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Combination approaches in hepatocellular carcinoma:How systemic treatment can benefit candidates to locoregional modalities

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World Journal of Gastroenterology 2022年第28期28卷 3573-3585页

作者： leonardo gomes da fonseca Raphael L C Araujo Department of Medical Oncology Instituto do Cancer do Estado de Sao PauloUniversity of Sao PauloSão Paulo 01246-000São PauloBrazil Hospital e Maternidade Brasil-Rede D'Or São Luiz Santo André09030-590São PauloBrazil Department of Digestive Surgery Escola Paulista de Medicina-UNIFESPSão Paulo 04023-062São PauloBrazil

The management of hepatocellular carcinoma(HCC)is challenging because most patients have underlying cirrhosis,and the treatment provides,historically,a limited impact on the natural history of patients with advanced-stage disease.Additionally,recurrence rates are high for those patients who receive local and locoregional modalities,such as surgical(resection and transplantation)or imageguided(ablation and intra-arterial)therapies.Translational research has led to new concepts that are reshaping the current clinical practice.Substantial advancements were achieved in the understanding of the hallmarks that drive hepatocarcinogenesis.This has primed a successful incorporation of novel agents with different targets,such as anti-angiogenic drugs,targeted-therapies,and immune-checkpoint inhibitors.Although clinical trials have proven efficacy of systemic agents in advanced stage disease,there is no conclusive evidence to support their use in combination with loco-regional therapy.While novel local modalities are being incorporated(e.g.,radioembolization,microwave ablation,and irreversible electroporation),emerging data indicate that locoregional treatments may induce tumor microenvironment changes,such as hyperexpression of growth factors,release of tumor antigens,infiltration of cytotoxic lymphocytes,and modulation of adaptative and innate immune response.Past trials that evaluated the use of antiangiogenic drugs in the adjuvant setting after ablation or chemoembolization fail to demonstrate a substantial improvement.Current efforts are directed to investigate the role of immunotherapy-based regimens in this context.The present review aims to describe the current landscape of systemic and locoregional treatments for HCC,present evidence to support combination approaches,and address future perspectives.

关键词： Liver cancer Hepatocellular carcinoma Immunotherapy Systemic therapy Ablation Embolization

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Trial eligibility in advanced hepatocellular carcinoma: Does it support clinical practice in underrepresented subgroups?

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World Journal of Gastroenterology 2021年第24期27卷 3429-3439页

作者： Federico Piñero leonardo gomes da fonseca Hepatology and Liver Unit Hospital Universitario AustralSchool of MedicineAustral UniversityBuenos Aires B1629HJArgentina Clinical Oncology Insituto do Cancer do Estado de São PauloUniversity of São PauloSão Paulo 05403-000Brazil

Although hepatocellular carcinoma is considered a highly lethal malignancy,recent therapeutic advances have been achieved during the last 10 years.This scenario resulted in an unprecedented improvement in survival for patients with advanced hepatocellular carcinoma,almost reaching 20-26 mo of overall survival after first-second line sequential treatment.The advent of the combination of atezolizumab with bevacizumab showed,for the first time,superiority over sorafenib with improvement in overall survival.However,first and second-line trials were correctly based on the premise that a strict selection of patients enhances the power to capture the positive effect of treatment by excluding competing risks for mortality such as liver failure,decompensated cirrhosis or other underlying medical conditions.As a result,the inclusion criteria used in clinical trials do not support the use of novel therapies in several real-world scenarios involving underrepresented subgroups,such as patients with unpreserved liver function,other comorbid conditions,a history of solid-organ transplantation,autoimmune disorders and those with a high risk of bleeding.The present text aims at discussing treatment strategies in these subgroups.

关键词： Eligibility Systemic therapies End-stage Hepatocellular carcinoma

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Animal models applied to acute-on-chronic liver failure:Are new models required to understand the human condition?

