Artigos e Materiais de Revistas Científicas - LIM/19

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A coleção de Artigos e Materiais de Revistas Científicas engloba artigos originais, artigos de revisão, artigos de atualização, artigos técnicos, relatos de experiências, resenhas, ensaios, editoriais, cartas ao editor, debates, notas científicas e técnicas, depoimentos, entrevistas e pontos de vista. Consideram-se como artigos científicos originais os trabalhos redigidos para divulgação de informações e resultados sobre determinada pesquisa científica, publicados em periódico científico após avaliação por outros pesquisadores.

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Thinking out of the box: revisiting health surveillance based on medical records
(2023) SAMPAIO, V. S.; LOPES, R.; OZAHATA, M. C.; NAKAYA, H. I.; SOUSA, E.; ARAúJO, J. D.; BRAGATTE, M. A. S.; BRITO, A. F.; GRESPAN, R. M. Z.; CAPUANI, M. L. D.; DOMINGUES, H. H.; PELLINI, A. C. G.; MATEOS, S. D. O. G.; CONDE, M. T. R. P.; LEAL, F. Eudes; SABINO, E.; SIMãO, M.; KALIL, J.
Despite the considerable advances in the last years, the health information systems for health surveillance still need to overcome some critical issues so that epidemic detection can be performed in real time. For instance, despite the efforts of the Brazilian Ministry of Health (MoH) to make COVID-19 data available during the pandemic, delays due to data entry and data availability posed an additional threat to disease monitoring. Here, we propose a complementary approach by using electronic medical records (EMRs) data collected in real time to generate a system to enable insights from the local health surveillance system personnel. As a proof of concept, we assessed data from São Caetano do Sul City (SCS), São Paulo, Brazil. We used the fever term as a sentinel event. Regular expression techniques were applied to detect febrile diseases. Other specific terms such as malaria, dengue, Zika, or any infectious disease were included in the dictionary and mapped to fever. Additionally, after tokenizing, we assessed the frequencies of most mentioned terms when fever was also mentioned in the patient complaint. The findings allowed us to detect the overlapping outbreaks of both COVID-19 Omicron BA.1 subvariant and Influenza A virus, which were confirmed by our team by analyzing data from private laboratories and another COVID-19 public monitoring system. Timely information generated from EMRs will be a very important tool to the decision-making process as well as research in epidemiology. Quality and security on the data produced is of paramount importance to allow the use by health surveillance systems.
ABX464 (obefazimod) for patients with COVID-19 at risk for severe disease: miR-AGE, a randomized, double-blind placebo-controlled trial
(2023) GIAVINA-BIANCHI, P.; CUA, E.; RISSO, K.; MONDAIN, V.; VISSIAN, A.; JOIE, C.; POULETTY, P.; GINESTE, P.; EHRLICH, H. J.; KALIL, J.
Background: ABX464 (obefazimod) is a small molecule that upregulates a single microRNA (miR-124) in immune cells and reduces the production of various inflammatory cytokines and chemokines. Objective: We assessed the efficacy and safety of the standard of care (SoC) plus oral obefazimod (SoC plus ABX464), 50 mg once daily, versus the SoC plus placebo for prevention of severe acute respiratory syndrome in patients with coronavirus disease 2019 (COVID-19) who are at risk for severe disease. Methods: Eligible patients for this phase 2/3 double-blind, placebo-controlled miR-AGE study were randomized (2:1) into 2 groups: SoC-ABX464 (n = 339) and SoC-placebo (n = 170). The primary end point was the percentage of patients who did not require use of high-flow oxygen or invasive or noninvasive mechanical ventilation within 28 days. The safety analyses included patients who had been randomly assigned and had received at least 1 dose of the study treatment. Results: At the time of the interim analysis, obefazimod showed no benefit over placebo when added to the SoC; the study enrollment was stopped for futility. The evaluation of the safety of obefazimod in 505 patients showed significantly more treatment-emergent adverse events in the SoC-ABX464 group than in the SoC-placebo group (P = .007). Frequently reported AEs in the SoC-ABX464 group included headache (14.6%), abdominal pain (9.6%), diarrhea (9.0%), back pain (6.9%), and nausea (6.0%). No treatment-related changes in laboratory parameters were reported. Conclusion: For patients who have severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and are at risk for severe COVID-19, obefazimod, 50 mg, provided no benefit over placebo when added to the SoC, although it did have a good safety profile (comparable to that reported in many therapeutic areas).
