier for Indeterminate Thyroid Nodules: Development and Multicenter Accuracy Study
- Author
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Soledad Urra, Elsa Bruce, Tatiana Arias, Natalia Mena, Patricia Arroyo, Pedro Pineda, Antonieta Solar, Jesús Véliz, Giovanna Miranda, Luis Marín, Loreto P. Véliz, Manuel Meneses, Hernán E. González, Francisco Cruz, José R Martínez, Eleonora Horvath, Milagros Bracamonte, René E Díaz, Sergio Vargas-Salas, Nelson Wohllk, Soledad Loyola, Eufrosina Traipe, and Hernán Tala
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Thyroid nodules ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Biopsy, Fine-Needle ,Thyroid Gland ,030209 endocrinology & metabolism ,gene classifier ,Expert Systems ,Bioinformatics ,Sensitivity and Specificity ,In vitro diagnostic ,Cohort Studies ,Diagnosis, Differential ,Machine Learning ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,in vitro diagnostic test ,indeterminate thyroid nodules ,Predictive Value of Tests ,Cytology ,Biomarkers, Tumor ,Prevalence ,Medicine ,Humans ,Prospective Studies ,Thyroid Neoplasms ,Thyroid Nodule ,Chile ,Gene ,Neoplasm Staging ,business.industry ,Thyroid ,Computational Biology ,Reproducibility of Results ,Thyroid Cancer and Nodules ,medicine.disease ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,qPCR ,Real-time polymerase chain reaction ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Practice Guidelines as Topic ,Radiology ,business ,Indeterminate ,Classifier (UML) ,Follow-Up Studies - Abstract
Background: In most of the world, diagnostic surgery remains the most frequent approach for indeterminate thyroid cytology. Although several molecular tests are available for testing in centralized commercial laboratories in the United States, there are no available kits for local laboratory testing. The aim of this study was to develop a prototype in vitro diagnostic (IVD) gene classifier for the further characterization of nodules with an indeterminate thyroid cytology. Methods: In a first stage, the expression of 18 genes was determined by quantitative polymerase chain reaction (qPCR) in a broad histopathological spectrum of 114 fresh-tissue biopsies. Expression data were used to train several classifiers by supervised machine learning approaches. Classifiers were tested in an independent set of 139 samples. In a second stage, the best classifier was chosen as a model to develop a multiplexed-qPCR IVD prototype assay, which was tested in a prospective multicenter cohort of fine-needle aspiration biopsies. Results: In tissue biopsies, the best classifier, using only 10 genes, reached an optimal and consistent performance in the ninefold cross-validated testing set (sensitivity 93% and specificity 81%). In the multicenter cohort of fine-needle aspiration biopsy samples, the 10-gene signature, built into a multiplexed-qPCR IVD prototype, showed an area under the curve of 0.97, a positive predictive value of 78%, and a negative predictive value of 98%. By Bayes' theorem, the IVD prototype is expected to achieve a positive predictive value of 64–82% and a negative predictive value of 97–99% in patients with a cancer prevalence range of 20–40%. Conclusions: A new multiplexed-qPCR IVD prototype is reported that accurately classifies thyroid nodules and may provide a future solution suitable for local reference laboratory testing.
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- 2017
6. TrkA Receptor Activation by Nerve Growth Factor Induces Shedding of the p75 Neurotrophin Receptor Followed by Endosomal γ-Secretase-mediated Release of the p75 Intracellular Domain
- Author
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Claudia A. Escudero, Niccolò Zampieri, Paulina Covarrubias, Francisca C. Bronfman, Soledad Urra, Jose I. Parraguez, Fernanda Lisbona, Edgardo Allende, W. Annaert, Moses V. Chao, and Patricio Ramos
- Subjects
musculoskeletal diseases ,Endosomes ,Tropomyosin receptor kinase A ,PC12 Cells ,Receptor, Nerve Growth Factor ,Biochemistry ,Growth factor receptor ,Nerve Growth Factor ,Animals ,Low-affinity nerve growth factor receptor ,Receptor, trkA ,skin and connective tissue diseases ,Molecular Biology ,Brain-derived neurotrophic factor ,biology ,Brain-Derived Neurotrophic Factor ,Cell Biology ,Endocytosis ,biological factors ,Protein Structure, Tertiary ,Rats ,Cell biology ,nervous system ,Trk receptor ,biology.protein ,Tetradecanoylphorbol Acetate ,sense organs ,Amyloid Precursor Protein Secretases ,Signal transduction ,Amyloid precursor protein secretase ,Signal Transduction ,Neurotrophin - Abstract