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World Journal of Clinical Cases 2022年第9期10卷 2687-2699页

作者： Jaciara Fernanda gomes Gama Liana Monteiro da fonseca Cardoso Jussara Machado Lagrota-Candido LuizAnastacio Alves Laboratory of Cellular Communication Oswaldo Cruz InstituteOswaldo Cruz FoundationRio de Janeiro 21045900Rio de JaneiroBrazil Laboratory of Immunopathology Department of ImmunobiologyFluminense Federal UniversityNiteroi 24210-200Rio de JaneiroBrazil

The liver is a multifaceted organ;its location and detoxifying function expose this organ to countless injuries.Acute-on-chronic failure liver(ACLF)is a severe syndrome that affects the liver due to acute decompensation in patients with chronic liver disease.An infection environment,ascites,increased liver enzymes and prothrombin time,encephalopathy and fast-evolving multiorgan failure,leading to death,usually accompany this.The pathophysiology remains poorly understand.In this context,animal models become a very useful tool in this regard,as understanding;the disease may be helpful in developing novel therapeutic methodologies for ACLF.However,although animal models display several similarities to the human condition,they do not represent all ACLF manifestations,resulting in significant challenges.An initial liver cirrhosis framework followed by the induction of an acute decompensation by administering lipopolysaccharide and D-Ga IN,potentiating liver damage supports the methodologies applied to induce experimental ACLF.The entire methodology has been described mostly for rats.Nevertheless,a quick Pub Med database search indicates about 30 studies concerning ACFL models and over 1000 regarding acute liver failure models.These findings demonstrate the clear need to establish easily reproducible ACFL models to elucidate questions about this quickly established and often fatal syndrome.

关键词： Liver disease Acute-on-chronic liver failure Cirrhosis Acute decompensate event Translational study Animal models

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Updates in immunotherapy for hepatocellular carcinoma

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Hepatoma Research 2019年第10期5卷 19-31页

作者： leonardo G.da fonseca Flair JoséCarrilho Medical Oncology São Paulo Clínicas Liver Cancer GroupHospital das Clínicas ComplexInstituto do Cancer do Estado de São PauloUniversity of São Paulo School of MedicineSão PauloSP 05403-000Brazil Department of Gastroenterology São Paulo Clínicas Liver Cancer GroupHospital das Clínicas ComplexInstituto do Cancer do Estado de São PauloUniversity of São Paulo School of MedicineSão PauloSP 05403-000Brazil

Hepatocellular carcinoma(HCC)carries an unfavorable prognosis and novel therapeutic strategies are needed.Until now,only few systemic agents have improved survival in patients with advanced stage disease.Immunotherapy changed the landscape in several tumor types by producing unprecedented clinical outcomes with a favorable safety profile.Liver presents a particular immune-suppressive microenvironment and HCC develops in a background of chronic inflammation in the vast majority of cases.In this regard,immunotherapy may be a suitable strategy.Preliminary research focused on therapies involving immune cells and anti-tumor immune response for HCC has shown encouraging preliminary results.Immune checkpoint inhibitors,such the anti-PD-1/PD-L1 monoclonal antibodies,have provided durable responses in patients with advanced stage disease,although the pioneers phaseⅢtrials did not confirm survival superiority over the available agents.Cancer vaccines,adoptive cellular therapies and combinations of local modalities with immunotherapy are promising approaches under active research.

关键词： Hepatocellular carcinoma immunotherapy immunosuppression prognosis immunology antibody vaccine

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TLBO with variable weights applied to shop scheduling problems

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CAAI Transactions on Intelligence Technology 2019年第3期4卷 148-158页

作者： leonardo Ramos Rodrigues Joao Paulo Pordeus gomes Electronics Division Institute of Aeronautics and SpacePraca Marechal Eduardo Gomes50Sao Josedos Campos 12228-904Brazil Computer Science Department Federal University of CearaRua Campus do PiciSnFortaleza 60440-554Brazil

The teaching–learning-based optimisation (TLBO) algorithm is a population-based metaheuristic inspired on the teaching–learning process observed in a classroom. It has been successfully used in a wide range of applications. In this study, the authors present a variant version of TLBO. In the proposed version, different weights are assigned to students during the student phase, with higher weights being assigned to students with better solutions. Three different approaches to assign weights are investigated. Numerical experiments with benchmark instances of the flow-shop and the job-shop scheduling problems are carried out to investigate the performance of the proposed approaches. They compare the proposed approaches with the original TLBO algorithm and with two variants of TLBOs proposed in the literature in terms of solution quality, convergence speed and simulation time. The results obtained by the application of a Friedman statistical test showed that the proposed approaches outperformed the original version of TLBO in terms of convergence, with no significant losses in the average makespan. The additional simulation time required by the proposed approaches is small. The best performance was achieved with the approach of assigning a fixed weight to half the students with the best solutions and assigning zero to other students.