Effect of adjuvant probiotic therapy (Lactobacillus reuteri) in the treatment of periodontitis associated with diabetes mellitus: clinical, controlled, and randomized study
(2024) JARDINI, Maria Aparecida Neves; PEDROSO, Juliana Fatima; FERREIRA, Camila Lopes; NUNES, Camilla Magnoni Moretto; REICHERT, Cadiele Oliana; ALDIN, Marlene Nunez; FIGUEIREDO NETO, Antonio Martins; LEVY, Debora; DAMASCENO, Nagila Raquel Teixeira
Objectives Subgingival instrumentation (SI) with probiotics may be a proposal for the treatment of periodontitis (P), for patients with type 2 diabetes mellitus (T2DM). The Lactobacillus reuteri probiotic as an adjunctive therapy in the treatment of P associated with T2DM was evaluated.Materials and methods Forty diabetic participants diagnosed with P (stage III and IV, grade B) were randomized into SI + Placebo (n = 20): subgingival instrumentation plus placebo lozenges and SI + Probi (n = 20): subgingival instrumentation plus probiotics. Probing depth (PD), gingival recession (GR), clinical attachment level (CAL), plaque index (PI), bleeding on probing (BoP), and PISA index were performed at baseline and 30, 90, and 180 days. Cytokine concentration in the gingival crevicular fluid, subgingival biofilm sample, and LDL and HDL subfractions were evaluated.Results In the deep pockets, PD in SI + Probi showed increased values (p = 0.02) compared to SI + Placebo at 90 days. For CAL, SI + Probi showed increased values compared to SI + Placebo, with a significant difference at 30 days (p = 0.03), 90 days (p = 0.02), and 180 days (p = 0.04). At #PD >= 7 mm, SI + Probi had a more frequent number of sites (p = 0.03) compared to SI + Placebo only at baseline. For the PISA, SI + Probi showed a significant difference (p = 0.04) compared to SI + Placebo at 90 days. For cytokines, SI + Probi showed higher quantification than SI + Placebo for IL-10 (p < 0.001) at 90 days, IL-12 (p = 0.010) at 90 days, IL-1 beta (p = 0.035) at 90 days, and IL-8 (p = 0.003) at baseline. SI + Placebo showed higher quantification of IL-1 beta (p = 0.041) compared to SI + Probi only at 30 days. There was a reduction in all microbial complexes. SI + Probi improved LDL size (246.7 nm vs 260.4 nm; p < 0.001), while large HDL subfractions were reduced aft 180 days of treatment (24.0% vs 20.3%; p = 0.022) when compared with SI + Placebo; this response was dependent of probiotics (1.0 mg/dL vs - 6.2 mg/dL; p = 0.002).Conclusion Subgingival instrumentation improved the clinical periodontal parameters in patients with T2DM. The use of L. reuteri probiotics had no additional effects compared with the placebo; however, there was a positive effect on the lipoprotein subfraction.
Parasite DNA and Markers of Decreased Immune Activation Associate Prospectively with Cardiac Functional Decline over 10 Years among Trypanosoma cruzi Seropositive Individuals in Brazil
(2024) SUNDERRAJ, Ashwin; CUNHA, Luisa Marin; AVILA, Matheus; ALEXANDRIA, Shaina; FERREIRA, Ariela Mota; SILVA, Lea Campos de Oliveira-da; RIBEIRO, Antonio L. P.; NUNES, Maria do Carmo Pereira; SABINO, Ester C.; LANDAY, Alan; KALIL, Jorge; CHEVILLARD, Christophe; CUNHA-NETO, Edecio; FEINSTEIN, Matthew J.
Parasitemia and inflammatory markers are cross-sectionally associated with chronic Chagas cardiomyopathy (CCC) among patients with Trypanosoma cruzi. However, the prospective association of the parasite load and host immune response-related characteristics with CCC (that is, progressors) among T. cruzi seropositive individuals has only been partially defined. In a cohort of T. cruzi seropositive patients in Montes Claros and Sao Paulo, Brazil who were followed over 10 years, we identified the association of a baseline T. cruzi parasite load and systemic markers of inflammation with a decline in cardiac function and/or the presence of cardiac congestion 10 years later. The progressors (n = 21) were individuals with a significant decline in the left ventricular ejection fraction and/or elevated markers of cardiac congestion after 10 years. The controls (n = 31) had normal markers of cardiac function and congestion at the baseline and at the follow-up. They were matched with the progressors on age, sex, and genetic ancestry. The progressors had higher mean parasite loads at the baseline than the controls (18.3 vs. 0.605 DNA parasite equivalents/20 mL, p < 0.05). Of the 384 inflammation-related proteins analyzed, 47 differed significantly at a false discovery rate- (FDR-) corrected p < 0.05 between the groups. There were 44 of these 47 proteins that were significantly higher in the controls compared to in the progressors, including the immune activation markers CCL21, CXCL12, and HCLS1 and several of the tumor necrosis factor superfamily of proteins. Among the individuals who were seropositive for T. cruzi at the baseline and who were followed over 10 years, those with incident CCC at the 10-year marker had a comparatively higher baseline of T. cruzi parasitemia and lower baseline markers of immune activation and chemotaxis. These findings generate the hypothesis that the early impairment of pathogen-killing immune responses predisposes individuals to CCC, which merits further study.
Vaccines past and future - a Brazilian perspective
(2023) KALIL, Jorge
In this opinion article, I provide a brief history of vaccine development, commenting on the classic ways of obtaining vaccines using the infectious agent itself. Then, I address the issue of viral vaccines, their successes , difficulties, discussing the issue of viral serotypes. Bacterial vaccines and their relative success. I present our studies on Rheumatic Heart Disease and the development of an anti-streptococcal vaccine. Then, I discuss vaccine development platforms, especially with the successes achieved with non-replicating viral vector vaccines and, above all, the great success of mRNA vaccines. mRNA vaccines were only possible after the advances obtained with the replacement of nucleotides that reduced the action of innate immunity. Will all vaccines be made from mRNA in the future? Next, I address the issue of vaccine administration routes, whether subcutaneously, intradermally, intramuscularly or nasal instillation. I expose data from my laboratory on the development of an intranasal vaccine that induced a protective mucosal response, preventing infection , consequently the transmission of the SARS-CoV-2 virus. Then, I discuss which future vaccines could be developed beyond acute infectious diseases. Finally, I discuss the advantages of developing safe, effective, multiple-use vaccines and how to make them accessible to the world's population by promoting health equity.
