166 results on '"Lucia de Noronha"'
Search Results
2. Transcriptomic profiling of cardiac tissues from <scp>SARS‐CoV</scp> ‐2 patients identifies <scp>DNA</scp> damage
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Arutha Kulasinghe, Ning Liu, Chin Wee Tan, James Monkman, Jane E Sinclair, Dharmesh D Bhuva, David Godbolt, Liuliu Pan, Andy Nam, Habib Sadeghirad, Kei Sato, Gianluigi Li Bassi, Ken O’Byrne, Camila Hartmann, Anna Flavia Ribeiro dos Santo Miggiolaro, Gustavo Lenci Marques, Lidia Zytynski Moura, Derek Richard, Mark Adams, Lucia de Noronha, Cristina Pellegrino Baena, Jacky Y Suen, Rakesh Arora, Gabrielle T. Belz, Kirsty R Short, Melissa J Davis, Fernando Souza-FonsecaGuimaraes, and John F Fraser
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Immunology ,virus diseases ,Immunology and Allergy ,skin and connective tissue diseases - Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known to present with pulmonary and extra-pulmonary organ complications. In comparison with the 2009 pandemic (pH1N1), SARS-CoV-2 infection is likely to lead to more severe disease, with multi-organ effects, including cardiovascular disease. SARS-CoV-2 has been associated with acute and long-term cardiovascular disease, but the molecular changes govern this remain unknown.In this study, we investigated the landscape of cardiac tissues collected at rapid autopsy from SARS-CoV-2, pH1N1, and control patients using targeted spatial transcriptomics approaches. Although SARS-CoV-2 was not detected in cardiac tissue, host transcriptomics showed upregulation of genes associated with DNA damage and repair, heat shock, and M1-like macrophage infiltration in the cardiac tissues of COVID-19 patients. The DNA damage present in the SARS-CoV-2 patient samples, were further confirmed by γ−H2Ax immunohistochemistry. In comparison, pH1N1 showed upregulation of Interferon-stimulated genes (ISGs), in particular interferon and complement pathways, when compared with COVID-19 patients.These data demonstrate the emergence of distinct transcriptomic profiles in cardiac tissues of SARS-CoV-2 and pH1N1 influenza infection supporting the need for a greater understanding of the effects on extra-pulmonary organs, including the cardiovascular system of COVID-19 patients, to delineate the immunopathobiology of SARS-CoV-2 infection, and long term impact on health.
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- 2022
3. Physical Training Protects Against Brain Toxicity in Mice Exposed to an Experimental Model of Glioblastoma
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Amanda K. Costa, Luis F. B. Marqueze, Bruna B. Gattiboni, Giulia S. Pedroso, Franciane F. Vasconcellos, Eduardo B. B. Cunha, Hanna C. Justa, Antonielle B. Baldissera, Seigo Nagashima, Lucia de Noronha, Zsolt Radak, Luiz C. Fernandes, and Ricardo A. Pinho
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Cellular and Molecular Neuroscience ,General Medicine ,Biochemistry - Published
- 2022
4. Development of a SARS-COV-2 monoclonal antibody panel and its applicability as a reagent in high-throughput fluorescence reduction neutralization and immunohistochemistry assays
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Gabriela Mattoso, Allan Cataneo, Sonia Mara Raboni, Meri Bordignon Nogueira, Caroline Vaz de Paula, Ana Clara Almeida, Vanessa Rogerio, Nilson Zanchin, Lucia de Noronha, Camila Zanluca, and Claudia N Duarte dos Santos
- Abstract
Since its emergence in late 2019, infection by SARS-CoV-2 (COVID-19 disease) has quickly spread worldwide, leading to a pandemic that has caused millions of deaths and huge socio-economic losses. Although vaccination against COVID-19 has significantly reduced disease mortality, it has been shown that protection wanes over time, and that circulating SARS-CoV-2 variants may escape vaccine-derived immunity. Therefore, serological studies are still necessary to assess protection in the population and better guide vaccine booster programs. A common measure of protective immunity is the presence of neutralizing antibodies (nAbs). However, the gold standard method for measuring nAbs (plaque reduction neutralization test, or PRNT) is laborious and time-consuming, limiting its large-scale applicability. In this study, we developed a high-throughput fluorescence reduction neutralization assay (FRNA) to detect SARS-CoV-2 nAbs. Because the assay relies on immunostaining, we also developed and characterized in-house monoclonal antibodies (mAbs) to lower assay costs and reduce the vulnerability of the test to reagent shortages. Using samples collected before the pandemic and from individuals vaccinated against COVID-19, we showed that the results of the FRNA we developed using commercial and in-house mAbs strongly correlated with those of the standard PRNT method while providing results in 70% less time. In addition to providing a fast, reliable, and high-throughput alternative for measuring nAbs, the FRNA can be easily customized to assess other SARS-CoV-2 variants of concern (VOCs). We also demonstrated the applicability of the mAbs produced in immunohistochemistry assays.
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- 2023
5. Expression of Immune Checkpoint Markers PD-1, PD-L1, CD8, MSI, and p53 in Advanced Serous Ovarian Carcinoma
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Ana Paula Dergham, Seigo Nagashima, Caroline Busatta Vaz de Paula, Marcia Olandoski, Lucia De Noronha, and Vanessa Santos Sotomaior
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Advanced high-grade serous ovarian carcinoma is a serious malignant neoplasm with a late diagnosis and high mortality rate. Even when treated with standard therapy, such as surgery followed by carboplatin and paclitaxel chemotherapy, the prognosis remains unfavorable. Im-munotherapy is a treatment alternative that requires further study. Therefore, we aimed to evaluate the expression of the immunotherapy markers: PD-1, PD-L1, CD8, MSI (MLH1, MSH2, MSH6, and PMS2), and p53 in the paraffin samples of high-grade serous ovarian carcinoma. A retrospective study of 28 southern Brazilian patients with advanced serous ovarian carcinoma (EC III or IV) was conducted between 2009 and 2020. The expression of these proteins was evaluated using im-munohistochemistry, and the results were correlated with the patients' clinicopathological data. At diagnosis, the mean age was 61 years, and the most common clinical stage (60%) was EC III. Among the cases, 84.6% exhibited p53 overexpression, 14.8% had MSI, 92.0% were sensitive to platinum, and more than 50.0% relapsed after treatment. Patients with MSI had a lower CD8/PD-1 ratio and more relapses (p=0.03). In conclusion, analysis of immunotherapeutic markers in paraf-fin-embedded samples of advanced serous ovarian carcinoma is feasible and may assist in prog-nosis.
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- 2023
6. Pediatric Astrocytomas and Their Association With Polymorphisms in Embryonic Stem Cell Marker Genes
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Eduardo Morais de Castro, Leonardo Vinícius Barbosa, Aline Simoneti Fonseca, Seigo Nagashima, Caroline Busatta Vaz de Paula, Rafaela Zeni, Luciane R. Cavalli, Luiz Fernando Bleggi Torres, Lucia de Noronha, and Cleber Machado-Souza
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SOXB1 Transcription Factors ,Pediatrics, Perinatology and Child Health ,Humans ,Nanog Homeobox Protein ,Neurology (clinical) ,Astrocytoma ,Child ,Embryonic Stem Cells - Abstract
Background Embryonic stem cell markers, such as SOX2, NANOG, and OCT4, are transcription factors expressed in pluripotent stem cells, involved in the mediation of pluripotency and self-renewal. Especially after the discovery of cancer stem cells, these proteins have been associated with several types of neoplasia, including astrocytomas. In the pediatric population, astrocytomas are the most common solid neoplasia and present the highest mortality rates. Methods Our study evaluated 5 polymorphisms in SOX2, NANOG, and POU5F1 genes in 101 pediatric astrocytoma samples. Results We describe the associations between wild and polymorphic alleles in astrocytomas. Conclusions In our results, the intronic polymorphic G allele in SOX2 rs77677339 [G/A] had a borderline association with low-grade astrocytomas, and the intronic polymorphic T allele in NANOG rs10845877 [C/T] showed a higher frequency in grade 2, compared to grade 1 astrocytomas, thus showing promising results. Impact Our study is relevant because it shows a potential correlation between polymorphic embryonic stem cell marker genes and pediatric astrocytomas.
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- 2022
7. Carnosine supplementation and retina oxidative parameters in diet-induced obesity model
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Rogil José de Almeida Torres, Fernando Moreto, Andrea Luchini, Rogerio Joao de Almeida Torres, Sofia Pimentel Longo, Ricardo A Pinho, Seigo Nagashima, Lucia de Noronha, Artur Junio Togneri Ferron, Carol Vagula de Almeida Silva, Camila Renata Correa, Giancarlo Aldini, and Ana Lucia Anjos Ferreira
- Abstract
Purpose: To describe retina oxidative parameters and carnosine influence in diet-induced obesity model. Methods: Wistar rats were randomly divided into four groups: Standard diet (SD), high sugar-fat diet (HcD), standard diet + carnosine (SD+Carn), and high sugar-fat diet + carnosine (HcD+Car). Evaluation in animals included body weight, adiposity index, plasma glucose, total lipids, high density lipoprotein (HDL), and low-density lipoprotein (LDL), uric acid, creatinine, and triglycerides. The retinas were analyzed for markers of oxidative stress. Hydrogen peroxide production was assessed by oxidation of 2', 7'-dichlorodihydrofluorescein diacetate (DCFH-DA). The analysis of the antioxidant system included total glutathione (tGSH), total antioxidant capacity (TAC), protein carbonyl, and sulfhydryl type. Results: The hypercaloric diet induced higher body weight, adiposity index, glucose, and triglyceride. Carnosine supplementation influenced on plasma triglyceride. Absence of diet effect was verified in retina fluorescent derivative of oxidized DCFH-DA (DCF), TAC, GSH reduced levels and GSH:GSSG ratio. High retina TAC levels were found in rats treated with carnosine. Retina GSH reduced levels and GSH:GSSG ratio improved in carnosine-supplemented rats treated with high sugar-fat diet (vs.SD+Car). Diet was associated with increase in retina carbonyl content and decrease in sulphydryl levels. However, carnosine supplementation had no interference in both retina parameters from animals treated with high sugar-fat diet. Conclusion: The results suggest that the sugar- and fat-enriched diet fed the rats may trigger an imbalance in the retinal redox state and that carnosine may improve the oxidative parameters.
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- 2023
8. The role of IL17 and IL17RA polymorphisms in lethal pandemic acute viral pneumonia (Influenza A virus H1N1 subtype)
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Vanessa Yumie Salomão Watanabe Liberalesso, Marina Luise Viola Azevedo, Mineia Alessandra Scaranello Malaquias, Caroline Busatta Vaz de Paula, Seigo Nagashima, Daiane Gavlik de Souza, Plínio Cézar Neto, Kauana Oliveira Gouveia, Larissa Cristina Biscaro, Ana Luisa Garcia Giamberardino, Gabrielle Tasso Gonçalves, Thais Teles Soares Kondo, Sonia Maria Raboni, Isabelle Weiss, Cleber Machado-Souza, and Lucia de Noronha
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General Medicine - Abstract
Background The cytokines play an essential role in acute inflammatory processes, and the IL-17 may be responsible for ambiguous aspects, and the correlation with genetic polymorphisms could improve the search for this critical biomarker. Thus, this study aimed to evaluate the IL-17A and IL-17RA tissue expression and the polymorphisms that codified these proteins in a population that died of pandemic Influenza A virus H1N1 subtype compared to a non-pandemic Influenza virus population. Methods Necropsy lung samples immunohistochemistry was performed to assess the presence of IL-17A and IL-17RA in the pulmonary tissue. Eight single nucleotide polymorphisms were genotyped using TaqMan® technology. Results The Influenza A H1N1 pandemic group had higher tissue expression of IL-17A, higher neutrophil recruitment and shorter survival time between admission and death. Three single nucleotide polymorphisms conferred risk for pandemic influenza A H1N1, the AA genotype of rs3819025 G/A, the CC genotype of rs2241044 A/C, and the TT genotype of rs 2,241,043 C/T. Conclusions One IL17A polymorphism (rs381905) and two IL17RA polymorphisms (rs2241044 and rs2241043) represented biomarkers of worse prognosis in the population infected with pandemic influenza A H1N1. The greater tissue expression of IL-17A shows a Th17 polarization and highlights the aggressiveness of the pandemic influenza virus with its duality in the protection and pathogenesis of the pulmonary infectious process.
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- 2023
9. Whole transcriptome profiling of placental pathobiology in SARS-CoV-2 pregnancies identifies a preeclampsia-like gene signature
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Nataly Stylianou, Ismail Sebina, Nicholas Matigian, James Monkman, Hadeel Doehler, Joan Röhl, Mark Allenby, Andy Nam, Liuliu Pan, Anja Rockstroh, Habib Sadeghirad, Kimberly Chung, Thais Sobanski, Ken O’Byrne, Patricia Zadorosnei Rebutini, Cleber Machado-Souza, Emanuele Therezinha Schueda Stonoga, Majid E Warkiani, Carlos Salomon, Kirsty Short, Lana McClements, Lucia de Noronha, Ruby Huang, Gabrielle T. Belz, Fernando Souza-Fonseca-Guimaraes, Vicki Clifton, and Arutha Kulasinghe
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In recent years, pregnant people infected with the SARS-CoV-2 virus have shown a higher incidence of “preeclampsia-like syndrome”. Preeclampsia is a systematic syndrome that affects 5-8 % of pregnant people worldwide and is the leading cause of maternal mortality and morbidity. It is unclear what causes preeclampsia, and is characterised by placental dysfunction, leading to poor placental perfusion, maternal hypertension, proteinuria, thrombocytopenia, or neurological disturbances.In this study, we used whole-transcriptome, digital spatial profiling of placental tissues to analyse the expression of genes at the cellular level between placentae from pregnant participants who contracted SARS-CoV-2 in the third trimester of their pregnancy and those prior to the start of the pandemic. Our focused analysis of the trophoblast and villous core stromal cell populations revealed tissue-specific pathways enriched in the SARS-CoV-2 placentae that align with a pre-eclampsia signature. Most notably, we found enrichment of pathways involved in vascular tension, blood pressure, inflammation, and oxidative stress.This study illustrates how spatially resolved transcriptomic analysis of placental tissue can aid in understanding the underlying pathogenic mechanisms of SARS-CoV-2 in pregnancy that are thought to induce “preeclampsia-like syndrome”. Moreover, our study highlights the benefits of using digital spatial profiling to map the crosstalk between trophoblast and villous core stromal cells linked to pathways involved in “preeclampsia-like syndrome” presenting in pregnant people with SARS-CoV-2.