关键词： TLBO variable weights shop scheduling problems

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Collagen membrane functionalized with magnesium oxide via room-temperature atomic layer deposition promotes osteopromotive and antimicrobial properties

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Bioactive Materials 2023年第12期30卷 46-61页

作者： Soumya Saha Raphael Cavalcante Costa Mirela Caroline Silva Joao Matheus fonseca-Santos Lin Chen Abhijit H.Phakatkar Harshdeep Bhatia leonardo P.Faverani Valentim A.R.Barao Tolou Shokuhfar Cortino Sukotjo Christos Takoudis Department of Biomedical Engineering University of Illinois ChicagoChicagoUSA Department of Prosthodontics and Periodontology Piracicaba Dental SchoolUniversity of Campinas(UNICAMP)PiracicabaSao PauloBrazil Department of Diagnosis and Surgery Division of Oral and Maxillofacial Surgery and ImplantologySao Paulo State University(UNESP)School of DentistryAraçatubaSao PauloBrazil Department of Periodontics Center for Wound Healing and Tissue RegenerationCollege of DentistryUniversity of Illinois ChicagoChicagoUSA Department of Chemical Engineering University of Illinois ChicagoChicagoUSA Department of Restorative Dentistry University of Illinois Chicago College of DentistryChicagoUSA

Artificial bone grafting materials such as collagen are gaining interest due to the ease of production and implantation.However,collagen must be supplemented with additional coating materials for improved osteointegration.Here,we report room-temperature atomic layer deposition(ALD)of MgO,a novel method to coat collagen membranes with MgO.Characterization techniques such as X-ray photoelectron spectroscopy,Raman spectroscopy,and electron beam dispersion mapping confirm the chemical nature of the film.Scanning electron and atomic force microscopies show the surface topography and morphology of the collagen fibers were not altered during the ALD of MgO.Slow release of magnesium ions promotes bone growth,and we show the deposited MgO film leaches trace amounts of Mg when incubated in phosphate-buffered saline at 37◦C.The coated collagen membrane had a superhydrophilic surface immediately after the deposition of MgO.The film was not toxic to human cells and demonstrated antibacterial properties against bacterial biofilms.Furthermore,in vivo studies performed on calvaria rats showed MgO-coated membranes(200 and 500 ALD)elicit a higher inflammatory response,leading to an increase in angiogenesis and a greater bone formation,mainly for Col-MgO500,compared to uncoated collagen.Based on the characterization of the MgO film and in vitro and in vivo data,the MgO-coated collagen membranes are excellent candidates for guided bone regeneration.

关键词： coating magnesium atomic

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Extraintestinal manifestations of inflammatory bowel disease, nitroxidative stress and dysbiosis: What is the link between them?

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BIOCELL 2021年第3期45卷 461-481页

作者： AMYLLY SANUELLY da PAZ MARTINS SAMARA BOMFIM gomes CAMPOS MARÍLIA OLIVEIRA fonseca GOULART FABIANA ANDRÉA MOURA Programa de Pós-Graduação da Rede Nordeste de Biotecnologia(RENORBIO) Universidade Federal de Alagoas(UFAL)MaceióAL 57072-970Brazil Programa de Pós-Graduação em Ciências da Saúde(PPGCS) Universidade Federal de Alagoas(UFAL)MaceióAL 57072-970Brazil Programa de Pós-Graduação em Química e Biotecnologia(PPGQB/UFAL) Campus A.C.SimõesAvenida Lourival Melo Motas/nTabuleiro dos MartinsMaceióAL 57072-970Brazil Programa de Pós-Graduação em Nutrição(PPGNU/UFAL) Programa de Pós-Graduação em Ciências Médicas(PPGCM/UFAL)Universidade Federal de Alagoas(UFAL)MaceióAL 57072-970Brazil

Inflammatory bowel disease(IBD),which includes Crohn’s disease and ulcerative colitis,has a not yet completely defined aetiology and is characterized by a progressive chronic inflammation that involves nitroxidative stress and dysbiosis.Extraintestinal manifestations can occur and affect several organs,including the liver and bile ducts,joints,skin,eyes,and less frequently,the heart,brain,and kidneys,increasing the risk of morbidity and mortality.These repercussions may be associated with the activity or severity of IBD.The present review proposes to report and analyse the participation of dysbiosis and nitroxidative stress in the genesis of extraintestinal manifestations,aiming to contribute to a better understanding of the disease and to focus on the development of individualized preventive and therapeutic strategies.