Fructose biphosphate aldolase: A new cassava allergen
(2023) VENTURA, Anne K. R. M.; ALVES, Safiri de P.; CASTRO, Roberta A.; ROSSINI, Bruno C.; DELAZARI, Lucilense S.; OLIVEIRA, Amanda M. de; MORETTI, Ana I. S.; CASTRO, Fabio F. M.; KALIL, Jorge; YANG, Ariana C.; SANTOS, Keity S.
Background: Food allergy has considerably increased in recent years and this situation has been aggravated mainly by the consumption of more processed and complex foods, since minor or potentially allergenic foods are not required to be labeled. Manihot esculenta (cassava) is a widely consumed food in South America, Africa, and Asia and can be used in the production of flour and starch, as well as several other products. This root can cause allergic reactions with symptoms ranging from mild to severe. Methods: Thus, the aim of this study was the characterization of the immunogenic cassava proteins responsible for sensitizing patients allergic to it. Using a 2D-SDS-PAGE based proteomic approach, six proteins were identified, including Fructose Bisphosphate Aldolase (FBA). Recom-binant FBA was produced in Expi293 cells and evaluated by immunoblotting with the serum of 10 individual study subjects. Results: Our results showed six cassava IgE-reactive proteins. From those, recombinant fructose bisphosphate aldolase (FBA) showed a positivity of 80% among tested sera, proving to be a highly sensitizing protein. Conclusion: The recombinant FBA molecule obtained in this study can be important for in vivo diagnostic assays, by producing more accurate results, and for desensitization protocols, in which the use of the isolated molecule produces more precise results by avoiding secondary sensitization. Trial registration: All patients signed a consent form approved by the internal ethics committee CAPPesq, Comissao de etica para Analise de Projetos de Pesquisa do HC FMUSP (CAAE: 10420619.6.0000.0068).
Efficacy of the mRNA-1273 SARS-CoV-2 Vaccine at Completion of Blinded Phase
(2021) SAHLY, H. M. El; BADEN, L. R.; ESSINK, B.; DOBLECKI-LEWIS, S.; MARTIN, J. M.; ANDERSON, E. J.; CAMPBELL, T. B.; CLARK, J.; JACKSON, L. A.; FICHTENBAUM, C. J.; ZERVOS, M.; RANKIN, B.; EDER, F.; FELDMAN, G.; KENNELLY, C.; HAN-CONRAD, L.; LEVIN, M.; NEUZIL, K. M.; COREY, L.; GILBERT, P.; JANES, H.; FOLLMANN, D.; MAROVICH, M.; POLAKOWSKI, L.; MASCOLA, J. R.; LEDGERWOOD, J. E.; GRAHAM, B. S.; AUGUST, A.; CLOUTING, H.; DENG, W.; HAN, S.; LEAV, B.; MANZO, D.; PAJON, R.; SCHODEL, F.; TOMASSINI, J. E.; ZHOU, H.; MILLER, J.
BACKGROUND At interim analysis in a phase 3, observer-blinded, placebo-controlled clinical trial, the mRNA-1273 vaccine showed 94.1% efficacy in preventing coronavirus disease 2019 (Covid-19). After emergency use of the vaccine was authorized, the protocol was amended to include an open-label phase. Final analyses of efficacy and safety data from the blinded phase of the trial are reported. METHODS We enrolled volunteers who were at high risk for Covid-19 or its complications; participants were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 mu g) or placebo, 28 days apart, at 99 centers across the United States. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The data cutoff date was March 26, 2021. RESULTS The trial enrolled 30,415 participants; 15,209 were assigned to receive the mRNA-1273 vaccine, and 15,206 to receive placebo. More than 96% of participants received both injections, 2.3% had evidence of SARS-CoV-2 infection at baseline, and the median follow-up was 5.3 months in the blinded phase. Vaccine efficacy in preventing Covid-19 illness was 93.2% (95% confidence interval [CI], 91.0 to 94.8), with 55 confirmed cases in the mRNA-1273 group (9.6 per 1000 person-years; 95% CI, 7.2 to 12.5) and 744 in the placebo group (136.6 per 1000 person-years; 95% CI, 127.0 to 146.8). The efficacy in preventing severe disease was 98.2% (95% CI, 92.8 to 99.6), with 2 cases in the mitNA-1273 group and 106 in the placebo group, and the efficacy in preventing asymptomatic infection starting 14 days after the second injection was 63.0% (95% CI, 56.6 to 68.5), with 214 cases in the mRNA-1273 group and 498 in the placebo group. Vaccine efficacy was consistent across ethnic and racial groups, age groups, and participants with coexisting conditions. No safety concerns were identified. CONCLUSIONS The mRNA-1273 vaccine continued to be efficacious in preventing Covid-19 illness and severe disease at more than 5 months, with an acceptable safety profile, and protection against asymptomatic infection was observed.
COVID-19 mechanisms on cardio-vascular dysfunction: from membrane receptors to immune response, volume II
(2023) MORETTI, Ana Iochabel Soares; SCHREIBER, Roberto; WANSCHEL, Amarylis B. A.