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- 2023
10. Role of the NF-kB/parkin/vegfr-1 pathway associated with hypoxic-ischemic insult in germinal matrix samples of newborn infants
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Eliane Amaral Ghirelli, Felipe Paes Gomes da Silva, Alessandro Gonçalves Gomes Oricil, Caroline Busatta Vaz de Paula, Seigo Nagashima, Carlos Frederico Oldenburg Neto, Eduardo Storti, Fernando Yochiteru Rolim Sakiyama, Rafael Martins Kayano, Renata Rolim Sakiyama, Vinícius da Silva Moreira, Vanessa Santos Sotomaior, and Lucia de Noronha
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Pediatrics, Perinatology and Child Health - Abstract
Objective: Given the high proliferative activity of germinal matrix and its direct correlation with hypoxemia, it is necessary to investigate the possible molecular regulation pathways, to understand the existing clinical relationship between the hypoxic-ischemic insult and the biomarkers NF-kB, AKT-3, Parkin, TRK-C and VEGFR-1. Methods: A hundred and eighteen germinal matrix samples of the central nervous system of patients who died in the first 28 days of life were submitted to histological and immunohistochemistry analysis to identify the tissue immunoexpression of those biomarkers related to asphyxia, prematurity, and death events within 24h. Results: A significantly increased tissue immunoexpression of NF-kB, AKT-3 and Parkin was observed in the germinal matrix of preterm infants. In addition, significantly decreased tissue immunoexpression of VEGFR-1 and NF-kB was observed in patients who experienced asphyxia followed by death within 24 hours. Conclusions: The results suggest a direct involvement between the hypoxic-ischemic insult and NF-kB and VEGFR-1 markers since a decreased immunoexpression of these biomarkers was observed in asphyxiated patients. Furthermore, it is suggested that there was not enough time for VEGFR-1 to be transcribed, translated and expressed on the surface of the plasma membrane. This temporality can be observed in the relationship between NF-kB expression and the survival time of individuals who died within 24 hours, suggesting that this factor is essential for the production of VEGFR-1 and, therefore, to carry out the necessary remodeling effect to neovascularize the affected region.
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- 2023
11. Significância prognóstica da expressão de ki-67, receptores de estrógeno e receptores de progesterona em pacientes com melanoma cutâneo / Prognostic significance of ki-67, estrogen receptors and progesterone receptors expression in patients with cutaneous melanoma
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Claudia Adriane Kuhn, Mário Rodrigues Montemor Netto, Cynthia Holzmann Koehler, and Lucia de Noronha
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Marketing ,Pharmacology ,Organizational Behavior and Human Resource Management ,biology ,business.industry ,Strategy and Management ,Melanoma ,Pharmaceutical Science ,Estrogen receptor ,medicine.disease ,Molecular biology ,Ki-67 ,Drug Discovery ,Cutaneous melanoma ,biology.protein ,Medicine ,In patient ,Receptor ,business - Abstract
Introducao: O Melanoma Cutâneo (MC) e a forma mais agressiva de câncer de pele. Pouco se conhece sobre marcadores biologicos que representam uma maior ou menor agressividade desta neoplasia. Estudos indicam uma relacao entre os hormonios sexuais e o indice de proliferacao celular (Ki-67) com o MC. Objetivo: Analisar o perfil molecular de pacientes com MC invasor, verificando a significância prognostica dos Receptores de Estrogeno (RE), Receptores de Progesterona (RP) e Ki-67. Metodos: Trata-se de um estudo caso-controle que analisou 179 casos de MC invasor, que ocorreram na regiao dos Campos Gerais – PR, Brasil, no periodo de 2002 a 2014. Foi construido um banco de dados com informacoes anatomopatologicas, clinicas, e imuno-histoquimicas. Posteriormente, os dados foram analisados pelos testes Kolmogorov-Smirnov, Student uni-caudal e exato de Fisher. Resultados: A incidencia de metastases foi maior nos casos de Ki-67 alto (p=0,021). Observou-se que a marcacao citoplasmatica, tanto pelo RE, quanto pelo RP, esta associada com pacientes que nao possuem metastases (p=0,006; 0,001 respectivamente). Sexo masculino, sitio anatomico, estadiamento clinico, nivel de Clark, espessura de Breslow, ulceracao e invasao linfatica foram os fatores que apresentaram significância estatistica como preditores de metastases. Nao foi evidenciada correlacao entre o Ki- 67 e os outros marcadores. Conclusao: Este estudo foi estatisticamente significante, corroborando as evidencias do envolvimento dos hormonios sexuais e do Ki-67 na progressao do MC. Novos estudos devem ser realizados para comprovar os reais papeis do Ki-67 e dos hormonios sexuais, assim como os mecanismos de acao por eles adotados.
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- 2021
12. Immune Response Gaps Linked to SARS-CoV-2 Infection: Cellular Exhaustion, Senescence, or Both?
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Leonardo Vinicius Barbosa, Daniele Margarita Marani Prá, Seigo Nagashima, Marcos Roberto Curcio Pereira, Rebecca Benicio Stocco, Francys de Luca Fernandes da Silva, Milena Rueda Cruz, Djessyka Dallagassa, Thiago João Stupak, George Willian Xavier da Rosa Götz, Georgia Garofani Nasimoto, Luiz Augusto Fanhani Cracco, Isabela Busto Silva, Karen Fernandes de Moura, Marina de Castro Deus, Ana Paula Camargo Martins, Beatriz Akemi Kondo Van Spitzenbergen, Andréa Novais Moreno Amaral, Caroline Busatta Vaz de Paula, Cleber Machado-Souza, and Lucia de Noronha
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Immunity, Cellular ,Arginase ,Perforin ,SARS-CoV-2 ,Organic Chemistry ,inflammation ,pathogenesis ,cellular exhaustion ,senescence ,CD8 ,perforin ,COVID-19 ,General Medicine ,Catalysis ,Computer Science Applications ,Inorganic Chemistry ,Influenza A Virus, H1N1 Subtype ,Sphingosine ,Humans ,Interleukin-4 ,Physical and Theoretical Chemistry ,Molecular Biology ,Pandemics ,Spectroscopy - Abstract
The COVID-19 pandemic, promoted by the SARS-CoV-2 respiratory virus, has resulted in widespread global morbidity and mortality. The immune response against this pathogen has shown a thin line between protective effects and pathological reactions resulting from the massive release of cytokines and poor viral clearance. The latter is possibly caused by exhaustion, senescence, or both of TCD8+ cells and reduced activity of natural killer (NK) cells. The imbalance between innate and adaptive responses during the early stages of infection caused by SARS-CoV-2 contributes to the ineffective control of viral spread. The present study evaluated the tissue immunoexpression of the tissue biomarkers (Arginase-1, CCR4, CD3, CD4, CD8, CD20, CD57, CD68, CD138, IL-4, INF-α, INF-γ, iNOS, PD-1, Perforin and Sphingosine-1) to understand the cellular immune response triggered in patients who died of COVID-19. We evaluated twenty-four paraffin-embedded lung tissue samples from patients who died of COVID-19 (COVID-19 group) and compared them with ten lung tissue samples from patients who died of H1N1pdm09 (H1N1 group) with the immunohistochemical markers mentioned above. In addition, polymorphisms in the Perforin gene were genotyped through Real-Time PCR. Significantly increased tissue immunoexpression of Arginase, CD4, CD68, CD138, Perforin, Sphingosine-1, and IL-4 markers were observed in the COVID-19 group. A significantly lower immunoexpression of CD8 and CD57 was also found in this group. It is suggested that patients who died from COVID-19 had a poor cellular response concerning viral clearance and adaptive response going through tissue repair.
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- 2022
13. Immunohistochemical detection of NANOG in oral leukoplakia
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Paulo Henrique Couto Souza, Aline Cristina Batista Rodrigues Johann, Sérgio Aparecido Ignácio, Edinson Manuel Pérez Quispe, Marina Luise Viola de Azevedo, Bruno C. Jham, Maria Carolina Albini Tyski, Suelen Teixeira Luiz, Ana Maria Trindade Grégio Hardy, Arieli Carini Michels, Patrícia Vida Cassi Bettega, Lucia de Noronha, Luciana Reis Azevedo Alanis, Izabela Mozzer, Seigo Nagashima, Giovanna Ribeiro Souto, Aldini Beuting Pereira Kitahara, Rafaela Scariot, Filipe Modolo, Maria Cássia Ferreira de Aguiar, and Ana Paula Camargo Martins
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Homeobox protein NANOG ,Oral leukoplakia ,Otorhinolaryngology ,business.industry ,Cancer research ,Immunohistochemistry ,Medicine ,Stem cell ,business ,General Dentistry - Published
- 2021
14. The role of the lectin pathway of the complement system in SARS-CoV-2 lung injury
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Marina Luise Viola de Azevedo, Ana Carolina Gadotti, Jarbas da Silva Motta-Junior, Leticia Arianne Panini do Carmo, Ana Paula Kubaski Benevides, Aline S. Fonseca, Cleber Machado-Souza, Lucia de Noronha, Rafaela Chiuco Zeni, Andrea N Moreno-Amaral, Sonia Mara Raboni, Mineia Alessandra Scaranello Malaquias, Plínio Cézar-Neto, and Ana Paula Camargo Martins
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Male ,0301 basic medicine ,IHC, Immunohistochemistry ,medicine.disease_cause ,Influenza A Virus, H1N1 Subtype ,0302 clinical medicine ,Lectins ,Influenza A virus ,Complement Activation ,Lung ,Aged, 80 and over ,biology ,H&E, Hematoxylin and Eosin ,Lung Injury ,General Medicine ,Middle Aged ,Immunohistochemistry ,030220 oncology & carcinogenesis ,Lectin pathway ,Cytokines ,Original Article ,Female ,Autopsy ,Antibody ,rRT-PCR, Reverse Transcriptase-Polymerase Chain Reaction ,Adult ,DAD, Diffuse Alveolar Damage ,Genotype ,Lung injury ,ACE-2, Angiotensin-Convertase-Enzyme-2 Receptors ,FFPE, Formalin-Fixed Paraffin-Embedded ,MBL, Mannose-Binding Lectin ,Polymorphism, Single Nucleotide ,Proinflammatory cytokine ,Young Adult ,03 medical and health sciences ,Physiology (medical) ,Influenza, Human ,medicine ,Humans ,Aged ,Biochemistry, medical ,HPF, High-Power Field ,SARS-CoV-2 ,Biochemistry (medical) ,Public Health, Environmental and Occupational Health ,COVID-19 ,Complement system ,030104 developmental biology ,H1N1pdm09, Pandemic Influenza A Virus H1N1 Subtype Infection ,Case-Control Studies ,Immunology ,biology.protein ,CD163 - Abstract
Although some evidence showed the activation of complement systems in COVID-19 patients, proinflammatory status and lectin pathway remain unclear. Thus, the present study aimed to demonstrate the role of MBL and ficolin-3 in the complement system activation and compared to pandemic Influenza A virus H1N1 subtype infection (H1N1pdm09) and control patients. A total of 27 lungs formalin-fixed paraffin-embedded samples (10 from H1N1 group, 6 from the COVID-19 group, and 11 from the control group) were analyzed by immunohistochemistry using anti-IL-6, TNF-alfa, CD163, MBL e FCN3 antibodies. Genotyping of target polymorphisms in the MBL2 gene was performed by real-time PCR. Proinflammatory cytokines such as IL-6 and TNF-alpha presented higher tissue expression in the COVID-19 group compared to H1N1 and control groups. The same results were observed for ICAM-1 tissue expression. Increased expression of the FCN3 was observed in the COVID-19 group and H1N1 group compared to the control group. The MBL tissue expression was higher in the COVID-19 group compared to H1N1 and control groups. The genotypes AA for rs180040 (G/A), GG for rs1800451 (G/A) and CC for rs5030737 (T/C) showed a higher prevalence in the COVID-19 group. The intense activation of the lectin pathway, with particular emphasis on the MBL pathway, together with endothelial dysfunction and a massive proinflammatory cytokines production, possibly lead to a worse outcome in patients infected with SARS-Cov-2. Moreover, 3 SNPs of our study presented genotypes that might be correlated with high MBL tissue expression in the COVID-19 pulmonary samples.
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- 2021
15. Intrauterine Transmission of SARS-CoV-2
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Jullie Anne Chiste, Laura de Almeida Lanzoni, André Luiz Permegiani de Oliveira, Cyllian Arias Fugaça, Ana Paula Percicote, Lucia de Noronha, Andrea Maciel de Oliveira Rossoni, Patricia Zadorosnei Rebutini, Daniele Margarita Marani Prá, Meri Bordignon Nogueira, Emanuele Therezinha Schueda Stonoga, and Sonia Mara Raboni
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Pathology ,diagnosis ,Epidemiology ,Expedited ,coronavirus ,lcsh:Medicine ,medicine.disease_cause ,Umbilical cord ,Lymphocytic Infiltrate ,upper respiratory swab samples ,0302 clinical medicine ,Pregnancy ,030212 general & internal medicine ,Pregnancy Complications, Infectious ,Intrauterine Transmission of SARS-CoV-2 ,swabs ,Coronavirus ,testing ,Infectious Diseases ,medicine.anatomical_structure ,coronavirus disease ,embryonic structures ,Female ,stillbirth ,Brazil ,severe acute respiratory syndrome coronavirus 2 ,Adult ,Microbiology (medical) ,medicine.medical_specialty ,placenta ,Transplacental transmission ,030231 tropical medicine ,RT-PCR ,2019 novel coronavirus disease ,lcsh:Infectious and parasitic diseases ,respiratory infections ,03 medical and health sciences ,Fetus ,autopsy ,Placenta ,Research Letter ,medicine ,Humans ,viruses ,lcsh:RC109-216 ,Fetal Death ,saliva ,SARS-CoV-2 ,business.industry ,lcsh:R ,COVID-19 ,congenital transmission ,medicine.disease ,intrauterine transmission ,Infectious Disease Transmission, Vertical ,zoonoses ,Chronic histiocytic intervillositis ,business - Abstract
We documented fetal death associated with intrauterine transmission of severe acute respiratory syndrome coronavirus 2. We found chronic histiocytic intervillositis, maternal and fetal vascular malperfusion, microglial hyperplasia, and lymphocytic infiltrate in muscle in the placenta and fetal tissue. Placenta and umbilical cord blood tested positive for the virus by PCR, confirming transplacental transmission.