Neurotrophins are trophic factors that regulate important neuronal functions. They bind two unrelated receptors, the Trk family of receptor-tyrosine kinases and the p75 neurotrophin receptor (p75). p75 was recently identified as a new substrate for gamma-secretase-mediated intramembrane proteolysis, generating a p75-derived intracellular domain (p75-ICD) with signaling capabilities. Using PC12 cells as a model, we studied how neurotrophins activate p75 processing and where these events occur in the cell. We demonstrate that activation of the TrkA receptor upon binding of nerve growth factor (NGF) regulates the metalloprotease-mediated shedding of p75 leaving a membrane-bound p75 C-terminal fragment (p75-CTF). Using subcellular fractionation to isolate a highly purified endosomal fraction, we demonstrate that p75-CTF ends up in endosomes where gamma-secretase-mediated p75-CTF cleavage occurs, resulting in the release of a p75-ICD. Moreover, we show similar structural requirements for gamma-secretase processing of p75 and amyloid precursor protein-derived CTFs. Thus, NGF-induced endocytosis regulates both signaling and proteolytic processing of p75. ispartof: Journal of Biological Chemistry vol:282 issue:10 pages:7606-15 ispartof: location:United States status: published
- Published
- 2007
7. Acetylcholinesterase (AChE) - Amyloid-β-Peptide Complexes in Alzheimers Disease. The Wnt Signaling Pathway
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Nibaldo C. Inestrosa, Soledad Urra, and Marcela Colombres
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Amyloid ,Amyloid beta ,Wnt signaling pathway ,Neurotoxicity ,LRP5 ,Biology ,medicine.disease ,Acetylcholinesterase ,Neuroprotection ,Cell biology ,chemistry.chemical_compound ,Neurology ,chemistry ,Biochemistry ,mental disorders ,biology.protein ,medicine ,Neurology (clinical) ,Senile plaques - Abstract
Alzheimer's disease (AD) is characterized by selective neuronal cell death, which is probably caused by amyloid beta-peptide (Abeta) oligomers and fibrils. We have found that acetylcholinesterase (AChE), a senile plaque component, increases amyloid fibril assembly with the formation of highly toxic complexes (Abeta-AChE). The neurotoxic effect induced by Abeta-AChE complexes was higher than that induced by the Abeta peptide alone as shown both in vitro (hippocampal neurons) and in vivo (rats injected with Abeta peptide in the dorsal hippocampus). Interestingly, treatment with Abeta-AChE complexes decreases the cytoplasmic beta-catenin level, a key component of Wnt signaling. Conversely, the activation of this signaling pathway by Wnt-3a promotes neuronal survival and rescues changes in Wnt components (activation or subcellular localization). Moreover Frzb-1, a Wnt antagonist reverses the Wnt-3a neuroprotection effect against Abeta neurotoxicity. Compounds that mimic the Wnt signaling or modulate the cross-talking with this pathway could be used as neuroprotective agents for therapeutic strategies in AD patients.
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- 2004
8. Serological response toHelicobacter pylorirecombinant antigens in Chilean infected patients with duodenal ulcer, non-ulcer dyspepsia and gastric cancer
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Ilse Müller, Soledad Urra, Arturo Yudelevich, Ruth García‐ De La Guarda, Antonio Roll´n, Patricio Opazo, Alejandro Venegas, and Pablo Valenzuela
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Microbiology (medical) ,medicine.medical_specialty ,Spirillaceae ,Population ,Gastroenterology ,Pathology and Forensic Medicine ,Serology ,Antigen ,Internal medicine ,medicine ,Immunology and Allergy ,CagA ,education ,education.field_of_study ,biology ,business.industry ,Stomach ,General Medicine ,Helicobacter pylori ,bacterial infections and mycoses ,biology.organism_classification ,digestive system diseases ,medicine.anatomical_structure ,Immunology ,Duodenum ,bacteria ,business - Abstract
We have previously cloned 10 Helicobacter pylori antigen genes from a Chilean strain including: cytotoxin VacA, a truncated region of CagA (called A17), a species-specific protein (Ag26), urease subunits (UreA, UreB), a flagellin, (FlaB), heat shock proteins (HspA and HspB), an adhesin (HpaA) and a lipoprotein (Lpp20). Immunogenicity of these antigens was tested by immunoblot with sera of Chilean infected patients, revealing that HpaA, A17, HspB and VacA were more frequently recognized (86%, 82%, 68% and 68%, respectively). According to the clinical condition, it was determined that Lpp20 was preferentially recognized by sera from non-ulcer dyspepsia patients (80%), A17 and VacA by patients with duodenal ulcer (92% and 83% respectively), and HspB by patients with duodenal ulcer (83%) and gastric cancer (90%). An ELISA was developed with a purified mixture of A17 and VacA antigens to test the different groups of patients. It was found that sera from duodenal ulcer patients showed higher values than those from non-ulcer dyspepsia patients, but this difference was not significant (p
- Published
- 1999