Incidental Diagnosis of Rheumatic Myocarditis during Cardiac Surgery-Impact on Late Prognosis
(2023) VIEIRA, Paulo Pinto Alves Campos; PEREIRA, Rodrigo Furtado; BRANCO, Carlos Eduardo Barros; ROSA, Vitor Emer Egypto; VIEIRA, Marcelo Luiz Campos; DEMARCHI, Lea Maria Macruz Ferreira; SILVA, Livia Santos; GUILHERME, Luiza; TARASOUTCHI, Flavio; SAMPAIO, Roney Orismar
Rheumatic fever (RF) and rheumatic heart disease (RHD) are still highly prevalent, particularly in low- and middle-income countries. RHD is a neglected and underdiagnosed disease for which no specific laboratory diagnostic test is completely reliable. This is a retrospective observational study, which included 118 patients with RHD who underwent cardiac surgery from 1985 to 2018. The aim of this investigation was to evaluate the clinical, epidemiological, echocardiographic and pathological characteristics in two cohorts of RHD patients: one cohort with Aschoff bodies present in their pathological results and the other without such histopathological characteristics. No conventional clinical and laboratory tests for RHD myocarditis were able to identify active carditis during the preoperative phase of valve repair or replacement. Patients who had Aschoff bodies in their pathological results were younger (median age of 13 years (11-24 years) vs. 27 years (17-37 years), p = 0.001) and had higher rate of late mortality (22.9% vs. 5.4%, p = 0.043). In conclusion, the presence of Aschoff bodies in pathological findings may predict increased long-term mortality, emphasizing the importance of comprehensive pathology analysis for suspected myocarditis during heart surgery.
Distinct anti-NP, anti-RBD and anti-Spike antibody profiles discriminate death from survival in COVID-19
(2023) SERVIAN, Carolina do Prado; SPADAFORA-FERREIRA, Monica; ANJOS, Deborah Carolina Carvalho dos; GUILARDE, Adriana Oliveira; GOMES-JUNIOR, Antonio Roberto; BORGES, Moara Alves Santa Barbara; MASSON, Leticia Carrijo; SILVA, Joao Marcos Maia; LIMA, Matheus Henrique Assis de; MORAES, Brenda Grazielli Nogueira; SOUZA, Sueli Meira; XAVIER, Luiz Eterno; OLIVEIRA, Denise Cristina Andre de; BATALHA-CARVALHO, Joao Victor; MORO, Ana Maria; BOCCA, Anamelia Lorenzetti; PFRIMER, Irmtraut Araci Hoffmann; COSTA, Nadia Lago; FERES, Valeria Christina de Rezende; FIACCADORI, Fabiola Souza; SOUZA, Menira; GARDINASSI, Luiz Gustavo; DURIGON, Edison Luiz; ROMAO, Pedro Roosevelt Torres; JORGE, Soraia Attie Calil; COELHO, Veronica; BOTOSSO, Viviane Fongaro; FONSECA, Simone Goncalves
IntroductionInfection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces rapid production of IgM, IgA, and IgG antibodies directed to multiple viral antigens that may have impact diverse clinical outcomes.MethodsWe evaluated IgM, IgA, and IgG antibodies directed to the nucleocapsid (NP), IgA and IgG to the Spike protein and to the receptor-binding domain (RBD), and the presence of neutralizing antibodies (nAb), in a cohort of unvaccinated SARS-CoV-2 infected individuals, in the first 30 days of post-symptom onset (PSO) (T1).ResultsThis study included 193 coronavirus disease 2019 (COVID-19) participants classified as mild, moderate, severe, critical, and fatal and 27 uninfected controls. In T1, we identified differential antibody profiles associated with distinct clinical presentation. The mild group presented lower levels of anti-NP IgG, and IgA (vs moderate and severe), anti-NP IgM (vs severe, critical and fatal), anti-Spike IgA (vs severe and fatal), and anti-RBD IgG (vs severe). The moderate group presented higher levels of anti-RBD IgA, comparing with severe group. The severe group presented higher levels of anti-NP IgA (vs mild and fatal) and anti-RBD IgG (vs mild and moderate). The fatal group presented higher levels of anti-NP IgM and anti-Spike IgA (vs mild), but lower levels of anti-NP IgA (vs severe). The levels of nAb was lower just in mild group compared to severe, critical, and fatal groups, moreover, no difference was observed among the more severe groups. In addition, we studied 82 convalescent individuals, between 31 days to 6 months (T2) or more than 6 months (T3), PSO, those: 12 mild, 26 moderate, and 46 severe plus critical. The longitudinal analyzes, for the severe plus critical group showed lower levels of anti-NP IgG, IgA and IgM, anti-Spike IgA in relation T3. The follow-up in the fatal group, reveals that the levels of anti-spike IgG increased, while anti-NP IgM levels was decreased along the time in severe/critical and fatal as well as anti-NP IgG and IgA in several/critical groups.DiscussionIn summary, the anti-NP IgA and IgG lower levels and the higher levels of anti-RBD and anti-Spike IgA in fatal compared to survival group of individuals admitted to the intensive care unit (ICU). Collectively, our data discriminate death from survival, suggesting that anti-RBD IgA and anti-Spike IgA may play some deleterious effect, in contrast with the potentially protective effect of anti-NP IgA and IgG in the survival group.
Promotion of neutralizing antibody-independent immunity to wild-type and SARS-CoV-2 variants of concern using an RBD-Nucleocapsid fusion protein
(2022) CASTRO, Julia T.; AZEVEDO, Patrick; FUMAGALLI, Marcilio J.; HOJO-SOUZA, Natalia S.; SALAZAR, Natalia; ALMEIDA, Gregorio G.; OLIVEIRA, Livia I.; FAUSTINO, Lidia; ANTONELLI, Lis R.; MARCAL, Tomas G.; AUGUSTO, Marconi; VALIATE, Bruno; FIORINI, Alex; RATTIS, Bruna; RAMOS, Simone G.; PICCIN, Mariela; NONATO, Osvaldo Campos; BENEVIDES, Luciana; MAGALHAES, Rubens; CASSARO, Bruno; BURLE, Gabriela; DORO, Daniel; KALIL, Jorge; DURIGON, Edson; SALAZAR, Andres; CABALLERO, Otavia; SANTIAGO, Helton; MACHADO, Alexandre; SILVA, Joao S.; FONSECA, Flavio da; FERNANDES, Ana Paula; TEIXEIRA, Santuza R.; GAZZINELLI, Ricardo T.