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- 2021
16. Acellular Biomaterials Associated with Autologous Bone Marrow-Derived Mononuclear Stem Cells Improve Wound Healing through Paracrine Effects
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Isio Carvalho de Souza, Aline Luri Takejima, Rossana Baggio Simeoni, Luize Kremer Gamba, Victoria Stadler Tasca Ribeiro, Katia Martins Foltz, Lucia de Noronha, Meila Bastos de Almeida, Jose Rocha Faria Neto, Katherine Athayde Teixeira de Carvalho, Paulo Cesar Lock da Silveira, Ricardo Aurino Pinho, Julio Cesar Francisco, and Luiz César Guarita-Souza
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Medicine (miscellaneous) ,human acellular amniotic membrane ,experimental animal models ,antioxidant system ,stem cells ,wound healing ,paracrine ,General Biochemistry, Genetics and Molecular Biology - Abstract
Wound healing is a complex process of repair that involves the interaction between different cell types and involves coordinated interactions between intracellular and extracellular signaling. Bone Marrow Mesenchymal Stem Cells (BMSCs) based and acellular amniotic membrane (AM) therapeutic strategies with the potential for treatment and regeneration of tissue. We aimed to evaluate the involvement of paracrine effects in tissue repair after the flap skin lesion rat model. In the full-thickness flap skin experiment of forty Wistar rats: A total of 40 male Wistar rats were randomized into four groups: group I: control (C; n = 10), with full-thickness lesions on the back, without (BMSCs) or AM (n = 10); group II: injected (BMSCs; n = 10); group III: covered by AM; group IV–injected (AM + BMSCs; n = 10). Cytokine levels, IL-1, and IL-10 assay kits, superoxide dismutase (SOD), glutathione reductase (GRs) and carbonyl activity levels were measured by ELISA 28th day, and TGF-β was evaluated by immunohistochemical, the expression collagen expression was evaluated by Picrosirius staining. Our results showed that the IL-1 interleukin was higher in the control group, and the IL-10 presented a higher mean when compared to the control group. The groups with BMSCs and AM showed the lowest expression levels of TGF-β. SOD, GRs, and carbonyl activity analysis showed a predominance in groups that received treatment from 80%. The collagen fiber type I was predominant in all groups; however, the AM + BMSCs group obtained a higher average when compared to the control group. Our findings suggest that the AM+ BMSCs promote skin wound healing, probably owing to their paracrine effect attributed to the promotion of new collagen for tissue repair.
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- 2023
17. Polymorphisms in TPT1 Pathways in Pediatric Astrocytomas
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Eduardo Morais de Castro, Leonardo Vinícius Barbosa, Aline Simoneti Fonseca, Seigo Nagashima, Caroline Busatta Vaz de Paula, Rafaela Zeni, Letícia Arianne Panini do Carmo, Luciane Regina Cavalli, Luiz Fernando Bleggi Torres, Andrea Senff Ribeiro, Lucia de Noronha, and Cleber Machado-Souza
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General Neuroscience ,Neurology (clinical) - Abstract
Central nervous system tumors, especially astrocytomas, are the solid neoplasms with the highest incidence and mortality rates in childhood. The diagnosis is based on histopathological characteristics, but molecular methods have been increasingly used. Translationally controlled tumor protein (TCTP) protein, encoded by the tumor protein, translationally controlled 1 ( TPT1) gene, is a multifunctional protein with an important physiological role in the cell cycle. Expression of this protein has been associated with several neoplasms, including astrocytomas in adults. However, the role of this protein in pediatric astrocytomas is largely unknown. We aim to evaluate in cases of pediatric astrocytomas, the frequency of polymorphisms in the TPT1 gene and other genes associated with its molecular pathways, such as MTOR, MDM2, TP53, and CDKN1A, correlating it with protein expression and clinical variables, in formalin-fixed, paraffin-embedded (FFPE) samples. These samples were submitted to genotyping and immunohistochemistry analyses. The most revealing results refer to the MDM2 gene, rs117039649 [G/C], in which C polymorphic allele was observed only in the glioblastomas ( p = .028). The CDKN1A gene, rs3176334 [T/C] presented a homozygous polymorphic genotype only in high-grade astrocytomas, when infiltrating tumors were compared ( p = .039). The immunohistochemical expression of cytoplasmic MDM2 correlated with better survival rates in patients with glioblastoma ( p = .018). The presence of polymorphisms in the MDM2 and CDKN1A genes, as well as a specific correlation between MDM2 expression, suggests a likely association with risk in pediatric astrocytomas. This study sought the probable role involved in the TCTP pathway, and associated proteins, in the tumorigenesis of pediatric astrocytomas, and some could have potential impact as prognostic markers in these patients.
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- 2023
18. Acellular Human Amniotic Membrane Scaffold with 15d-PGJ2 Nanoparticles in Postinfarct Rat Model
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Ricardo Cunha, Guilherme Naves, Luiz Cesar Guarita-Souza, Lucia de Noronha, Paulo Ricardo Baggio Simeoni, Marcelo Napimoga, Laercio Uemura, Julio Cesar Francisco, Rossana Baggio Simeoni, Bassam Felipe Mogharbel, Luiz Felipe P. Moreira, and Katherine Athayde Teixeira de Carvalho
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0303 health sciences ,Scaffold ,medicine.drug_class ,Chemistry ,Regeneration (biology) ,0206 medical engineering ,Rat model ,Biomedical Engineering ,Bioengineering ,02 engineering and technology ,medicine.disease ,020601 biomedical engineering ,Biochemistry ,Anti-inflammatory ,Cell biology ,Biomaterials ,03 medical and health sciences ,Membrane ,Heart failure ,medicine ,15d pgj2 ,Myocardial infarction ,030304 developmental biology - Abstract
The difficulty in the regeneration of cardiomyocytes after myocardial infarction is a major cause of heart failure. Together, the amniotic membrane and 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) c...
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- 2020
19. Paracoccidioides sp infection impairs central nervous system cell junctional complexes
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Sergio Monteiro de Almeida, Amanda Kulik, Mineia Alessandra Scaranello Malaquias, Seigo Nagashima, Caroline Busatta Vaz de Paula, Marisol Dominguez Muro, and Lucia de Noronha
- Abstract
Paracoccidioidomycosis (PCM), a systemic mycosis caused by the fungus Paracoccidioides sp. is the most prevalent fungal infection among immunocompetent patients in Latin America. The estimated frequency of central nervous system (CNS) involvement among the human immunodeficiency virus (HIV)/PCM-positive population is 2.5%. We aimed to address the impact of neuroparacoccidioidomycosis (NPCM) and HIV/NPCM co-infection on the tight junctions (TJ) and adherens junction (AJ) proteins of the CNS. Four CNS formalin-fixed paraffin-embedded (FFPE) tissue specimens were studied: NPCM, NPCM/HIV co-infection, HIV-positive without opportunistic CNS infection, and normal brain autopsy (negative control). Immunohistochemistry was used to analyze the endothelial cells and astrocytes expressions of TJ markers: claudins (CLDN)-1, -3, -5 and occludin; AJ markers: β-catenin and E-cadherin; and pericyte marker: alpha-smooth muscle actin in formalin-fixed paraffin-embedded CNS tissue specimens were analyzed using the immunoperoxidase assay. CLDN-5 expression in the capillaries of the HIV/NPCM coinfected tissues (acute/subacute clinical form of PCM) was lower than that in the capillaries of the HIV or NPCM monoinfected (chronic clinical form of PCM) tissues. A marked decrease in CLDN-5 expression and a compensatory increase in CLDN-1 expression in the NPCM/HIV co-infection tissue samples was observed. The authors suggest that Paracoccidioides sp. crosses the blood–brain barrier through paracellular pathway, owing to the alteration in the CLDN expression, or inside the macrophages (Trojan horse).
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- 2022
20. The Impact of Paracoccidioides spp Infection on Central Nervous System Cell Junctional Complexes
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Sérgio Monteiro de Almeida, Amanda Kulik, Mineia Alessandra Scaranello Malaquias, Seigo Nagashima, Caroline Busatta Vaz de Paula, Marisol Dominguez Muro, and Lucia de Noronha
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Central Nervous System ,Central Nervous System Fungal Infections ,Coinfection ,Veterinary (miscellaneous) ,Humans ,Endothelial Cells ,Paracoccidioides ,HIV Infections ,Paracoccidioidomycosis ,Agronomy and Crop Science ,Applied Microbiology and Biotechnology ,Microbiology - Abstract
Paracoccidioidomycosis (PCM), a systemic mycosis caused by the fungus Paracoccidioides spp. is the most prevalent fungal infection among immunocompetent patients in Latin America. The estimated frequency of central nervous system (CNS) involvement among the human immunodeficiency virus (HIV)/PCM-positive population is 2.5%. We aimed to address the impact of neuroparacoccidioidomycosis (NPCM) and HIV/NPCM co-infection on the tight junctions (TJ) and adherens junction (AJ) proteins of the CNS. Four CNS formalin-fixed paraffin-embedded (FFPE) tissue specimens were studied: NPCM, NPCM/HIV co-infection, HIV-positive without opportunistic CNS infection, and normal brain autopsy (negative control). Immunohistochemistry was used to analyze the endothelial cells and astrocytes expressions of TJ markers: claudins (CLDN)-1, -3, -5 and occludin; AJ markers: β-catenin and E-cadherin; and pericyte marker: alpha-smooth muscle actin. FFPE CNS tissue specimens were analyzed using the immunoperoxidase assay. CLDN-5 expression in the capillaries of the HIV/NPCM coinfected tissues (mixed clinical form of PCM) was lower than that in the capillaries of the HIV or NPCM monoinfected (chronic clinical form of PCM) tissues. A marked decrease in CLDN-5 expression and a compensatory increase in CLDN-1 expression in the NPCM/HIV co-infection tissue samples was observed. The authors suggest that Paracoccidioides spp. crosses the blood-brain barrier through paracellular pathway, owing to the alteration in the CLDN expression, or inside the macrophages (Trojan horse).
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- 2022
21. Histologic spectrum of polymorphous adenocarcinoma of the salivary gland harbor genetic alterations affecting PRKD genes
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Arnaud Da Cruz Paula, Ilan Weinreb, Fresia Pareja, Bin Xu, Ronald Ghossein, Lucia de Noronha, Britta Weigelt, Nora Katabi, Ana Paula Martins Sebastiao, Edaise M da Silva, John R. Lozada, Felipe C Geyer, and Jorge S. Reis-Filho
- Subjects
Adult ,Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Locus (genetics) ,Adenocarcinoma ,Biology ,Genetic analysis ,Article ,Pathology and Forensic Medicine ,Young Adult ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Genotype ,medicine ,Humans ,Genetic Association Studies ,Protein Kinase C ,Aged ,Aged, 80 and over ,Sanger sequencing ,Salivary gland ,medicine.diagnostic_test ,Middle Aged ,Salivary Gland Neoplasms ,medicine.disease ,Phenotype ,cribriform adenocarcinoma of (minor) salivary gland ,3. Good health ,PRKD genes ,030104 developmental biology ,medicine.anatomical_structure ,Polymorphous adenocarcinoma ,030220 oncology & carcinogenesis ,Mutation ,symbols ,Female ,Fluorescence in situ hybridization - Abstract
Polymorphous adenocarcinoma (PAC) and cribriform adenocarcinoma of (minor) salivary gland (CASG) are salivary gland tumors with overlapping spectrum of morphology. Whether these represent distinct entities or a histologic spectrum of the same tumor remains contentious. PACs harbor recurrent PRKD1 E710D hotspot mutations in >70% of cases, whereas 80% of CASGs display rearrangements involving PRKD1, PRKD2, or PRKD3 (PRKD1/2/3). We studied the molecular and morphologic features of 37 PACs/CASGs, seeking to identify the associations among genotype, histologic phenotype, and classification. DNA was subjected to Sanger sequencing analysis of the PRKD1 hotspot locus. Fluorescence in situ hybridization (FISH) analysis for PRKD1/2/3 was performed using dual-color break-apart probes. Tumors were classified into four categories as described previously: PAC, CASG, tumor with indeterminate features (TIF), and tumor with a predominant papillary pattern (TPPP). PRKD1 E710D hotspot mutations were identified in 56%, 20%, 43% and 0% of PACs, CASGs, TIFs, and TPPPs, respectively. FISH demonstrated PRKD1/2/3 rearrangements in 13%, 78%, 36%, and 75% of PACs, CASGs, TIFs, and TPPPs, respectively. Histologically, fusion-positive tumors were associated with a high percentage of papillary growth, low percentage of single filing arrangement, a propensity of base of tongue location, and frequent (50%) lymph node metastasis, compared with the mutation-related tumors which had negligible nodal metastasis risk. Our results demonstrated that (1) PACs/CASGs are underpinned by genetic alterations affecting PRKD genes; (2) despite the associations between PAC and PRKD1 hotspot mutations and CASG and PRKD1/2/3 fusion, such distinction is not absolute; and (3) there is of a novel genotypic-phenotypic association whereby fusion-positive tumors are usually located in the base of the tongue, show papillary architecture and have a high risk of nodal metastasis. Genetic analysis of PRKD genes appears to be useful characterizing this spectrum of tumors, not only histologically but also clinically identifying those tumors with high risk of nodal metastasis.