关键词： Oxidative stress Microbiota Bacterial translocation Ulcerative colitis Crohn disease

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Energetic-protein supplementation in the last 60 days of gestation improves performance of beef cows grazing tropical pastures

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Journal of Animal Science and Biotechnology 2018年第1期9卷 208-216页

作者： Aline gomes da Silva Mário fonseca Paulino Edenio Detmann Henrique Jorge Fernandes Lincoln da Silva Amorim Román Enrique Maza Ortega Victor Valério de Carvalho Josilaine Aparecida da Costa Lima Felipe Henrique de Moura Mariana Benevides Monteiro Jéssika Almeida Bitencourt Universidade Federal de Vicosa VicosaMinas Gerais 36570-000Brazil Universidade Federal de Mato Grosso do Sul Campo GrandeMato Grosso do Sul 79074-460Brazil Universidade Estadual de Mato Grosso do Sul AquidauanaMato Grosso do Sul 79200-000Brazil Biotran Biotecnologia e Treinamento em Reproducao Animal AlfenasMinas Gerais 37130-000Brazil Universidade Federal do Acre Rio BrancoAcre 69920-900Brazil

Background： Nutrition is one of the most important factors that affect animal performance, and it therefore also impacts on financial results in beef systems. In this way, finding the best strategy for feeding supplements is of paramount importance. Aiming to evaluate the effect of supplement feeding strategies for beef cows in the last third of gestation, two experiments were conducted. In Experiment 1, 35 pregnant Nellore cows were assigned to a completely randomized design with four treatments： control, which received no supplement; supplementation for the last 30 d of gestation（30-d; 3.0 kg/d）; supplementation for the last 60 d of gestation（60-d; 1.5 kg/d）; or supplementation for the last 90 d of gestation（90-d; 1.0 kg/d）. All supplemented treatments received the same total amount of supplement throughout the experiment： 90 kg（20% of crude protein）. A second experiment（Experiment 2） was delineated to evaluate the effects of the amounts offered in Experiment 1 on intake and metabolism. Four multiparous pregnant Nellore cows were assigned to a 4 × 4 Latin square design, with periods of15 d each.Results： There was a linear effect of the number of days of supplementation on calving body weight（BW; P 〈 0.05）and a quadratic effect on BW change from parturition to d 31 post-calving（P 〈 0.05）, with cows on the 60-d strategy losing less BW post-calving. No difference was found in offspring birth BW（P 〉 0.10）. A significant linear effect on interval from parturition to conception（P 〈 0.05） was observed, with the highest calving to conception interval being observed in the 90-d strategy. The level of supplementation did not affect forage intake or neutral detergent fiber digestibility（P 〉 0.10）. Nitrogen excreted through urine tended to increase linearly with the level of supplementation（P 〈 0.10）.Conclusion： Providing 1.5 kg of supplement during the last 60 d of gestation improves cow performance after calving, reducing the magnitude of BW lost, and reduces the number of days from calving to re-conception in the follow

关键词： Flushing Nutrition Parturition Reproduction

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Multi-omics Analysis of Young Portulaca oleracea L.Plants’Responses to High NaCl Doses Reveals Insights into Pathways and Genes Responsive to Salinity Stress in this Halophyte Species

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Phenomics 2023年第1期3卷 1-21页

作者： Vivianny Nayse Belo Silva Thalliton Luiz Carvalho da Silva Thalita Massaro Malheiros Ferreira Jorge Candido Rodrigues Neto AndréPereira Leão JoséAntônio de Aquino Ribeiro Patrícia Verardi Abdelnur leonardo fonseca Valadares Carlos Antônio Ferreira de Sousa Manoel Teixeira Souza Júnior Graduate Program of Plant Biotechnology Federal University of LavrasCP 3037LavrasMG 37200-000Brazil Institute of Chemistry Federal University of GoiásCampus SamambaiaGoiâniaGO 74690‐900Brazil Brazilian Agricultural Research Corporation Embrapa Mid-NorthTeresinaPI 64008-780Brazil Brazilian Agricultural Research Corporation Embrapa AgroenergyBrasíliaDF 70770‐901Brazil