9. P75 neurotrophin receptor-mediated apoptosis in sympathetic neurons involves a biphasic activation of jnk and up-regulation of tumor necrosis factor-alpha-converting enzyme/adam17
- Author
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Sung Ok Yoon, Rajappa S. Kenchappa, Bruce D. Carter, Chhavy Tep, Francisca C. Bronfman, Zeljka Korade, and Soledad Urra
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Programmed cell death ,Blotting, Western ,MAP Kinase Kinase Kinase 1 ,Apoptosis ,Receptors, Nerve Growth Factor ,Superior Cervical Ganglion ,Tropomyosin receptor kinase A ,ADAM17 Protein ,Biochemistry ,Cell Line ,Rats, Sprague-Dawley ,Mice ,Neurobiology ,Neurotrophic factors ,Mitogen-Activated Protein Kinase 10 ,Nerve Growth Factor ,Low-affinity nerve growth factor receptor ,Animals ,Humans ,Receptor ,Molecular Biology ,Cells, Cultured ,Brain-derived neurotrophic factor ,Anthracenes ,Mice, Knockout ,Neurons ,biology ,Brain-Derived Neurotrophic Factor ,Cell Biology ,Molecular biology ,Rats ,Up-Regulation ,Enzyme Activation ,ADAM Proteins ,Kinetics ,Nerve growth factor ,nervous system ,biology.protein ,RNA Interference ,Neurotrophin - Abstract
During the development of the sympathetic nervous system, the p75 neurotrophin receptor (p75NTR) has a dual function: promoting survival together with TrkA in response to NGF, but inducing cell death upon binding pro or mature brain-derived neurotrophic factor (BDNF). Apoptotic signaling through p75NTR requires activation of the stress kinase, JNK. However, the receptor also undergoes regulated proteolysis, first by a metalloprotease, and then by gamma-secretase, in response to pro-apoptotic ligands and this is necessary for receptor mediated neuronal death (Kenchappa, R. S., Zampieri, N., Chao, M. V., Barker, P. A., Teng, H. K., Hempstead, B. L., and Carter, B. D. (2006) Neuron 50, 219-232). Hence, the relationship between JNK activation and receptor proteolysis remains to be defined. Here, we report that JNK3 activation is necessary for p75NTR cleavage; however, following release of the intracellular domain, there is a secondary activation of JNK3 that is cleavage dependent. Receptor proteolysis and apoptosis were prevented in sympathetic neurons from jnk3(-/-) mice, while activation of JNK by ectopic expression of MEKK1 induced p75NTR cleavage and cell death. Proteolysis of the receptor was not detected until 6 h after BDNF treatment, suggesting that JNK3 promotes cleavage through a transcriptional mechanism. In support of this hypothesis, BDNF up-regulated tumor necrosis factor-alpha-converting enzyme (TACE)/ADAM17 mRNA and protein in wild-type, but not jnk3(-/-) sympathetic neurons. Down-regulation of TACE by RNA interference blocked BDNF-induced p75NTR cleavage and apoptosis, indicating that this metalloprotease is responsible for the initial processing of the receptor. Together, these results demonstrate that p75NTR-mediated activation of JNK3 is required for up-regulation of TACE, which promotes receptor proteolysis, leading to prolonged activation of JNK3 and subsequent apoptosis in sympathetic neurons.
- Published
- 2010
10. [Presence of bacterial DNA in valvular tissue of patients with chronic rheumatic heart disease]
- Author
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Fernando E, Figueroa, Flavio, Carrión A, Sylvia, Valenzuela M, Eduardo, Turner G, Cristian, Aceitón E, Carolina, Hirigoyen P, Katherine, Bogdanic W, Claudia, Solís D, Karina, Mansilla A, and Soledad, Urra G
- Subjects
Adult ,DNA, Bacterial ,Male ,Antigens, Bacterial ,Rheumatic Heart Disease ,Streptococcus ,Pharyngitis ,Middle Aged ,Heart Valves ,Streptococcal Infections ,Chronic Disease ,Humans ,Pharynx ,Female ,Aged - Abstract
Rheumatic heart disease (RHD) is a delayed consequence of a pharyngeal infection with Group A streptococcus (GAS), usually ascribed to a cross-reactive immune response to the host cardiac tissues. Acute rheumatic fever (ARF) and its ensuing valvular sequelae are thus considered the prototype of a post-infectious autoimmune disease, with no direct evidence of residual streptococcal antigen in diseased valvular tissues. However, recent studies concerning the antigenic specificity and clonality of intralesional lymphocytes have revealed oligoclonal expansions characteristic of an antigen specific response, that might be related to GAS.To search for bacterial DNA in valvular tissue from RHD patients and controls.We extracted DNA from surgically excised valve specimens from 15 RHD patients and 6 non RHD controls and tested for the presence of bacterial DNA by Polymerase Chain Reaction (PCR) with primers for 16S rRNA.Eighty percent (12/15) of valve specimens from RHD patients were positive for bacterial DNA, as opposed to none of the valves (n =6) from non RHD controls.These results suggest that GAS might persist in valvular tissue in patients with ARF and contribute to the inflammatory scarring lesion that leads to cardiovascular sequelae.