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- 2020
22. Potential of Human Neural Precursor Cells in Diabetic Retinopathy Therapeutics - Preclinical Model
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Seigo Nagashima, Ana Carolina Irioda, Dilcele Silva Moreira Dziedzic, Eltyeb Abdelwahid, Marianna Bacelar-Galdino, Fabiano Montiani-Ferreira, Maiara Carolina Perussolo, Priscila Elias Ferreira Stricker, André Tavares Somma, Lucia de Noronha, Juan Carlos Duque Moreno, Mário Teruo Sato, Claudia Sayuri Saçaki, Peterson Triches Dornbusch, Célia Regina Cavichiolo Franco, Bassam Felipe Mogharbel, Katherine Athayde Teixeira de Carvalho, and Naoye Shiokawa
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Pathology ,medicine.medical_specialty ,Retina ,Diabetes Mellitus, Experimental ,Cell therapy ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Neural Stem Cells ,Precursor cell ,Neurosphere ,medicine ,Animals ,Humans ,Rats, Wistar ,Retinal pigment epithelium ,Diabetic Retinopathy ,medicine.diagnostic_test ,business.industry ,Mesenchymal stem cell ,Retinal ,Diabetic retinopathy ,medicine.disease ,Sensory Systems ,Rats ,Ophthalmology ,medicine.anatomical_structure ,chemistry ,business ,Electroretinography - Abstract
Purpose: This study aimed to evaluate a cell therapy strategy with human neural precursor cells (hNPCs) to treat diabetic retinopathy (DR) in Wistar rats induced to diabetes by injecting streptozotocin. Material and methods: Wharton's Jelly Mesenchymal stem cells (WJ-MSCs) were isolated, expanded, and seeded onto a biopolymer substrate to develop neurospheres and obtain the hNPCs. The animals were divided into three groups; non-diabetic (ND) n = four; diabetic without treatment (DM) n = nine; and diabetic with cell therapy (DM + hNPCs) n = nine. After eight weeks of diabetes induction and DR characteristics installed, intravitreal injection of hNPCs (1 x 106 cel/µL) was performed in the DM + hNPCs group. Optical Coherence Tomography (OCT) and Electroretinography (ERG) evaluations were before and during diabetes and after cell therapy. Four weeks post-treatment, histopathological and immunohistochemistry analyses were performed. Results: The repair of the retinal structures in the treated group (DM + hNPCs) was observed by increased thickness of neuroretinal layers, especially in the ganglion cell and photoreceptor layers, higher ERG oscillatory potentials (OPs) amplitudes, and transplanted hNPCs integration into the Retinal Pigment Epithelium. Conclusions: The results indicate that hNPCs reduced DR progression by a neuroprotective effect and promoted retinal repair, making them potential candidates for regenerating the neuroretinal tissue.
- Published
- 2021
23. IFI27 transcription is an early predictor for COVID-19 outcomes; a multi-cohort observational study
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Timothy J. Wells, Ya Wang, Jon Iredell, Amy Phu, Sally Teoh, Win Sen Kuan, Yanshan Zhu, Melissa J. Davis, Timothy McCulloch, Majid Ebrahimi Warkiani, Tiana M Pelaia, Yao Xia, Chin Wee Tan, Timothy Kwan, Lucia de Noronha, Velma Herwanto, Reza Alizadeh-Navaei, Amir Shamshirian, Carmen Lúcia Kuniyoshi Rebelatto, John F. Fraser, Tracy Chew, Reza Valadan, Liliana Lamperti, Kenneth J. O'Byrne, Marek Nalos, Gabrielle T. Belz, Yvette Jee, Quan Nguyen, Keng Yih Chew, Maryam Shojaei, Anthony S. McLean, Benjamin Tang, Alexandra Cristina Senegaglia, Carlos Salomon Gallo, Laura F. Grice, Ben Knippenberg, Arutha Kulasinghe, Kirsty R. Short, Felipe Zuñiga, Omolbanin Amjadi, Sepideh Motamen, Estefania Nova-Lamperti, Rajan Gogna, Anna Flavia Ribeiro dos Santos, Minh Tran, Karan Kim, Fernando Souza-Fonseca-Guimaraes, James Monkman, Gustavo Rodrigues Rossi, Gonzalo Labarca, Esha Madan, and Claudio Luciano Franck
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,COVID-19 ,Alpha interferon ,medicine.disease_cause ,Virus ,Coronavirus ,Respiratory failure ,Internal medicine ,Pandemic ,Cohort ,medicine ,Respiratory virus ,business ,Viral load - Abstract
BackgroundRobust biomarkers that predict disease outcomes amongst COVID-19 patients are necessary for both patient triage and resource prioritisation. Numerous candidate biomarkers have been proposed for COVID-19. However, at present, there is no consensus on the best diagnostic approach to predict outcomes in infected patients. Moreover, it is not clear whether such tools would apply to other potentially pandemic pathogens and therefore of use as stockpile for future pandemic preparedness.MethodsWe conducted a multi-cohort observational study to investigate the biology and the prognostic role of interferon alpha-inducible protein 27 (IFI27) in COVID-19 patients.FindingsWe show that IFI27 is expressed in the respiratory tract of COVID-19 patients and elevated IFI27 expression is associated with the presence of a high viral load. We further demonstrate that systemic host response, as measured by blood IFI27 expression, is associated with COVID-19 severity. For clinical outcome prediction (e.g. respiratory failure), IFI27 expression displays a high positive (0.83) and negative (0.95) predictive value, outperforming all other known predictors of COVID-19 severity. Furthermore, IFI27 is upregulated in the blood of infected patients in response to other respiratory viruses. For example, in the pandemic H1N1/09 swine influenza virus infection, IFI27-like genes were highly upregulated in the blood samples of severely infected patients.InterpretationThese data suggest that prognostic biomarkers targeting the family of IFI27 genes could potentially supplement conventional diagnostic tools in future virus pandemics, independent of whether such pandemics are caused by a coronavirus, an influenza virus or another as yet-to-be discovered respiratory virus.Research in contextEvidence before this studyWe searched the scientific literature using PubMed to identify studies that used the IFI27 biomarker to predict outcomes in COVID-19 patients. We used the search terms “IFI27”, “COVID-19, “gene expression” and “outcome prediction”. We did not identify any study that investigated the role of IFI27 biomarker in outcome prediction. Although ten studies were identified using the general terms of “gene expression” and “COVID-19”, IFI27 was only mentioned in passing as one of the identified genes. All these studies addressed the broader question of the host response to COVID-19; none focused solely on using IFI27 to improve the risk stratification of infected patients in a pandemic.Added value of this studyHere, we present the findings of a multi-cohort study of the IFI27 biomarker in COVID-19 patients. Our findings show that the host response, as reflected by blood IFI27 gene expression, accurately predicts COVID-19 disease progression (positive and negative predictive values; 0.83 and 0.95, respectively), outperforming age, comorbidity, C-reactive protein and all other known risk factors. The strong association of IFI27 with disease severity occurs not only in SARS-CoV-2 infection, but also in other respiratory viruses with pandemic potential, such as the influenza virus. These findings suggest that host response biomarkers, such as IFI27, could help identify high-risk COVID-19 patients - those who are more likely to develop infection complications - and therefore may help improve patient triage in a pandemic.Implications of all the available evidenceThis is the first systemic study of the clinical role of IFI27 in the current COVID-19 pandemic and its possible future application in other respiratory virus pandemics. The findings not only could help improve the current management of COVID-19 patients but may also improve future pandemic preparedness.
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- 2021
24. Role of mononuclear stem cells and decellularized amniotic membrane in the treatment of skin wounds in rats
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Aline Luri Takejima, Katherine Athayde Teixeira de Carvalho, Paulo André Bispo Machado Júnior, Isio C. Souza, Kátia M. Foltz, Ricardo A. Pinho, Rossana Baggio Simeoni, Julio Cesar Francisco, Luiz Cesar Guarita-Souza, Lucia de Noronha, and Luiz A.F.M. Garbers
- Subjects
Pathology ,medicine.medical_specialty ,Histology ,Inflammation ,Biochemistry ,Lesion ,Transforming Growth Factor beta ,medicine ,Animals ,Amnion ,Rats, Wistar ,Fibroblast ,Chemistry ,Stem Cells ,Cell Biology ,Rats ,Staining ,Matrix Metalloproteinase 8 ,medicine.anatomical_structure ,Collagen ,medicine.symptom ,Stem cell ,Wound healing ,Elastic fiber ,Type I collagen ,Research Article - Abstract
Stem cells (SC) and amniotic membrane (AM) are recognized for their beneficial impacts on the healing of cutaneous wounds. Thus, this study evaluated the capacity of tissue repair in a skin lesion rat model. Forty Wistar rats were randomized into four groups: group I – control, with full-thickness lesions on the back, without SC or AM; group II–injected SC; group III – covered by AM; group IV–injected SC and covered by AM. Lesion closure was assessed using contraction rate (Cr). Histochemical and immunohistochemical analyses were performed, and collagen, elastic fibers, fibroblast differentiation factor (TGF-β), collagen remodeling (MMP-8), and the number of myofibroblasts and blood vessels (α-SMA) were evaluated. On the 7(th) postoperative day, Cr 1(st)-7(th) day levels were higher in groups III and IV. However, on the 28(th) day, Cr 1(st)-28(th) day were higher in the control group. Picrosirius staining showed that type I collagen was predominant in all groups; however, the SC + AM group obtained a higher average when compared to the control group. Elastic fiber analysis showed a predominance in groups that received treatment. Groups II and IV showed the lowest expression levels of TGF-β and MMP-8, and α-SMA was significantly lower in group IV. The application of SC and AM accelerated the initial healing phase, probably owing to their anti-inflammatory effect that favored early formation of collagen and elastic fibers.
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- 2021
25. The induced dose of experimental autoimmune encephalomyelitis was not determinant and proportional to histopathological findings
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Bassam Felipe Mogharbel, Lucia de Noronha, Katherine Athayde Teixeira de Carvalho, and Maiara Carolina Perussolo
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Pathology ,medicine.medical_specialty ,medicine.anatomical_structure ,business.industry ,Multiple sclerosis ,Experimental autoimmune encephalomyelitis ,Public Health, Environmental and Occupational Health ,medicine ,medicine.disease ,business ,Spinal cord - Abstract
Background Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, characterized as an inflammatory demyelinating disease. It presents a diversity of neurologic signs and symptoms as well the incapacities. Since the need for advances in MS treatment, many studies are for new therapeutic technologies, mainly through using preclinical models as experimental autoimmune encephalomyelitis (EAE). This study aimed to observe and analyze the development in Lewis rats-induced model of EAE. Methods It was used 23 females of Rattus norvegicus, from 6 to 8 weeks, weighing around 170 g. Of 23 rats, 19 underwent EAE induction distributed in six groups to establish the evolution of clinical signs. B. pertussis toxin (PTX) doses were 200, 250, 300, 350–400 ng, and four animals as the control group. The animals had weight and scores analyzed daily, starting seven and ending 24 days after induction. Then, all animals were euthanized, and the brain and spinal cord were collected for histopathological analyses. Results The results showed that the dose of 250 ng of PTX induced de higher score and weight reduction. All groups who received the PTX demonstrated histopathological findings. Those characterized as leukocyte infiltration, activation of microglia and astrocytes, and demyelinated plaques in the brain. In the spinal cord, the loosening of the myelinated fibers was observed by increasing the axonal space in all tested doses of PTX. Conclusions EAE was not dose-dependent. Histopathological findings do not proportionally related to clinical signs, as in human patients with MS.
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- 2021
26. Therapeutic potential of human neural precursor cells in diabetic retinopathy—preclinical model
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Claudia Sayuri Saçaki, Bassam Felipe Mogharbel, Priscila Elias Ferreira Stricker, Dilcele Silva Moreira Dziedzic, Ana Carolina Irioda, Maiara Carolina Perussolo, Fabiano Montiani Ferreira, Juan Moreno, Peterson Dornbusch, Mário Sato, Naoye Shiokawa, Lucia de Noronha, Marianna Bacelar Galdino, Eltyeb Abdelwahid, Célia Regina Cavichiolo Franco, and Katherine Athayde Teixeira de Carvalho
- Subjects
Public Health, Environmental and Occupational Health - Abstract
Background Considering the expressive number of individuals being diagnosed with diabetes worldwide, it is relevant to find medicines and treatments, in order to achieve diabetes complications, as diabetic retinopathy (DR) long-awaited regression and/or cure. The study aimed to evaluate cell therapy with human neural precursor cells (hNPCs) on induced diabetic retinopathy (DR) in Wistar rats. Methods Wharton's Jelly Mesenchymal stem cells (WJ-MSCs) were isolated, expanded, and seeded onto a biopolymer substrate without growth factors to develop neurospheres, then hNPCs were obtained and characterized by immunocytochemistry. The animals were divided into three groups; non-diabetic (ND) n = 4; diabetic without treatment (DM) n = 9; diabetic with cell therapy (DM + hNPCs) n = 9. Cells were transplanted by intravitreal injection (1 x 106 cel/µL) into each of Streptozotocin (STZ) induced diabetes rats. Evaluations by Optical Coherence Tomography (OCT) and Electroretinography (ERG) were done before and after diabetes induction and post cell therapy. Four weeks after treatment, eye enucleation allowed histopathological and immunohistochemistry (IHC) analysis. Results hNPCs increased the number of retina ganglion cells, ameliorated the photoreceptor layer, and decreased the microvessel points, evidenced by ERG, OCT, histopathological, and IHC findings. The most relevant differences in morphological analysis (treated vs untreated), exhibit the retinal improvement in many layers, notably in the retinal pigment epithelium and photoreceptors. Conclusions hNPCs reduced DR progression, as demonstrated by a neuroprotective effect and promotion of retinal regeneration.