Soil salinity is among the abiotic stressors that threaten agriculture the most,and purslane(Portulaca oleracea L.)is a dicot species adapted to inland salt desert and saline habitats that hyper accumulates salt and has high phytoremediation potential.Many researchers consider purslane a suitable model species to study the mechanisms of plant tolerance to drought and salt stresses.Here,a robust salinity stress protocol was developed and used to characterize the morphophysiological responses of young purslane plants to salinity stress;then,leaf tissue underwent characterization by distinct omics platforms to gain further insights into its response to very high salinity stress.The salinity stress protocol did generate different levels of stress by gradients of electrical conductivity at field capacity and water potential in the saturation extract of the substrate,and the morphological parameters indicated three distinct stress levels.As expected from a halophyte species,these plants remained alive under very high levels of salinity stress,showing salt crystal-like structures constituted mainly by Na^(+),Cl^(−),and K^(+)on and around closed stomata.A comprehensive and large-scale metabolome and transcriptome single and integrated analyses were then employed using leaf samples.The multi-omics integration(MOI)system analysis led to a data-set of 51 metabolic pathways with at least one enzyme and one metabolite differentially expressed due to salinity stress.These data sets(of genes and metabolites)are valuable for future studies aimed to deepen our knowledge on the mechanisms behind the high tolerance of this species to salinity stress.In conclusion,besides showing that this species applies salt exclusion already in young plants to support very high levels of salinity stress,the initial analysis of metabolites and transcripts data sets already give some insights into other salt tolerance mechanisms used by this species to support high levels of salinity stress.

关键词： Purslane RNA-Seq Chemometrics High-resolution mass spectrometry Abiotic stress Multi-omics integration

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Elevated calprotectin levels are associated with mortality in patients with acute decompensation of liver cirrhosis

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World Journal of Hepatology 2022年第11期14卷 1964-1976页

作者： Camila Matiollo Elayne Cristina de Morais Rateke Emerita Quintina de Andrade Moura Michelle Andrigueti Fernanda Cristina de Augustinho Tamara Liana Zocche Telma Erotides Silva Lenyta Oliveira gomes Mareni Rocha Farias Janaina Luz Narciso-Schiavon leonardo Lucca Schiavon Clinical Analysis Laboratory Unit University HospitalFederal University of Santa CatarinaFlorianopolis 88040-900Brazil Division of Gastroenterology University HospitalFederal University of Santa CatarinaFlorianópolis 88040-900Brazil Department of Pharmaceutical Sciences Health Sciences Center Federal University of Santa CatarinaFlorianópolis 88040-370Brazil Division of Gastroenterology Department of Internal MedicineFederal University of Santa CatarinaFlorianopolis 88040-900SCBrazil

BACKGROUND Acute decompensation(AD)of cirrhosis is related to systemic inflammation and elevated circulating cytokines.In this context,biomarkers of inflammation,such as calprotectin,may be of prognostic value.AIM To evaluate serum calprotectin levels in patients hospitalized for complications of cirrhosis.METHODS This is a prospective cohort study that included 200 subjects hospitalized for complications of cirrhosis,20 outpatients with stable cirrhosis,and 20 healthy controls.Serum calprotectin was measured by enzyme-linked immunosorbant assay.RESULTS Calprotectin levels were higher among groups with cirrhosis when compared to healthy controls.Higher median calprotectin was related to Child-Pugh C,ascites,and hepatic encephalopathy.Higher calprotectin was related to acute-on-chronic liver failure(ACLF)and infection in the bivariate,but not in multivariate analysis.Calprotectin was not associated with survival among patients with ACLF;however,in patients with AD without ACLF,higher calprotectin was associated with a lower 30-d survival,even after adjustment for chronic liver failure-consortium(CLIF-C)AD score.A high-risk group(CLIF-C AD score≥60 and calprotectin≥580 ng/mL)was identified,which had a 30-d survival(27.3%)similar to that of patients with grade 3 ACLF(23.3%).CONCLUSION Serum calprotectin is associated with prognosis in patients with AD without ACLF and may be useful in clinical practice to early identify patients with a very low short-term survival.

关键词： Inflammation Liver cirrhosis Acute-on-chronic liver failure

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