- Published
- 2007
11. Presencia de ADN bacteriano en el tejido valvular de pacientes con cardiopatía reumática crónica
- Author
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Sylvia Valenzuela M., Karina Mansilla A, Katherine Bogdanic W, Claudia Solís D, Soledad Urra G, Eduardo Turner G, Carolina Hirigoyen P, Cristian Aceitón E, Fernando E Figueroa, and Flavio Carrión A
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Pathology ,medicine.medical_specialty ,Heart disease ,business.industry ,Streptococcus ,Pharynx ,Acute rheumatic fever ,DNA ,General Medicine ,medicine.disease ,medicine.disease_cause ,Group A ,Pharyngitis ,Immune system ,medicine.anatomical_structure ,Antigen specific ,Immunology ,medicine ,bacterial ,medicine.symptom ,business ,Rheumatic heart disease - Abstract
Background: Rheumatic heart disease (RHD) is a delayed consequence of a pharyngeal infection with Group A streptococcus (GAS), usually ascribed to a cross-reactive immune response to the host cardiac tissues. Acute rheumatic fever (ARF) and its ensuing valvular sequelae are thus considered the prototype of a post-infectious autoimmune disease, with no direct evidence of residual streptococcal antigen in diseased valvular tissues. However, recent studies concerning the antigenic specificity and clonality of intralesional lymphocytes have revealed oligoclonal expansions characteristic of an antigen specific response, that might be related to GAS. Aim: To search for bacterial DNA in valvular tissue from RHD patients and controls. Material and methods: We extracted DNA from surgically excised valve specimens from 15 RHD patients and 6 non RHD controls and tested for the presence of bacterial DNA by Polymerase Chain Reaction (PCR) with primers for 16S rRNA. Results: Eighty percent (12/15) of valve specimens from RHD patients were positive for bacterial DNA, as opposed to none of the valves (n =6) from non RHD controls. Conclusions: These results suggest that GAS might persist in valvular tissue in patients with ARF and contribute to the inflammatory scarring lesion that leads to cardiovascular sequelae (Rev Méd Chile 2007; 135: 959-66)
- Published
- 2007
12. Acetylcholinesterase (AChE)--amyloid-beta-peptide complexes in Alzheimer's disease. the Wnt signaling pathway
- Author
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Nibaldo C, Inestrosa, Soledad, Urra, and Marcela, Colombres
- Subjects
Wnt Proteins ,Amyloid beta-Peptides ,Alzheimer Disease ,Acetylcholinesterase ,Animals ,Humans ,Intercellular Signaling Peptides and Proteins ,Signal Transduction - Abstract
Alzheimer's disease (AD) is characterized by selective neuronal cell death, which is probably caused by amyloid beta-peptide (Abeta) oligomers and fibrils. We have found that acetylcholinesterase (AChE), a senile plaque component, increases amyloid fibril assembly with the formation of highly toxic complexes (Abeta-AChE). The neurotoxic effect induced by Abeta-AChE complexes was higher than that induced by the Abeta peptide alone as shown both in vitro (hippocampal neurons) and in vivo (rats injected with Abeta peptide in the dorsal hippocampus). Interestingly, treatment with Abeta-AChE complexes decreases the cytoplasmic beta-catenin level, a key component of Wnt signaling. Conversely, the activation of this signaling pathway by Wnt-3a promotes neuronal survival and rescues changes in Wnt components (activation or subcellular localization). Moreover Frzb-1, a Wnt antagonist reverses the Wnt-3a neuroprotection effect against Abeta neurotoxicity. Compounds that mimic the Wnt signaling or modulate the cross-talking with this pathway could be used as neuroprotective agents for therapeutic strategies in AD patients.
- Published
- 2005
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