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- 2021
27. The Pathogenesis of COVID-19 Myocardial Injury: An Immunohistochemical Study of Postmortem Biopsies
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Camila Hartmann, Anna Flavia Ribeiro dos Santos Miggiolaro, Jarbas da Silva Motta, Lucas Baena Carstens, Caroline Busatta Vaz De Paula, Sarah Fagundes Grobe, Larissa Hermann de Souza Nunes, Gustavo Lenci Marques, Peter Libby, Lidia Zytynski Moura, Lucia de Noronha, and Cristina Pellegrino Baena
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Endothelium ,endothelium ,Biopsy ,Immunology ,Inflammation ,Apoptosis ,heart ,Pathogenesis ,Fibrosis ,Immunology and Allergy ,Medicine ,Humans ,myocardial injury ,Aged ,Original Research ,TUNEL assay ,business.industry ,SARS-CoV-2 ,Myocardium ,Caspase 1 ,fibrosis ,COVID-19 ,RC581-607 ,medicine.disease ,Intercellular Adhesion Molecule-1 ,Immunohistochemistry ,medicine.anatomical_structure ,Heart Injuries ,Matrix Metalloproteinase 9 ,Cytokines ,Myocardial fibrosis ,Female ,pathology ,Collagen ,medicine.symptom ,Immunologic diseases. Allergy ,business ,CD163 - Abstract
RationaleMyocardial injury associates significantly and independently with mortality in COVID-19 patients. However, the pathogenesis of myocardial injury in COVID-19 remains unclear, and cardiac involvement by SARS-CoV-2 presents a major challenge worldwide.ObjectiveThis histological and immunohistochemical study sought to clarify the pathogenesis and propose a mechanism with pathways involved in COVID-19 myocardial injury.Methods and ResultsPostmortem minimally invasive autopsies were performed in six patients who died from COVID-19, and the myocardium samples were compared to a control group (n=11). Histological analysis was performed using hematoxylin-eosin and toluidine blue staining. Immunohistochemical (IHC) staining was performed using monoclonal antibodies against targets: caspase-1, caspase-9, gasdermin-d, ICAM-1, IL-1β, IL-4, IL-6, CD163, TNF-α, TGF-β, MMP-9, type 1 and type 3 collagen. The samples were also assessed for apoptotic cells by TUNEL. Histological analysis showed severe pericardiocyte interstitial edema and higher mast cells counts per high-power field in all COVID-19 myocardium samples. The IHC analysis showed increased expression of caspase-1, ICAM-1, IL-1β, IL-6, MMP-9, TNF-α, and other markers in the hearts of COVID-19 patients. Expression of caspase-9 did not differ from the controls, while gasdermin-d expression was less. The TUNEL assay was positive in all the COVID-19 samples supporting endothelial apoptosis.ConclusionsThe pathogenesis of COVID-19 myocardial injury does not seem to relate to primary myocardiocyte involvement but to local inflammation with associated interstitial edema. We found heightened TGF-β and interstitial collagen expression in COVID-affected hearts, a potential harbinger of chronic myocardial fibrosis. These results suggest a need for continued clinical surveillance of patients for myocardial dysfunction and arrythmias after recovery from the acute phase of COVID-19.
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- 2021
28. Tracheal Repair with Human Umbilical Cord Mesenchymal Stem Cells Differentiated in Chondrocytes Grown on an Acellular Amniotic Membrane: A Pre-Clinical Approach
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Luiz Cesar Guarita-Souza, Nelson Bergonse Neto, Julio Cesar Francisco, Lucia de Noronha, Anna Flavia Ribeiro dos Santos Miggiolaro, Meila Bastos de Almeida, Nádia Nascimento da Rosa, Rossana Baggio Simeoni, Guilherme Naves, Paulo Ricardo Baggio Simeoni, Priscila Elias Ferreira Stricker, Dilcele Silva Moreira Dziedzic, Katherine Athayde Teixeira de Carvalho, and Paulo André Bispo Machado Júnior
- Subjects
Pathology ,medicine.medical_specialty ,Science ,chondrocytes ,tracheostomy ,Umbilical cord ,General Biochemistry, Genetics and Molecular Biology ,Article ,human umbilical cord mesenchymal stem cells ,Tissue engineering ,medicine ,Cartilaginous Tissue ,Ecology, Evolution, Behavior and Systematics ,business.industry ,Mesenchymal stem cell ,Paleontology ,Biomaterial ,Chondrogenesis ,Biocompatible material ,medicine.anatomical_structure ,Membrane ,Space and Planetary Science ,tissue engineering ,business ,acellular amniotic membrane - Abstract
Acellular amniotic membrane (AM) has been studied, with promising results on the reconstruction of lesioned tissues, and has become an attractive approach for tracheal repair. This study aimed to evaluate the repair of the trachea with human umbilical cord mesenchymal stem cells (hucMSCs) differentiated in chondrocytes, grown on an experimental model. Tracheal defects were induced by surgical tracheostomy in 30 New Zealand rabbits, and the acellular amniotic membrane, with or without cells, was covering the defect. The hucMSCs were isolated and cultivated with chondrogenic differentiation over the culture of 14 days, and then grown on the AM. In this study, the AM was biocompatible and hucMSCs differentiated into chondrocytes. Our results demonstrated an important role for AM with cultured cells in the promotion of immature collagen, known to produce tissue regeneration. In addition, cartilaginous tissue was found at the tracheal defects, demonstrated by immunohistology results. This study suggests that this biomaterial implantation can be an effective future therapeutic alternative for patients with tracheal injury.
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- 2021
29. Invasive aspergillosis complication in yellow fever vaccine induced viscerotropic disease
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Camila Zanluca, Rodrigo Sfredo Kruger, Flavio Queiroz-Telles, Sonia Mara Raboni, Claudia Nunes Duarte dos Santos, Giovanni Luis Breda, Lucia de Noronha, and Natália Ramos Domino
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0301 basic medicine ,medicine.medical_specialty ,030231 tropical medicine ,030106 microbiology ,Yellow fever vaccine ,Disease ,Severe influenza ,Aspergillosis ,Microbiology ,03 medical and health sciences ,0302 clinical medicine ,Medicine ,lcsh:QH301-705.5 ,lcsh:R5-920 ,COPD ,Critical patient ,Critically ill ,business.industry ,Yellow fever ,medicine.disease ,Dermatology ,Infectious Diseases ,lcsh:Biology (General) ,lcsh:Medicine (General) ,Complication ,business ,Vaccine ,medicine.drug - Abstract
Invasive aspergillosis (IA) usually occurs in immunocompromised hosts, but in the last decade IA has emerged in critically ill non-neutropenic patients, as those with severe Influenza and Chronic Obstructive Pulmonary Disease (COPD). We report an unusual fatal case of disseminated IA in a non-immunocompromised patient following yellow fever vaccine-associated viscerotropic disease.
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- 2020
30. Effects of oral probiotics administration on the expression of transforming growth factor β and the proinflammatory cytokines interleukin 6, interleukin 17, and tumor necrosis factor α in skin wounds in rats
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Lucia de Noronha, Leticia Fuganti Campos, Antonio Carlos Ligocki Campos, Thais Andrade Costa Casagrande, Eliane Tagliari, and Taise Fuchs
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Male ,Medicine (miscellaneous) ,Pharmacology ,Gastrointestinal epithelium ,Proinflammatory cytokine ,law.invention ,Probiotic ,Fibrosis ,law ,Oral administration ,Transforming Growth Factor beta ,medicine ,Animals ,Rats, Wistar ,Interleukin 6 ,Nutrition and Dietetics ,biology ,business.industry ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,Probiotics ,Interleukin-17 ,medicine.disease ,Rats ,biology.protein ,Cytokines ,Tumor necrosis factor alpha ,Interleukin 17 ,business - Abstract
Introduction Cytokines and growth factors play key roles during tissue repair. Probiotics have pro-healing properties both in the gastrointestinal epithelium and in the skin. Objective To evaluate the effect of perioperative oral probiotics, on the healing process in skin wound in rats, by histological aspects, and by the expression of TGFbeta, and the pro-inflammatory cytokines IL6, IL7, and TNF-alfa in skin wound tissue. Material and methods After 5 days of preoperative oral administration of either probiotics or maltodextrin, 72 adult male Wistar rats were split into two groups with 36 animals each: one control group and one probiotic group. The rats were anesthetized and subjected to an excisional dorsal square wound, standardized by a mold measuring 2.0×2.0 cm. Each group was subdivided into three subgroups with 12 animals each according to euthanasia day: 3th PO, 7th PO; and 10th PO day. Results Wound contraction was faster with the use of probiotics (p = 0.013). Also fibrosis was significantly higher in the Probiotic group in the 7th PO day (p = 0.028). As for the cytokines, in the probiotic group, there was a reduction of TNFalpha at 3th PO day (p = 0.023); and a reduction of IL6 in the 7th PO day (p = 0.030). There was also a reduction of the expression of IL-17 in 3rd PO day (p = 0.039) and in the 7th PO day (0.024). In contrast, TGF-b was lower in the 10th PO day (p = 0.031) in the probiotic group as compared to controls, indicating that the increase of the fibrosis caused negative feedback with the TGFbeta CONCLUSION: : Probiotics are associated with a shorter inflammatory phase by attenuating the expression of IL-6 and TNFalpha and accelerating the reduction of IL-17 and TGFbeta , leading to a faster and improved cutaneous healing in rats. This article is protected by copyright. All rights reserved.
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- 2021
31. Placental Morphologic Similarities Between ZIKV-Positive and HIV-Positive Pregnant Women
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Emily Scaranello Marini, Lucia de Noronha, Patricia Zadorosnei Rebutini, Camila Zanluca, Claudia Nunes Duarte dos Santos, Mineia Alessandra Scaranello Malaquias, Amanda Prokopenko, Seigo Nagashima, Plínio Cézar Neto, Leticia Arianne Panini do Carmo, and Daiane Cristine Martins Ronchi
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0301 basic medicine ,placenta ,030231 tropical medicine ,Immunology ,Human immunodeficiency virus (HIV) ,Antigens, Differentiation, Myelomonocytic ,Physiology ,HIV Infections ,Receptors, Cell Surface ,Congenital microcephaly ,medicine.disease_cause ,Zika virus ,03 medical and health sciences ,0302 clinical medicine ,Antigens, CD ,Pregnancy ,Placenta ,Humans ,Immunology and Allergy ,Medicine ,Pregnancy Complications, Infectious ,Pathological ,Microscopy ,Hyperplasia ,morphometric analysis ,biology ,Zika Virus Infection ,business.industry ,HIV ,RC581-607 ,medicine.disease ,biology.organism_classification ,030104 developmental biology ,medicine.anatomical_structure ,Perspective ,Microcephaly ,Gestation ,vertical transmission ,Female ,Immunologic diseases. Allergy ,business ,CD163 - Abstract
Zika virus (ZIKV) caused global concern due to Brazil's unexpected epidemic, and it was associated with congenital microcephaly and other gestational intercurrences. The study aimed to analyze the placenta morphometric changes of ZIKV-infected pregnant women (ZIKV group; n = 23) compared to placentas of HIV-infected (HIV group; n = 24) and healthy pregnant women (N-control group; n = 22). It also analyzed the relationship between the morphometric results and pathological alterations on conventional microscopy, gestational trimester of infection, and presence of the congenital Zika syndrome (CZS). There was a significant increase in area (p = 0.0172), as well as a higher number of knots (p = 0.0027), sprouts (p < 0.0001), and CD163 +Hofbauer cells (HCs) (p < 0.0001) in the ZIKV group compared to the N-control group, suggesting that villous dysmaturity and HCs hyperplasia could be associated with ZIKV infections. The HIV group had a higher area (p < 0.0001), perimeter (p = 0.0001), sprouts (p < 0.0001), and CD163 + HCs (p < 0.0001) compared to the N-control group, demonstrating that the morphometric abnormalities found in the ZIKV and HIV group are probably similar. However, when ZIKV and HIV groups are compared, it was observed a higher number of sprouts (p = 0.0066) and CD163+ HCs (p < 0.0001) in the first one, suggesting that placental ZIKV congenital changes could be more pronounced.
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- 2021
32. Integrative analysis reveals an indirect connection between COX-2/PTGS2 and extracellular matrix proteins in Ch11q-deleted neuroblastoma
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Lisiane de Castro Poncio, Selene Elifio Esposito, Saulo Henrique Weber, Lucia de Noronha, Bruno César Feltes, Luciane R. Cavalli, Bonald C. Figueiredo, Nilton de França Junior, Thatyanne Gradowski Farias da Costa do Nascimento, Roberto H. Herai, and Aline S. Fonseca
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Extracellular matrix ,Loss of heterozygosity ,Stromal cell ,Tumor progression ,Neuroblastoma ,Cancer research ,medicine ,Biology ,medicine.disease ,Gene ,Pediatric cancer ,PTGS2 Gene - Abstract
The COX-2 protein, encoded by the PTGS2 gene, is related to tumor progression in adult and pediatric cancer. In neuroblastoma (NB), COX-2 was associated with loss of heterozygosity on the long arm of chromosome 11 (Ch11q loss of heterozygosity, LOH), defining a subset of aggressive disease. The present study aimed to investigate the protein expression of COX-2 in a set of 82 pre-chemotherapy (CT) and 20 post-CT NB specimens and its correlation with clinical and genomic data. A systems biology approach elucidated the network interaction of PTGS2 and other inflammation-related genes with those codified in the Ch11q deleted regions. The results indicated a significantly higher expression of COX-2 in post-CT samples. In addition, a significant positive correlation between the presence of aberrations in Ch11q and COX-2 levels and an indirect connection between the COX-2 gene and extracellular matrix remodeling (ECM)-related proteins were observed. Our findings suggest that deregulation of ECM proteolysis in Ch11q–deleted NB could elicit stromal alterations, triggering inflammatory responses via COX-2 overexpression, ultimately supporting NB progression.
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- 2021
33. Parkin and its molecular associations in gliomas – a systematic review
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Eduardo Morais de Castro, João Vitor Alves Ferreira, Cleber Machado-Souza, Lucia de Noronha, Leonardo Vinícius Barbosa, Rosiane Guetter Mello, Diancarlos P. Andrade, and Luiz Fernando Bleggi Torres
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0301 basic medicine ,Mutation rate ,RD1-811 ,Context (language use) ,Disease ,Biology ,medicine.disease_cause ,GBM ,Parkin ,03 medical and health sciences ,0302 clinical medicine ,Pathology ,medicine ,Gliomas ,RB1-214 ,PRKN ,Mutation ,Melanoma ,Systematic reviews ,medicine.disease ,Protein ubiquitination ,nervous system diseases ,Leukemia ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,Surgery - Abstract
Parkin, a protein encoded by PRKN, discovered in the context of Parkinson’s disease, controls proteasomal degradation by protein ubiquitination and acts on cell cycle control and mitochondrial homeostasis, among other cellular processes. Parkin has been also implicated in several carcinomas, melanoma and leukemia. In the neoplastic setting, reduced parkin level usually indicates poorer prognosis. Some authors have described the associations between parkin and gliomas. Gliomas are a heterogeneous group of tumors that arise in the central nervous system, astrocytomas being the most common. The aim of this systematic review is to evaluate how parkin behaves in gliomas and the molecular pathways associated in this interaction. A search was conducted in PubMed, EBSCO and Scopus and 8 published articles were identified as eligible studies. The studies were categorized in three groups, according to their main emphasis: PRKN mutation patterns detected in gliomas, parkin effects on tumor growth and survival rates, and molecular interactions between parkin and other proteins. The studies showed higher PRKN mutation rates and lower parkin expression in high grade gliomas. Patients with higher parkin expression had better overall survival. Besides, different molecular pathways associated with parkin were described, some of them regarded as potential therapeutic targets.