Both T cells and B cells have been shown to be generated after infection with SARS-CoV-2 yet protocols or experimental models to study one or the other are less common. Here, we generate a chimeric protein (SpiN) that comprises the receptor binding domain (RBD) from Spike (S) and the nucleocapsid (N) antigens from SARS-CoV-2. Memory CD4(+) and CD8(+) T cells specific for SpiN could be detected in the blood of both individuals vaccinated with Coronavac SARS-CoV-2 vaccine and COVID-19 convalescent donors. In mice, SpiN elicited a strong IFN-gamma response by T cells and high levels of antibodies to the inactivated virus, but not detectable neutralizing antibodies (nAbs). Importantly, immunization of Syrian hamsters and the human Angiotensin Convertase Enzyme-2-transgenic (K18-ACE-2) mice with Poly ICLC-adjuvanted SpiN promotes robust resistance to the wild type SARS-CoV-2, as indicated by viral load, lung inflammation, clinical outcome and reduction of lethality. The protection induced by SpiN was ablated by depletion of CD4+ and CD8+ T cells and not transferred by antibodies from vaccinated mice. Finally, vaccination with SpiN also protects the K18-ACE-2 mice against infection with Delta and Omicron SARS-CoV-2 isolates. Hence, vaccine formulations that elicit effector T cells specific for the N and RBD proteins may be used to improve COVID-19 vaccines and potentially circumvent the immune escape by variants of concern.
Up-Front ASCT Overcomes the Survival Benefit Provided by HDAC-Based Induction Regimens in Mantle Cell Lymphoma: Data from a Real-Life and Long-Term Cohort
(2023) LAGE, Luis Alberto de Padua Covas; ELIAS, Marcela do Vale; REICHERT, Cadiele Oliana; CULLER, Hebert Fabricio; FREITAS, Fabio Alessandro de; COSTA, Renata de Oliveira; ROCHA, Vanderson; SIQUEIRA, Sheila Aparecida Coelho da; PEREIRA, Juliana
Simple Summary This study aimed to assess clinical outcomes, determine survival predictors, and compare responses between different primary therapeutic modalities in a large real-world cohort of patients with mantle cell lymphoma (MCL), with a focus on assessing the impact of intensified immunochemotherapy regimens based on high doses of cytarabine (HDAC) on outcomes in ASCT-eligible patients. A total of 165 Brazilian patients with biopsy-proven MCL were included from 2010 to 2022. After a long follow-up, our results demonstrated that patients treated with (R)-HDAC-based regimens had higher ORR (85.9% vs. 65.7%, p = 0.007) compared to those treated with (R)-CHOP, as well as lower rates of early relapses (61.9% vs. 80.4%, p = 0.043) and lower mortality (43.9% vs. 68.6%, p = 0.004). However, enhanced induction regimens employing (R)-HDAC were not associated with a real overall survival benefit in MCL patients undergoing ASCT (2-year OS: 88.7% for (R)-HDAC plus ASCT vs. 78.8% for (R)-CHOP plus ASCT, p = 0.289). Additionally, up-front ASCT was independently associated with improvement in OS (p < 0.001), EFS (p = 0.005), and POD-24 (p < 0.001) in MCL. In conclusion, in the largest real-world Latin American study involving MCL patients, we were able to ratify the benefit of up-front ASCT in young and physically fit patients regardless of the intensity of the induction immunochemotherapy regimen used. Although HDAC-based induction regimens were not associated with improved survival in ASCT-eligible patients, it was associated with higher ORR and lower rates of early relapses in the whole cohort. These findings can decisively impact the therapeutic management of MCL patients in different clinical settings.Abstract Background: Mantle cell lymphoma (MCL) is a rare malignancy with heterogeneous behavior. Despite the therapeutic advances recently achieved, MCL remains incurable. Currently, the standard of care for young and fit patients involves induction immunochemotherapy followed by up-front autologous stem cell transplantation (ASCT). However, the role of more intensive induction regimens, such as those based on high doses of cytarabine (HDAC), remains controversial in the management of ASCT-eligible patients. Methods: This retrospective, observational, and single-center study involved 165 MCL patients treated at the largest oncology center in Latin America from 2010 to 2022. We aimed to assess outcomes, determine survival predictors, and compare responses between different primary therapeutic strategies, with a focus on assessing the impact of HDAC-based regimens on outcomes in ASCT-eligible patients. Results: The median age at diagnosis was 65 years (38-89 years), and 73.9% were male. More than 90% of the cases had a classic nodal form (cnMCL), 76.4% had BM infiltration, and 56.4% presented splenomegaly. Bulky >= 7 cm, B-symptoms, ECOG >= 2, and advanced-stage III/IV were observed in 32.7%, 64.8%, 32.1%, and 95.8%, respectively. Sixty-four percent of patients were categorized as having high-risk MIPI. With a median follow-up of 71.1 months, the estimated 2-year OS and EFS were 64.1% and 31.8%, respectively. Patients treated with (R)-HDAC-based regimens had a higher ORR (85.9% vs. 65.7%, p = 0.007) compared to those receiving (R)-CHOP, as well as lower POD-24 rates (61.9% vs. 80.4%, p = 0.043) and lower mortality (43.9% vs. 68.6%, p = 0.004). However, intensified induction regimens with (R)-HDAC were not associated with a real OS benefit in MCL patients undergoing up-front consolidation with ASCT (2-year OS: 88.7% vs. 78.8%, p = 0.289). Up-front ASCT was independently associated with increased OS (p < 0.001), EFS (p = 0.005), and lower POD-24 rates (p < 0.001) in MCL. Additionally, CNS infiltration, TLS, hypoalbuminemia, and the absence of remission after induction were predictors of poor OS. Conclusions: In the largest Latin American cohort of MCL patients, we confirmed the OS benefit promoted by up-front consolidation with ASCT in young and fit patients, regardless of the intensity of the immunochemotherapy regimen used in the pre-ASCT induction. Although HDAC-based regimens were not associated with an unequivocal increase in OS for ASCT-eligible patients, it was associated with higher ORR and lower rates of early relapses for the whole cohort.
Identifying the Characteristics of Responders and Nonresponders in a Behavioral Intervention to Increase Physical Activity Among Patients With Moderate to Severe Asthma: Protocol for a Prospective Pragmatic Study
(2023) LIMA, Fabiano Francisco de; LUNARDI, Adriana Claudia; PINHEIRO, David Halen Araujo; CARVALHO-PINTO, Regina Maria; STELMACH, Rafael; GIAVINA-BIANCHI, Pedro; AGONDI, Rosana Camara; CARVALHO, Celso R. F.
Background: Previous research has suggested that most adults improve their asthma control after a short-term behavioral intervention program to increase physical activity in daily life (PADL). However, the characteristics of individuals who respond and do not respond to this intervention and the medium-term response remain unknown.Objective: This study aims to (1) identify the characteristics of adult responders and nonresponders with asthma to a behavioral intervention to increase physical activity and (2) evaluate the functional and clinical benefits in the medium term.Methods: This prospective pragmatic study will include adults with moderate to severe asthma who enroll in a behavioral intervention. All individuals will receive an educational program and an 8-week intervention to increase PADL (1 time/wk; up to 90 min/session). The educational program will be conducted in a class setting through group discussions and video presentations. Behavioral interventions will be based on the transtheoretical model using counseling, incentives, and individual feedback aiming to increase participation in physical activity. Motivational interviewing and guidelines for overcoming barriers will be used to stimulate individuals to reach their goals. Pre-and postintervention assessments will include the following: PADL (triaxial accelerometry), body composition (octopolar bioimpedance), barriers to PADL (questionnaire), clinical asthma control (Asthma Control Questionnaire), quality of life (Asthma Quality of Life Questionnaire), anxiety and depression levels (Hospital Anxiety and Depression Scale), and exacerbations. ""Responders"" to the intervention will be defined as those who demonstrate an increase in the number of daily steps (& GE;2500). Results: In December 2021, the clinical trial registration was approved. Recruitment and data collection for the trial is ongoing, and the results of this study are likely to be published in late 2024. Conclusions: The intervention will likely promote different effects according to the clinical characteristics of the individuals, including asthma control, age, anxiety and depression levels, obesity, and several comorbidities. Identifying individuals who respond or do not respond to behavioral interventions to increase PADL will help clinicians prescribe specific interventions to adults with asthma.Trial Registration: ClinicalTrials.gov NCT05159076; https://clinicaltrials.gov/ct2/show/NCT05159076International Registered Report Identifier (IRRID): DERR1-10.2196/49032
Basophil Activation Test as a Biomarker for Taxanes Anaphylaxis
(2022) CAMPOS, Lucila De; GIAVINA-BIANCHI, Pedro; ACHARYA, Shree; LYNCH, Donna-Marie; KALIL, Jorge; CASTELLS, Mariana C.
IntroductionTaxanes are widely used chemotherapy agents, and their administration, despite premedication, is associated with hypersensitivity reactions (HR) in up to 9% of patients, 1% of which are severe. The mechanisms of these reactions are not fully understood. Finding biomarkers for early diagnosis and better understanding the underlying mechanisms of these reactions are key to defining the best treatment strategy for patients.MethodsThe purpose of this study was to evaluate the effectiveness of the basophil activation test (BAT) to diagnose patients with anaphylactic reactions to taxanes. Patients with anaphylaxis to taxane compounds (n = 15) were assessed through clinical history, skin testing (when possible), and BAT. BAT was performed immediately before rapid drug desensitization or before skin testing using anti-CD123 conjugated (APC-Biolegend), anti-HLADR conjugated (FITC-Biolegend) to gate Basophils and anti-CD63 conjugated (PE-Biolegend), and anti-CD203c conjugated (BV-Biolegend) to assess CD203c and CD63 expression on basophils under taxane stimulation. BAT was also performed in eight healthy volunteers.ResultsBAT was positive for CD203c in eight out of 15 patients and for CD63 in four out of 15 patients and in two out of eight controls. The sensitivity for CD203c was 53%, the specificity was 87%, and the area under the curve was 0.66 (p = 0.19%). For CD63, these rates were 33%, 87%, and 0.6 (p = 0.4). In a subgroup analysis of patients with positive skin tests (11 patients), CD203c was positive in six patients (sensitivity of 54.5% and specificity of 87.5%), and CD63 was positive in five patients (sensitivity of 45% and specificity of 75%).ConclusionsBAT as a diagnostic tool for immediate hypersensitivity reactions to taxanes may be relevant in patients with selected phenotypes and endotypes, especially those with severe reactions or when the diagnosis cannot be established by the skin test. Increased expression of CD203c was more frequent than of CD63 in patients with positive results, and the sensitivity of this biomarker was higher in patient sub-group with positive skin tests, i.e., patients with IgE-mediated endotypes.