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- 2021
34. Collagen matrices are preserved following decellularization of a bovine bone scaffold
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Leticia Ramos Dantas, Victoria Stadler Tasca Ribeiro, Leticia Kraft, Ricardo Aurino Pinho, Paula Hansen Suss, Franciane Thais Falcão Vasconcellos, Lucia de Noronha, and Felipe Francisco Tuon
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Biomaterials ,Transplantation ,Tissue Engineering ,Tissue Scaffolds ,Preservation, Biological ,Biomedical Engineering ,Animals ,Cattle ,Cell Biology ,Collagen ,Extracellular Matrix - Abstract
The decellularization of bovine bone has emerged as a strategy for the repair, replacement, and regeneration of bone defects. To evaluate the effects of a new protocol of bone decellularization and its impact on the structure and collagen scaffold. Cancellous bone from bovine femur was dissected in fragments and decellularized based on protocol of multiple steps. The residual protein levels, histological, morphometric, and scanning electronic microscopy analyses were carried out to evaluate the effects of decellularization and the impact on the structure and collagen scaffold. A cytotoxicity assay was performed. Residual protein analysis showed an important removal of bone marrow components and cell debris from the bone. Sections revealed that collagen fibers presented integrity and absence of cells in the decellularized bone. Sirius Red-stained sections of collagen fiber collagen matrix were maintained after decellularization. Scanning electron microscopy revealed that the main bone structure, despite being irregular, was maintained in both groups, with no significant visual differences between the surface characteristics according to the groups. Decellularized bovine bone demonstrated a degree of toxicity of 3, indicating moderate reactivity. The present data demonstrate that the main bone structure was maintained. Additionally, the chemical and physical treatments were able to remove cellular debris, and extracellular matrix architecture and collagen were preserved. However, the tissue showed moderate toxicity.
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- 2021
35. Decellularization as a method to reduce calcification in bovine pericardium bioprosthetic valves
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Francisco Diniz Affonso da Costa, João Gabriel Roderjan, Claudinei Collatusso, Paula Hansen Suss, Lucia de Noronha, Allyson Klosowski, and Luiz Cesar Guarita-Souza
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Pulmonary and Respiratory Medicine ,Pathology ,medicine.medical_specialty ,Bovine pericardium ,medicine.medical_treatment ,chemistry.chemical_element ,02 engineering and technology ,030204 cardiovascular system & hematology ,Calcium ,Extracellular matrix ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Medicine ,Alternative methods ,Decellularization ,business.industry ,Mitral valve replacement ,021001 nanoscience & nanotechnology ,medicine.disease ,chemistry ,Surgery ,Glutaraldehyde ,0210 nano-technology ,Cardiology and Cardiovascular Medicine ,business ,Calcification - Abstract
OBJECTIVES Decellularization is an alternative method for processing biological tissues with decreased antigenicity and resistance to calcification. The aim of this study was to characterize the properties of decellularized (dCell) bovine pericardium fixed with 0.1% glutaraldehyde (GA) and to evaluate outcomes of bioprosthetic valves constructed with this tissue when implanted in the mitral position of juvenile sheep. METHODS Bioprosthetic mitral valves were constructed with fresh bovine pericardium fixed in 0.5% GA (control group) or dCell bovine pericardium fixed in 0.1% GA (study group). Before implantation, samples were submitted to histological (haematoxylin–eosin, Movat and 4′,6-diamidino-2-phenylindole), biochemical (residual deoxyribonucleic acid and α-gal epitopes) and biomechanical characterization. Valves were implanted (n = 8 in each group) as a mitral valve replacement for 180 days in sheep and explants were re-evaluated histologically and for calcification with radiological studies and calcium content determination. RESULTS Unimplanted dCell pericardia exhibited a well-preserved extracellular matrix with absence of cells, a 77% reduction in deoxyribonucleic acid levels and with no detectable α-gal epitopes. When compared to controls, they had lower ultimate tensile strength (7.3 ± 5.4 vs 10.2 ± 3.0 mPa, P = 0.04) and greater percentage elongation in the longitudinal direction (29 ± 6.5% vs 23.8 ± 5.1%, P = 0.02). After 180 days in mitral position, dCell valves showed pliable leaflets without macroscopic signs of calcification. Histologically, dCell leaflets had intact collagen fibres, better tissue remodelling and a significant 89% reduction in calcium content. CONCLUSIONS This study demonstrates that bioprosthetic valves constructed with dCell bovine pericardium fixed in low GA concentration were resistant to calcification and may thereby improve long-term durability of the tissue.
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- 2019
36. Biomolecular engineering of antidehydroepiandrosterone antibodies: a new perspective in cancer diagnosis and treatment using single-chain antibody variable fragment
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Larissa Magalhães Alvarenga, Bonald C. Figueiredo, Kádima Nayara Teixeira, Juliana de Moura, Lucia de Noronha, Rosana Nogueira Moraes, Philippe Billiald, Rafaela Lenzi Fogaça, Magali Noiray, Thiago Demetrius Woiski, Alessandra Becker-Finco, and Sabrina Karim Silva
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endocrine system ,Immunogen ,Protein Conformation ,medicine.drug_class ,Biomedical Engineering ,Gene Expression ,Medicine (miscellaneous) ,chemical and pharmacologic phenomena ,Bioengineering ,02 engineering and technology ,Development ,Biology ,Protein Engineering ,Monoclonal antibody ,law.invention ,03 medical and health sciences ,law ,Adrenocortical Carcinoma ,Biomarkers, Tumor ,polycyclic compounds ,medicine ,Animals ,Humans ,Adrenocortical carcinoma ,General Materials Science ,030304 developmental biology ,Tumor marker ,Mice, Inbred BALB C ,0303 health sciences ,Adrenal cortex ,Dehydroepiandrosterone ,021001 nanoscience & nanotechnology ,medicine.disease ,Molecular biology ,Adrenal Cortex Neoplasms ,Recombinant Proteins ,Zona Reticularis ,Molecular Docking Simulation ,medicine.anatomical_structure ,biology.protein ,Recombinant DNA ,Antibody ,0210 nano-technology ,human activities ,hormones, hormone substitutes, and hormone antagonists ,Keyhole limpet hemocyanin ,Single-Chain Antibodies - Abstract
Aim: To develop a monoclonal antibody against dehydroepiandrosterone (DHEA) and miniaturize it, generating a single-chain antibody variable fragment (scFv) against DHEA as an adrenocortical carcinoma (ACC) marker. Material & methods: DHEA conjugated to keyhole limpet hemocyanin was used as an immunogen to obtain anti-DHEA hybridomas. Variable fragments were cloned from hybridoma 5B7 total RNA, and used to detect DHEA in normal adrenal tissue and ACC cells. Results: IgM monoclonal antibody was highly specific, and the recombinant scFv preserved parental antibody characteristics, allowing tissue localization of DHEA. Conclusion: Undefined small lesions are challenges for clinicians and impact clinical adrenocortical tumor management. Generating an anti-DHEA scFv facilitates development of imaging tests for early diagnosis of pediatric ACC.
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- 2019
37. Mapping the spatial biology of COVID-19 immunopathology in placenta tissues
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Ning Ma, Oliver Braubach, Patricia Zadorosnei Rebutini, Cleber Machado-Souza, Emanuele Therezinha Schueda Stonoga, Lucia de Noronha, Fernando Souza-Fonseca-Guimaraes, and Arutha Kulasinghe
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Immunology ,Immunology and Allergy - Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged in late 2019 has spread globally, causing a pandemic of respiratory illness. The virus primarily affects the lungs, where it induces respiratory distress syndrome ranging from mild to acute. However, a growing body of evidence shows COVID-19 pathology in other organs that also carry the ACE-2 receptor, including the placenta. Most newborns delivered from COVID-19 positive mothers test negative following delivery, suggesting that there are protective mechanisms within the placenta. In this study, we compared a unique collection of placental tissue samples from COVID-19 positive and gestational age-matched non-COVID-19 samples. Using AKOYA’s ultrahigh-plex Phenocycler assay, we mapped dozens of protein biomarkers in situ with single-cell and subcellular spatial resolution to produce unbiased and comprehensive spatial biomarker maps of potential placental pathobiology associated with COVID-19 infections. Our antibody panel was aimed at in-depth identification of immune cell lineages, activation states, immune checkpoints, and tissue structures; infected cells were identified via the deployment of two antibodies directed at COVID-19 spike and capsid proteins, as well as an antibody directed against the ACE-2 receptor. All imaging data were obtained at single-cell resolution across whole tissue samples, and cellular phenotypes were subsequently identified via unsupervised clustering methods. These data are the first of their kind and will provide additional insight into the pathobiology of COVID-19.
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- 2022
38. Association Between COVID-19 Pregnant Women Symptoms Severity and Placental Morphologic Features
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Patricia Zadorosnei Rebutini, Aline Cristina Zanchettin, Emanuele Therezinha Schueda Stonoga, Daniele Margarita Marani Prá, André Luiz Parmegiani de Oliveira, Felipe da Silva Dezidério, Aline Simoneti Fonseca, Júlio César Honório Dagostini, Elisa Carolina Hlatchuk, Isabella Naomi Furuie, Jessica da Silva Longo, Bárbara Maria Cavalli, Carolina Lumi Tanaka Dino, Viviane Maria de Carvalho Hessel Dias, Ana Paula Percicote, Meri Bordignon Nogueira, Sonia Mara Raboni, Newton Sergio de Carvalho, Cleber Machado-Souza, and Lucia de Noronha
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0301 basic medicine ,Adult ,medicine.medical_specialty ,placenta ,Immunology ,Gestational Age ,placental histopathology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Pregnancy ,Placenta ,Immunology and Allergy ,Medicine ,Humans ,Pregnancy Complications, Infectious ,Sirius Red ,Original Research ,Fetus ,morphometric analysis ,business.industry ,Obstetrics ,SARS-CoV-2 ,Case-control study ,Gestational age ,COVID-19 ,RC581-607 ,Viral Load ,medicine.disease ,Comorbidity ,Immunohistochemistry ,Infectious Disease Transmission, Vertical ,030104 developmental biology ,medicine.anatomical_structure ,Chronic histiocytic intervillositis ,chemistry ,030220 oncology & carcinogenesis ,Case-Control Studies ,embryonic structures ,Host-Pathogen Interactions ,RNA, Viral ,Female ,vertical transmission ,Immunologic diseases. Allergy ,business ,Brazil - Abstract
Since the beginning of the pandemic, few papers describe the placenta’s morphological and morphometrical features in SARS-CoV-2–positive pregnant women. Alterations, such as low placental weight, accelerated villous maturation, decidual vasculopathy, infarcts, thrombosis of fetal placental vessels, and chronic histiocytic intervillositis (CHI), have been described.ObjectiveTo analyze clinical data and the placental morphological and morphometric changes of pregnant women infected with SARS-CoV-2 (COVID-19 group) in comparison with the placentas of non-infected pregnant women, matched for maternal age and comorbidities, besides gestational age of delivery (Control group).MethodThe patients in the COVID-19 and the Control group were matched for maternal age, gestational age, and comorbidities. The morphological analysis of placentas was performed using Amsterdam Placental Workshop Group Consensus Statement. The quantitative morphometric evaluation included perimeter diameter and number of tertiary villi, number of sprouts and knots, evaluation of deposition of villous fibrin, and deposition of intra-villous collagen I and III by Sirius Red. Additionally, Hofbauer cells (HC) were counted within villi by immunohistochemistry with CD68 marker.ResultsCompared to controls, symptomatic women in the COVID-19 group were more likely to have at least one comorbidity, to evolve to preterm labor and infant death, and to have positive SARS-CoV-2 RNA testing in their concepts. Compared to controls, placentas in the COVID-19 group were more likely to show features of maternal and fetal vascular malperfusion. In the COVID-19 group, placentas of symptomatic women were more likely to show CHI. No significant results were found after morphometric analysis.ConclusionPregnant women with symptomatic SARS-CoV-2 infection, particularly with the severe course, are more likely to exhibit an adverse fetal outcome, with slightly more frequent histopathologic findings of maternal and fetal vascular malperfusion, and CHI. The morphometric changes found in the placentas of the COVID-19 group do not seem to be different from those observed in the Control group, as far as maternal age, gestational age, and comorbidities are paired. Only the deposition of villous fibrin could be more accentuated in the COVID-19 group (p = 0.08 borderline). The number of HC/villous evaluated with CD68 immunohistochemistry did not show a difference between both groups.
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- 2021
39. Deregulated miRNA expression is associated with endothelial dysfunction in post-mortem lung biopsies of COVID-19 patients
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Lucia de Noronha, Ariana Centa, Luciane R. Cavalli, Anna Flavia Ribeiro dos Santos Miggiolaro, Caroline Busatta Vaz de Paula, Seigo Nagashima, Aline S. Fonseca, Cleber Machado-Souza, Cristina Pellegrino Baena, Marina Luise Viola de Azevedo, and Solange G. da Silva Ferreira
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0301 basic medicine ,Pulmonary and Respiratory Medicine ,Physiology ,Lung injury ,endothelial dysfunction ,Endothelial activation ,03 medical and health sciences ,0302 clinical medicine ,Physiology (medical) ,microRNA ,medicine ,Endothelial dysfunction ,Respiratory system ,Lung ,Rapid Report ,business.industry ,SARS-CoV-2 ,COVID-19 ,Cell Biology ,medicine.disease ,lung injuries ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer research ,Signal transduction ,business ,Homeostasis - Abstract
MicroRNAs (miRNAs) are critical modulators of endothelial homeostasis, which highlights their involvement in vascular diseases, including those caused by virus infections. Our main objective was to identify miRNAs involved in the endothelial function and determine their expression in post-mortem lung biopsies of COVID-19 patients with severe respiratory injuries and thrombotic events. Based on functional enrichment analysis, miR-26a-5p, miR-29b-3p, and miR-34a-5p were identified as regulators of mRNA targets involved in endothelial and inflammatory signaling pathways, as well as viral diseases. A miRNA/mRNA network, constructed based on protein–protein interactions of the miRNA targets and the inflammatory biomarkers characterized in the patients, revealed a close interconnection of these miRNAs in association to the endothelial activation/dysfunction. Reduced expression levels of selected miRNAs were observed in the lung biopsies of COVID-19 patients ( n = 9) compared to the Controls ( n = 10) ( P < 0.01-0.0001). MiR-26a-5p and miR-29b-3p presented the best power to discriminate these groups (area under the curve (AUC) = 0.8286, and AUC = 0.8125, respectively). The correlation analysis of the miRNAs with inflammatory biomarkers in the COVID-19 patients was significant for miR-26a-5p [IL-6 ( r2 = 0.5414), and ICAM-1 ( r2 = 0.5624)], and miR-29b-3p [IL-4 ( r2 = 0.8332) and IL-8 ( r2 = 0.2654)]. Altogether, these findings demonstrate the relevance and the non-random involvement of miR-26a-5p, miR-29b-3p, and miR-34a-5p in endothelial dysfunction and inflammatory response in patients with SARS-CoV-2 infection and the occurrence of severe lung injury and immunothrombosis.
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- 2021
40. Neuroinflammatory Regulation of Gold Nanoparticles Conjugated to Ethylene Dicysteine Diethyl Ester in Experimental Autoimmune Encephalomyelitis
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Paulo Emilio Feuser, Ricardo A. Pinho, Franciane T F Vasconcellos, Rubya Pereira Zaccaron, Caroline Busatta Vaz de Paula, Lucia de Noronha, Renata Tiscoski Nesi, Marcos Marques da Silva Paula, Paulo Cesar Lock da Silveira, Priscila S. Souza, and Eduardo B B Cunha
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Encephalomyelitis, Autoimmune, Experimental ,0206 medical engineering ,Central nervous system ,Biomedical Engineering ,Metal Nanoparticles ,02 engineering and technology ,Pharmacology ,Myelin oligodendrocyte glycoprotein ,Proinflammatory cytokine ,Biomaterials ,Myelin ,Mice ,medicine ,Animals ,Cysteine ,Neuroinflammation ,Autoimmune encephalitis ,biology ,Chemistry ,Multiple sclerosis ,Experimental autoimmune encephalomyelitis ,Esters ,021001 nanoscience & nanotechnology ,medicine.disease ,020601 biomedical engineering ,Mice, Inbred C57BL ,medicine.anatomical_structure ,biology.protein ,Female ,Gold ,0210 nano-technology - Abstract
Multiple sclerosis (MS) is a demyelinating chronic autoimmune inflammatory disease of the central nervous system (CNS). A large amount of proinflammatory cytokines is released in the CNS from the self-reactive T cells infiltrate, leading to the destruction of the myelin sheath and contributing to the development of MS. Several drugs have emerged in recent years to treat MS, and studies have shown that gold nanoparticles (GNPs) have anti-inflammatory properties in autoimmune diseases. Thus, the effects of GNP conjugation to ethylene dicysteine diethyl ester (ECD) were evaluated in C57BL/6 female mice exposed to experimental MS. Animals were exposed to experimental autoimmune encephalitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG35-55) in complete Freund's adjuvant supplemented with Mycobacterium tuberculosis. The clinical and cerebral effects of the different doses of ECD-GNPs (0.3, 0.6, and 1.0 mg/kg) were first studied, and the results showed that the group treated with 0.6 mg/kg ECD-GNPs improved clinical symptoms, inflammatory infiltrate, and myelin integrity. In the following step, GNPs and ECD-GNPs (0.6 mg/kg) showed improvements in the clinical signs of the disease. Moreover, there was a reduction in the levels of proinflammatory cytokines in both groups compared to EAE, and only the isolated use of GNPs increased IL-4 expression. Both NF-κB and TGFβ immunoexpression were significantly reduced following EAE + GNPs and EAE + ECD-GNPs treatment. In conclusion, GNPs and ECD-GNPs at 0.6 mg/kg attenuate the neurological signs of EAE likely due to inhibition of neuroinflammation induced by EAE.
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- 2021
41. Profiling of lung SARS-CoV-2 and influenza virus infection dissects virus-specific host responses and gene signatures
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Melissa J. Davis, Benjamin Tang, Gustavo Rodrigues Rossi, Paulo Souza-Fonseca-Guimaraes, Kirsty R. Short, Seigo Nagashima, Dharmesh D. Bhuva, Jarbas da Silva Motta Junior, Fernando Souza-Fonseca-Guimaraes, Habib Sadeghirad, Caroline Cooper, Arutha Kulasinghe, Lucia de Noronha, Timothy McCulloch, James Monkman, Chin Wee Tan, Cristina Pellegrino Baena, Anna Flavia Ribeiro dos Santos Miggiolaro, Caroline Busatta Vaz de Paula, Kenneth J. O'Byrne, and Gabrielle T. Belz
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Pulmonary and Respiratory Medicine ,Lung ,business.industry ,SARS-CoV-2 ,Viral pathogenesis ,COVID-19 ,Type I interferon production ,Virus ,Pathogenesis ,medicine.anatomical_structure ,Influenza A Virus, H1N1 Subtype ,Interferon ,Immunology ,Influenza, Human ,Interferon Type I ,medicine ,Biomarker (medicine) ,Humans ,Original Research Article ,business ,Viral load ,medicine.drug - Abstract
BackgroundThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which emerged in late 2019 has spread globally, causing a pandemic of respiratory illness designated coronavirus disease 2019 (COVID-19). A better definition of the pulmonary host response to SARS-CoV-2 infection is required to understand viral pathogenesis and to validate putative COVID-19 biomarkers that have been proposed in clinical studies.MethodsHere, we use targeted transcriptomics of formalin-fixed paraffin-embedded tissue using the NanoString GeoMX platform to generate an in-depth picture of the pulmonary transcriptional landscape of COVID-19, pandemic H1N1 influenza and uninfected control patients.ResultsHost transcriptomics showed a significant upregulation of genes associated with inflammation, type I interferon production, coagulation and angiogenesis in the lungs of COVID-19 patients compared to non-infected controls. SARS-CoV-2 was non-uniformly distributed in lungs (emphasising the advantages of spatial transcriptomics) with the areas of high viral load associated with an increased type I interferon response. Once the dominant cell type present in the sample, within patient correlations and patient–patient variation, had been controlled for, only a very limited number of genes were differentially expressed between the lungs of fatal influenza and COVID-19 patients. Strikingly, the interferon-associated gene IFI27, previously identified as a useful blood biomarker to differentiate bacterial and viral lung infections, was significantly upregulated in the lungs of COVID-19 patients compared to patients with influenza.ConclusionCollectively, these data demonstrate that spatial transcriptomics is a powerful tool to identify novel gene signatures within tissues, offering new insights into the pathogenesis of SARS-COV-2 to aid in patient triage and treatment.
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- 2021
42. Histological evaluation of capsules formed by texturized silicone implants with and without polyester mesh coverage (Parietex®). A study on female rats
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Ralf Berger, Jurandir Marcondes Ribas Filho, Osvaldo Malafaia, Paulo Afonso Nunes Nassif, Eduardo Nascimento Silva, Alfredo Benjamin Duarte da Silva, Milka Takejima, Marcelo Augusto de Souza, Pedro Henrique de Paula, Mário Rodrigues Montemor Netto, and Lucia de Noronha
- Subjects
Pathology ,medicine.medical_specialty ,RD1-811 ,Polyesters ,Breast Implants ,Mammaplasty ,Silicones ,H&E stain ,Capsules ,chemistry.chemical_compound ,Silicone ,medicine ,Animals ,Rats, Wistar ,Polyester mesh ,Synovial metaplasia ,Chemistry ,Granulation tissue ,Prostheses and Implants ,Surgical Mesh ,Rats ,Staining ,medicine.anatomical_structure ,Giant cell ,Original Article ,Female ,Surgery ,Collagen - Abstract
Purpose To evaluate capsules formed by microtextured silicone implants with and without Parietex® mesh coverage histologically. Methods Sixty Wistar rats were divided in two groups (meshed and unmeshed). Each group was, then, divided into two subgroups for evaluation at 30 and 90 days. Capsules were analyzed based on hematoxylin and eosin (HE) and picrosirius staining. Results The number of fibroblasts, neutrophils and macrophages was similar among all subgroups. There was a higher lymphocyte reaction in the 30-day meshed group (p = 0.003). Giant cell reaction, granulation tissue and neoangiogenesis were similar among the subgroups. Synovial metaplasia was milder at 90-day in the unmeshed (p = 0.002) and meshed group (p < 0.001). Capsular thickness was significantly greater in the meshed samples (30-day p < 0.001 and 90-day p < 0.001). There was a similar amount of collagen types I and III in both groups. Conclusions The mesh-covered implants produced capsules similar to the microtextured ones when analyzing inflammatory variables. Synovial metaplasia was milder at 90 than at 30 days, and the capsular thickness was significantly greater in the meshed group. A similar amount of collagen types I and III was observed. Due to these characteristics, the mesh coverage did not seem to significantly affect the local inflammatory activity.
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- 2021
43. Reduced Remodeling Biomarkers Tissue Expression in Nanotextured Compared With Polyurethane Implants Capsules: A Study in Rats
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Lucia de Noronha, Eduardo Nascimento Silva, Luis Alejandro Vargas Guerrero, Fernando Serra-Guimarães, Leandro Cavalcante Lipinski, Fernando Sérgio Mendes Carneiro Filho, and Gisela Hobson Pontes
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Pathology ,medicine.medical_specialty ,Breast Implants ,Polyurethanes ,H&E stain ,Capsules ,030230 surgery ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Rats, Wistar ,Fibroblast ,CD68 ,business.industry ,Capsule ,General Medicine ,Staining ,Rats ,medicine.anatomical_structure ,Immunohistochemistry ,Surgery ,Implant ,business ,Type I collagen ,Biomarkers - Abstract
Background In the biological response to biomaterials, the implant shell plays a key role in immune and inflammatory reactions. We hypothesized that the capsules formed around nanotextured implants exhibit an immunohistochemical behavior different to those formed around polyurethane implants. Objectives The aim of this study was to evaluate through immunohistochemistry markers the capsules formed around nanotextured and polyurethane implants. Methods Sixty albino female Wistar rats were divided into 2 groups (nanotextured and polyurethane), with 30 animals in each group. A mini silicone implant was inserted on the back of the animals. After a predetermined period, the animals were killed, and the capsules formed around the implants were studied. The capsules in the 30-, 60-, and 90-day subgroups were analyzed via immunohistochemistry to detect markers for fibroblast α smooth muscle actin (α-SMA), transforming growth factor β (TGF-β), cluster of differentiation 34 (CD34), and CD68, via picrosirius staining to determine the density of type I and III collagen fibers and via hematoxylin and eosin staining to assess capsule thickness. A Wilcoxon-Mann-Whitney test was used to compare the groups, and a Kruskal-Wallis test was used to compare the subgroups. Results Lower α-SMA, TGF-β, CD34 and CD68 immunoexpression was observed in the nanotextured 30- and 60-day subgroups than in the corresponding polyurethane subgroups. In the 90-day subgroup, more pronounced α-SMA and CD34 immunoexpression was observed in the nanotextured group; however, TGF-β and CD68 immunoexpression remained lower. The nanotextured implants showed reduced capsular thickness and greater formation of type I collagen in all the analyzed subgroups. Conclusions Nanotextured implants led to reduced immune and inflammatory reactions compared with polyurethane implants according to all analyzed variables.
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- 2020
44. Spatial Profiling of Lung SARS-CoV-2 and Influenza Virus Infection Dissects Virus-Specific Host Responses and Gene Signatures
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Kenneth J. O'Byrne, Gabrielle T. Belz, Caroline Cooper, Paulo Souza-Fonseca-Guimaraes, Dharmesh D. Bhuva, Chin Wee Tan, James Monkman, Jarbas da Silva Motta Junior, Cristina Pellegrino Baena, Kirsty R. Short, Melissa J. Davis, Benjamin Tang, Anna Flavia Ribeiro dos Santos Miggiolaro, Caroline Busatta Vaz de Paula, Fernando Souza-Fonseca-Guimaraes, Timothy McCulloch, Lucia de Noronha, Gustavo Rodrigues Rossi, Arutha Kulasinghe, and Seigo Nagashima
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Transcriptome ,Pathogenesis ,Lung ,medicine.anatomical_structure ,Interferon ,Pandemic ,Immunology ,medicine ,Biology ,Type I interferon production ,Viral load ,Virus ,medicine.drug - Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged in late 2019 has spread globally, causing a pandemic of respiratory illness designated coronavirus disease 2019 (COVID-19). Robust blood biomarkers that reflect tissue damage are urgently needed to better stratify and triage infected patients. Here, we use spatial transcriptomics to generate an in-depth picture of the pulmonary transcriptional landscape of COVID-19 (10 patients), pandemic H1N1 (pH1N1) influenza (5) and uninfected control patients (4). Host transcriptomics showed a significant upregulation of genes associated with inflammation, type I interferon production, coagulation and angiogenesis in the lungs of COVID-19 patients compared to non-infected controls. SARS-CoV-2 was non-uniformly distributed in lungs with few areas of high viral load and these were largely only associated with an increased type I interferon response. A very limited number of genes were differentially expressed between the lungs of influenza and COVID-19 patients. Specific interferon-associated genes (includingIFI27) were identified as candidate novel biomarkers for COVID-19 differentiating this COVID-19 from influenza. Collectively, these data demonstrate that spatial transcriptomics is a powerful tool to identify novel gene signatures within tissues, offering new insights into the pathogenesis of SARS-COV-2 to aid in patient triage and treatment.