Interview with Prof. Jorge Kalil: The Challenge of Doing Competitive Translational Research in Brazil
(2023) KALIL, Jorge
Up-front Therapy With CHOP Plus Etoposide in Brazilian nodal PTCL Patients: Increased Toxicity and No Survival Benefit Compared to CHOP Regimen–Results of a Real-Life Study From a Middle-Income Country
(2022) LAGE, L. A. D. P. C.; BRITO, C. V.; BARRETO, G. C.; CULLER, H. F.; REICHERT, C. O.; LEVY, D.; COSTA, R. D. O.; ZERBINI, M. C. N.; ROCHA, V.; PEREIRA, J.
Background: Nodal peripheral T-cell lymphoma (nPTCL) constitute a heterogeneous group of neoplasms with aggressive behavior and poor-survival. They are more prevalent in Latin America and Asia, although data from Brazil are scarce. Its primary therapy is still controversial and ineffective. Therefore, we aim to describe clinical-epidemiological characteristics, outcomes, predictors factors for survival and compare the results of patients treated with CHOP and CHOEP regimens. Methods: Retrospective, observational and single-center study involving 124 nPTCL patients from Brazil treated from 2000 to 2019. Results: With a median follow-up of 23.7 months, the estimated 2-year overall survival (OS) and progression-free survival (PFS) were 59.2% and 37.3%, respectively. The median age was 48.5 years and 57.3% (71/124) were male, 81.5% (101/124) had B-symptoms, 88.7% (110/124) had advanced disease (stage III/IV) and 58.1% (72/124) presented International Prognostic Index (IPI) score ≥3, reflecting a real-life cohort. ORR to first-line therapy was 58.9%, 37.9% (N = 47) received CHOP-21 and 35.5% (N = 44) were treated with CHOEP-21; 30.1% (37/124) underwent to consolidation with involved field radiotherapy (IF-RT) and 32.3% (40/124) were consolidated with autologous hematopoietic stem cell transplantation (ASCT). The overall response rate (ORR) was similar for CHOP-21 (76.6%) and CHOEP-21 (65.9%), P =.259. Refractory disease was less frequent in the CHOEP-21 group (4.5% vs. 21.2%, P =.018). However, few patients were able to complete 6-cycles of CHOEP-21 (31.8%) than to CHOP-21 (61.7%), P =.003. Delays ≥2 weeks among the cycles of chemotherapy were more frequent for patients receiving CHOEP-21 (43.1% vs. 10.6%), P =.0004, as well as the toxicities, including G3-4 neutropenia (88% vs. 57%, P =.001), febrile neutropenia (70% vs. 38%, P =.003) and G3-4 thrombocytopenia (63% vs. 27%, P =.0007). The 2-year OS was higher for CHOP (78.7%) than CHOEP group (61.4%), P =.05, as well as 2-year PFS (69.7% vs. 25.0%, P <.0001). In multivariate analysis, high LDH (HR 3.38, P =.007) was associated with decreased OS. CR at first line (HR: 0.09, P <.001) and consolidation with ASCT (HR: 0.08, P =.015) were predictors of increased OS. Conclusion: In the largest cohort of nPTCL from Latin America, patients had poor survival and high rate of chemo-resistance. In our cohort, the addition of etoposide to the CHOP-21 backbone showed no survival benefit and was associated with high-toxicity and frequent treatment interruptions. Normal LDH values, obtaintion of CR and consolidation with ASCT were independent factors associated with better outcomes. © 2022 Elsevier Inc.
Multicellular regulation of miR-196a-5p and miR-425-5 from adipose stem cell-derived exosomes and cardiac repair
(2022) OLIVEIRA, N. C. de Almeida; NERI, E. A.; SILVA, C. M.; VALADãO, I. C.; FONSECA-ALANIZ, M. H.; ZOGBI, C.; LEVY, D.; BYDLOWSKI, S. P.; KRIEGER, J. E.
Cardiac transplantation of adipose-derived stem cells (ASC) modulates the post-myocardial infarction (post-MI) repair response. Biomolecules secreted or shuttled within extracellular vesicles, such as exosomes, may participate in the concerted response. We investigated the exosome’s microRNAs due to their capacity to fine-tune gene expression, potentially affecting the multicellular repair response. We profiled and quantified rat ASC-exosome miRNAs and used bioinformatics to select uncharacterized miRNAs down-regulated in post-MI related to cardiac repair. We selected and validated miR-196a-5p and miR-425-5p as candidates for the concerted response in neonatal cardiomyocytes, cardiac fibroblasts, endothelial cells, and macrophages using a high-content screening platform. Both miRNAs prevented cardiomyocyte ischemia-induced mitochondrial dysfunction and reactive oxygen species production, increased angiogenesis, and polarized macrophages toward the anti-inflammatory M2 immunophenotype. Moreover, miR-196a-5p reduced and reversed myofibroblast activation and decreased collagen expression. Our data provide evidence that the exosome-derived miR-196a-5p and miR-425-5p influence biological processes critical to the concerted multicellular repair response post-MI. © 2022 The Author(s).
Time-dependent contraction of the SARS-CoV-2–specific T-cell responses in convalescent individuals
(2022) FERNANDES, E. R.; APOSTOLICO, J. de Souza; JACINTHO, L. C.; MARIN, M. L. Carnevale; JúNIOR, R. C. Vieira da Silva; RODRIGUES, H.; SANTOS, K. S.; COELHO, V.; BOSCARDIN, S. B.; KALIL, J.; CUNHA-NETO, E.; ROSA, D. S.