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- 2020
45. Potential benefits of antihypertensive therapy in NAFLD: results from an experimental model
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F N Viechineski, Dalton Bertolin Précoma, Marcia Olandoski, Lucia de Noronha, P.G.M Oliveira, G.A Broday, A.M Koscianski, M C Soares Sturzeneker, and B.J Scheidt
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medicine.medical_specialty ,Experimental model ,business.industry ,medicine ,Cardiology and Cardiovascular Medicine ,Intensive care medicine ,business - Abstract
Background and introduction Non-alcoholic fatty liver disease (NAFLD) is considered as the most frequent cause of chronic hepatic disease in adults. It is strictly correlated with insulin resistance. The renin-angiotensin system (RAS) has been correlated to the whole basic physiopathogenic mechanism of NAFLD in experimental models. Systemic arterial hypertension has been suggested to be associated with NAFLD in approximately 40% of the cases, and NAFLD has been independently associated with an increased risk of arterial hypertension in observational studies. Therefore, we can infer that treating arterial hypertension in NAFLD carriers will often be necessary and that the potential beneficial effects of the antihypertensive might, in this context, influence the choice of the respective drug. Purpose We aimed to evaluate the effects of the renin-angiotensin system blockade with angiotensin-converting enzyme inhibitor ramipril and angiotensin 2 type 1 receptor antagonist olmesartan, both used preventively, in NAFLD induced in rabbits fed a hypercholesterolemic diet and compared the results between the groups. Methods Forty-one rabbits were divided into four groups (normal, control, olmesartan and ramipril). The control, olmesartan and ramipril group were fed a hypercholesterolemic diet. Animals from olmesartan group were treated with olmesartan 1mg/kg/day and animals from ramipril group with ramipril 0.35 mg/kg/day. At the end of the 8th week, all rabbits underwent segmental hepatic resection and were euthanised. Blood samples were collected to determine glucose, creatinine, total cholesterol, triglycerides, high-density lipoprotein cholesterol, and aminotransferase levels at baseline and euthanasia. Haematoxylin and eosin and Gomori trichrome stained slides were analysed based on the histological scoring system for NAFLD. Results The comparison between two groups (olmesartan with placebo and ramipril with placebo) showed that olmesartan and ramipril significantly diminished the development of steatosis (p=0.015, p=0.032), lobular inflammation (p Conclusion(s) The preventive use of olmesartan and ramipril attenuates similarly, the development of hepatic steatosis, lobular inflammation, hepatocellular ballooning and fibrosis in hypercholesterolemic rabbits and based on NAFLD activity score both significantly reduced the development of nonalcoholic steatohepatitis. Funding Acknowledgement Type of funding source: None
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- 2020
46. IFN-γ is an independent risk factor associated with mortality in patients with moderate and severe COVID-19 infection
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Roberta Garcia Charello Ossoski, Alessandra Michalski de Padua, Lucia de Noronha, Marina Goes, Ana Carolina Gadotti, João Paulo Telles, Marina de Castro Deus, Rafael Wind, Andrea N Moreno-Amaral, Cristina Pellegrino Baena, and Felipe Francisco Tuon
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Male ,Cancer Research ,medicine.medical_treatment ,Disease ,Comorbidity ,Gastroenterology ,law.invention ,Interquartile range ,law ,Risk Factors ,Hospital Mortality ,Prospective Studies ,Prospective cohort study ,0303 health sciences ,food and beverages ,Middle Aged ,Prognosis ,Intensive care unit ,Intensive Care Units ,Infectious Diseases ,Viral pneumonia ,Disease Progression ,Cytokines ,Female ,Coronavirus Infections ,Cytokine Release Syndrome ,medicine.medical_specialty ,Pneumonia, Viral ,Biology ,Article ,03 medical and health sciences ,Betacoronavirus ,Interferon-gamma ,Th2 Cells ,Internal medicine ,Virology ,medicine ,Humans ,Risk factor ,Immune response ,Pandemics ,030304 developmental biology ,Aged ,Mechanical ventilation ,Inpatients ,030306 microbiology ,SARS-CoV-2 ,fungi ,COVID-19 ,Interleukin ,Th1 Cells ,medicine.disease ,Respiration, Artificial ,Immunity, Innate - Abstract
Highlights • Inflammatory innate immunity can be described as prognostic factors. • The balancing between Th1 and Th2 response can be associated with mortality in patients with moderate to severe COVID-19 infection. • IFN-γ was an independent risk factor associated with mortality in patients with SARS-Cov2., Background Innate and adaptive immune responses have been evaluated in infected patients with COVID-19. The severity of the disease has been supposed to be associated with some profile not reported with other bacterial and viral pneumonia. We proposed a study in patients with moderate to severe COVID-19 infection to evaluate the interleukin patterns and its role as prognosis factors. Methods A prospective cohort with moderate and severe cases of COVID-19 infection from June to July 2020. Blood samples from patients were collected regularly to evaluate IFN-γ, TNF-α, IL-4, IL-6, and IL-10. Clinical, laboratory, radiological data, and outcomes were recorded. The outcome variable was in-hospital death, survival, mechanical ventilation, and admission at the intensive care unit. Data are presented in median and interquartile range [IQR]. Results We evaluated the Th1 and Th2 responses according to evolution, distinguishing possible predictive markers. The IFN-γ median of 323 pg/mL [IQR 166−570] was found in patients who died and 208 pg/mL [IQR 155−392] in the survival group (p = 0.017). IFN-γ was also higher in the early stages of the disease (394 pg/mL [IQR 229–575] against 162 pg/mL [IQR 117–259], p < 0.001). IL-4 that was increased in late-stage (182 pg/mL [IQR 162–199] against 131 pg/mL [IQR 124–152], p < 0.001) but not associated with mortality. Also, death was also related to male gender (relative risk = 1.5 [95 % confidence interval = 1.1−2.0]). Conclusion Our results suggest that the activation of the host immune response between Th1 or Th2 in COVID-19 infection may be related to the final result between discharge or death. This implies an attempt to control cytokines, such as IFN-γ, with combined therapies for clinical treatment.
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- 2020
47. Endothelial Dysfunction and Thrombosis in Patients With COVID-19-Brief Report
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Lucia de Noronha, Thiago Mateus Godoy, Monalisa Castilho Mendes, Seigo Nagashima, Nícolas Henrique Borges, Ana Paula Camargo Martins, Cleber Machado-Souza, Anna Flavia Ribeiro dos Santos Miggiolaro, and Felipe da Silva Dezidério
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0301 basic medicine ,Male ,medicine.medical_treatment ,Pneumonia, Viral ,coronavirus ,Autopsy ,030204 cardiovascular system & hematology ,medicine.disease_cause ,Risk Assessment ,03 medical and health sciences ,0302 clinical medicine ,Cause of Death ,Medicine ,Humans ,Vascular Diseases ,Endothelial dysfunction ,Pandemics ,Coronavirus ,Cause of death ,Basic Sciences ,business.industry ,pyroptosis ,Biopsy, Needle ,Pyroptosis ,COVID-19 ,Endothelial Cells ,Thrombosis ,medicine.disease ,Immunohistochemistry ,030104 developmental biology ,Cytokine ,Immunology ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,Female ,Endothelium, Vascular ,Cardiology and Cardiovascular Medicine ,business ,Coronavirus Infections - Abstract
Supplemental Digital Content is available in the text., Objective: Alveolar-capillary endothelial cells can be activated by severe acute respiratory syndrome coronavirus 2 infection leading to cytokine release. This could trigger endothelial dysfunction, pyroptosis, and thrombosis, which are the vascular changes, commonly referred to as coronavirus disease 2019 (COVID-19) endotheliopathy. Thus, this study aimed to identify tissue biomarkers associated with endothelial activation/dysfunction and the pyroptosis pathway in the lung samples of patients with COVID-19 and to compare them to pandemic influenza A virus H1N1 subtype 2009 and control cases. Approach and Results: Postmortem lung samples (COVID-19 group =6 cases; H1N1 group =10 cases, and control group =11 cases) were analyzed using immunohistochemistry and the following monoclonal primary antibodies: anti-IL (interleukin)-6, anti-TNF (tumor necrosis factor)-α, anti-ICAM-1 (intercellular adhesion molecule 1), and anticaspase-1. From the result, IL-6, TNF-α, ICAM-1, and caspase-1 showed higher tissue expression in the COVID-19 group than in the H1N1 and control groups. Conclusions: Our results demonstrated endothelial dysfunction and suggested the participation of the pyroptosis pathway in the pulmonary samples. These conditions might lead to systemic thrombotic events that could impair the clinical staff’s efforts to avoid fatal outcomes. One of the health professionals’ goals should be to identify the high risk of thrombosis patients early to block endotheliopathy and its consequences.
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- 2020
48. Myocardial Injury in Post Mortem Biopsies of Patients with COVID-19
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Lidia Zytinsky Moura, Larissa Hermann de Souza Nunes, Anna Flavia Ribeiro dos Santos Miggiolaro, Caroline Busatta Vaz de Paula, Cristina Pellegrino Baena, José Rocha Faria Neto, Jarbas da Silva Motta Junior, Lucas Baena Carstens, Camila Hartmann, Gustavo Lenci Marques, and Lucia de Noronha
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Pathology ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Medicine ,business - Abstract
Background: Myocardial injury is significantly and independently associated with mortality in COVID-19 patients. However, the pathogenesis of myocardial injury in COVID-19 is still not clear, and cardiac involvement by SARS-CoV-2 remains a major challenge worldwide.Aim: This histopathological and immunohistochemical study seeks to clarify the pathogenesis of myocardial injury in COVID-19.Methods: Postmortem minimally invasive autopsies were performed in two patients who died from COVID-19, and the myocardium samples were compared to a control patient. Immunohistochemistry (IHC) staining was performed using monoclonal antibodies against the following targets: caspase-1, ICAM-1, TNF-α, IL-4, IL-6, CD163, TGF-β, MMP-9, type 1 and type 3 collagen.Results: The histopathological analysis showed severe pericellular interstitial edema surrounding each of the cardiomyocytes. The IHC analysis showed increased expression of caspase-1, ICAM-1, IL-4, IL-6, CD163, MMP-9 and type 3 collagen in the COVID-19 patients compared to the control. On the other hand, no difference from the control was observed in expression of TNF-α, TGF-β and type 1 collagen. Conclusion: Our findings point to a pathogenesis related with pyroptosis leading to endothelial disfunction. The subsequent inflammation with associated interstitial edema could explain the myocardial disfunction and arrythmias in COVID-19 patients. The presence of Th2 response, MMP-9 and type-3 collagen suggests progression to myocardial fibrosis in the long term.
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- 2020
49. Alveolar Neutrophilic Recruitment in COVID-19 May Not be Mediated by Th17 Response
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Cristina Pellegrino Baena, Seigo Nagashima, Marina Luise Viola de Azevedo, Lucia de Noronha, Sonia Mara Raboni, Caroline Busatta Vaz de Paula, Daiane Gavlik de Souza, Mineia Alessandra Scaranello Malaquias, Cleber Machado de Souza, Plínio Cézar Neto, Jarbas da Silva Motta Junior, and Anna Flavia Miggiolaro Ribeiro
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Text mining ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Immunology ,Medicine ,business - Abstract
Introduction: The COVID-19 current pandemic disease differs from the H1N1pdm09 caused by Influenza A virus H1N1 subtype, by how it induces a pro-inflammatory response in infected lungs. Objective: Investigate the role of Th17 response in the pathogenesis of COVID-19 injury by analyzing the tissue expression of interleukins 8 and 17A and the neutrophils in lung samples of patients who die of COVID-19, comparing to H1N1pdm09. Study design and post-mortem results: Six lung samples from patients SARS-CoV-2 infected (COVID-19 group), and ten lung samples from adults who died from H1N1pdm09 (H1N1 group), were tested. A control group was also added to the study. H&E slides were used for neutrophils scoring. The tissue expression of IL-8 and IL-17A was identified by immunohistochemistry. Tissue expression increasing of IL-17A and IL-8 and a higher number of neutrophils were identified in samples from the H1N1 group when compared to the COVID-19 group. Discussion: It is suggested that the SARS-CoV-2 virus evokes an exacerbated response of the host's immune system but differs from that observed in the H1N1pdm09 disease because it may not be trigger by Th17 response. With the low expression of IL-8, IL-17A, neutrophil recruitment to the site of infection becomes impaired, resulting in viral persistence. On the other hand, in the COVID-19 disease, the immune response by Th2 cells seems to be exacerbated, observed by the extent of the lung injury. This uncontrolled response and, mainly, the lack of a therapeutic target, culminates in disease progression and, consequently, in shorter survival time.
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- 2020
50. Mast Cells in Alveolar Septa of COVID-19 Patients: A Pathogenic Pathway That May Link Interstitial Edema to Immunothrombosis
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Jarbas da Silva Motta Junior, Anna Flavia Ribeiro dos Santos Miggiolaro, Seigo Nagashima, Caroline Busatta Vaz de Paula, Cristina Pellegrino Baena, Julio Scharfstein, and Lucia de Noronha
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0301 basic medicine ,Male ,Chemokine ,Pathology ,interleukin-4 (IL-4) ,0302 clinical medicine ,Influenza A Virus, H1N1 Subtype ,Immunology and Allergy ,Mast Cells ,Respiratory system ,Hyaline ,Aged, 80 and over ,biology ,respiratory system ,Middle Aged ,Pulmonary edema ,Proto-Oncogene Proteins c-kit ,medicine.anatomical_structure ,Perspective ,Female ,Coronavirus Infections ,COVID 19 ,lcsh:Immunologic diseases. Allergy ,Adult ,medicine.medical_specialty ,Pneumonia, Viral ,Immunology ,Pulmonary Edema ,mast cells (MC) ,03 medical and health sciences ,Betacoronavirus ,Influenza, Human ,medicine ,Humans ,cell-mediated immunity ,Pandemics ,Interleukin 4 ,Aged ,Lung ,Innate immune system ,business.industry ,SARS-CoV-2 ,COVID-19 ,Thrombosis ,medicine.disease ,immune responses ,Pulmonary Alveoli ,030104 developmental biology ,biology.protein ,Interleukin-4 ,lcsh:RC581-607 ,business ,Cytokine storm ,030215 immunology - Abstract
It is currently believed that innate immunity is unable to prevent the spread of SARS-CoV-2 from the upper airways to the alveoli of high-risk groups of patients. SARS-CoV-2 replication in ACE-2-expressing pneumocytes can drive the diffuse alveolar injury through the cytokine storm and immunothrombosis by upregulating the transcription of chemokine/cytokines, unlike several other respiratory viruses. Here we report histopathology data obtained in post-mortem lung biopsies of COVID-19, showing the increased density of perivascular and septal mast cells (MCs) and IL-4-expressing cells (n = 6), in contrast to the numbers found in pandemic H1N1-induced pneumonia (n = 10) or Control specimens (n = 10). Noteworthy, COVID-19 lung biopsies showed a higher density of CD117+ cells, suggesting that c-kit positive MCs progenitors were recruited earlier to the alveolar septa. These findings suggest that MC proliferation/differentiation in the alveolar septa might be harnessed by the shift toward IL-4 expression in the inflamed alveolar septa. Future studies may clarify whether the fibrin-dependent generation of the hyaline membrane, processes that require the diffusion of procoagulative plasma factors into the alveolar lumen and the endothelial dysfunction, are preceded by MC-driven formation of interstitial edema in the alveolar septa.
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- 2020
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