Background: Adaptive immunity in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is decisive for disease control. Delayed activation of T cells is associated with a worse outcome in coronavirus disease 2019 (COVID-19). Although convalescent individuals exhibit solid T-cell immunity, to date, long-term immunity to SARS-CoV-2 is still under investigation. Objectives: We aimed to characterize the specific T-cell response on the basis of the in vitro recall of IFN-γ–producing cells to in silico–predicted peptides in samples from SARS-CoV-2 convalescent individuals. Methods: The sequence of the SARS-CoV-2 genome was screened, leading to the identification of specific and promiscuous peptides predicted to be recognized by CD4+ and CD8+ T cells. Next, we performed an in vitro recall of specific T cells from PBMC samples from the participants. The results were analyzed according to clinical features of the cohort and HLA diversity. Results: Our results indicated heterogeneous T-cell responsiveness among the participants. Compared with patients who exhibited mild symptoms, hospitalized patients had a significantly higher magnitude of response. In addition, male and older patients showed a lower number of IFN-γ–producing cells. Analysis of samples collected after 180 days revealed a reduction in the number of specific circulating IFN-γ–producing T cells, suggesting decreased immunity against viral peptides. Conclusion: Our data are evidence that in silico–predicted peptides are highly recognized by T cells from convalescent individuals, suggesting a possible application for vaccine design. However, the number of specific T cells decreases 180 days after infection, which might be associated with reduced protection against reinfection over time. © 2022 The Authors
Inflammatory cytokines and white matter microstructure in the acute phase of first-episode psychosis: A longitudinal study
(2023) SERPA, Mauricio; DOSHI, Jimit; JOAQUIM, Helena P. G.; VIEIRA, Erica L. M.; ERUS, Guray; CHAIM-AVANCINI, Tiffany M.; CAVALLET, Mikael; GUGLIELMI, Luiza Guilherme; SALLET, Paulo C.; TALIB, Leda; TEIXEIRA, Antonio L.; BILT, Martinus T. van de; MCGUIRE, Philip; GATTAZ, Wagner F.; DAVATZIKOS, Christos; BUSATTO, Geraldo F.; V, Marcus Zanetti
Objectives: Schizophrenia-related psychosis is associated with abnormalities in white matter (WM) microstructure and structural brain dysconnectivity. However, the pathological process underlying such changes is unknown. We sought to investigate the potential association between peripheral cytokine levels and WM microstructure during the acute phase of first-episode psychosis (FEP) in a cohort of drug-naive patients.Methods: Twenty-five non-affective FEP patients and 69 healthy controls underwent MRI scanning and blood collection at study entry. After achieving clinical remission, 21 FEP were reassessed; 38 age and biological sex -matched controls also had a second assessment. We measured fractional anisotropy (FA) of selected WM regions -of-interest (ROIs) and plasma levels of four cytokines (IL-6, IL-10, IFN-& gamma;, and TNF-& alpha;).Results: At baseline (acute psychosis), the FEP group showed reduced FA relative to controls in half the examined ROIs. Within the FEP group, IL-6 levels were negatively correlated with FA values. Longitudinally, patients showed increments of FA in several ROIs affected at baseline, and such changes were associated with reductions in IL-6 levels.Conclusions: A state-dependent process involving an interplay between a pro-inflammatory cytokine and brain WM might be associated with the clinical manifestation of FEP. This association suggests a deleterious effect of IL-6 on WM tracts during the acute phase of psychosis.
MiRNA-30d and miR-770-5p as potential clinical risk predictors of Vasoplegic Syndrome in Patients undergoing on-pump coronary artery bypass grafting
(2023) MEJIA, Omar Asdrubal Vilca; SOUZA, Renato Cesar de; SANTOS, Aritania S.; MENEGHINI, Bianca; SILVA, Ana Carolina Carvalho; BRASIL, Guilherme Visconde; RIGAUD, Vagner Oliveira Carvalho; DALLAN, Luis Roberto Palma; MOREIRA, Luiz Felipe Pinho; LISBOA, Luiz Augusto Ferreira; DALLAN, Luis Alberto Oliveira; KALIL, Jorge; CUNHA-NETO, Edecio; FERREIRA, Ludmila Rodrigues Pinto; JATENE, Fabio Biscegli
The aims of this study were to perform pre-surgery miRNA profiling of patients who develop Vasoplegic syndrome (VS) after coronary artery bypass grafting (CABG) and identify those miRNAs that could be used as VS prognostic tools and biomarkers. The levels of 754 microRNAs (miRNAs) were measured in whole blood samples from a cohort of patients collected right before the coronary artery bypass grafting (CABG) surgery. We compared the miRNA levels of those who developed VS (VASO group) with those who did not (NONVASO group) after surgery. Six miRNAs (hsa-miR-548c-3p, -199b-5p, -383-5p -571 -183-3p, -30d-5p) were increased and two (hsa-1236-3p, and hsa-miR770-5p) were decreased in blood of VASO compared to NONVASO groups. Receiver Operating Characteristic (ROC) curve analysis revealed that a combination of the miRNAs, hsa-miR-30d-5p and hsa-miR-770-5p can be used as VS predictors (AUC = 0.9615, p < 0.0001). The computational and functional analyses were performed to gain insights into the potential role of these dysregulated miRNAs in VS and have identified the ""Apelin Liver Signaling Pathway"" as the canonical pathway containing the most target genes regulated by these miRNAs. The expression of the combined miRNAs hsa-miR-30d and hsa-miR-770-5p allowed the ability to distinguish between patients who could and could not develop VS, representing a potential predictive biomarker of VS.

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