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Cell membrane and bioactive factors derived from mesenchymal stromal cells: Cell-free based therapy for inflammatory bowel diseases

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World Journal of Stem Cells 2019年第9期11卷 618-633页

作者： Fabiany da Costa Goncalves ana helena paz Nephrology and Transplantation Internal MedicineErasmus Medical CenterRotterdamGD 3015Netherlands Experimental Research Center Hospital de Clínicas de Porto AlegrePorto AlegreRS 90035-903Brazil

Inflammatory bowel diseases(IBD)are chronic inflammatory disorders of the gastrointestinal tract associated with multifactorial conditions such as ulcerative colitis and Crohn’s *** the underlying mechanisms of IBD remain unclear,growing evidence has shown that dysregulated immune system reactions in genetically susceptible individuals contribute to mucosal ***,conventional treatments have been effective in inducing remission of IBD but not in preventing the relapse of *** this way,mesenchymal stromal cells(MSC)therapy has been recognized as a promising treatment for IBD due to their immunomodulatory properties,ability to differentiate into several tissues,and homing to inflammatory *** so,literature is conflicted regarding the location and persistence of MSC in the body after *** this reason,recent studies have focused on the paracrine effect of the biofactors secreted by MSC,especially in relation to the immunomodulatory potential of soluble factors(cytokines,chemokines,and growth factors)and extracellular vehicles that are involved in cell communication and in the transfer of cellular material,such as proteins,lipids,and nucleic ***,treatment with interferon-γ,tumor necrosis factor-α,and interleukin-1βcauses MSC to express immunomodulatory molecules that mediate the suppression via cell-contact dependent *** together,we present an overview of the role of bioactive factors and cell membrane proteins derived from MSC as a cell-free therapy that can improve IBD treatment.

关键词： Bioactive factors Cell membrane Mesenchymal stem cells Cell-free therapy Inflammatory bowel diseases

Effects of living and metabolically inactive mesenchymal stromal cells and their derivatives on monocytes and macrophages

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World Journal of Stem Cells 2021年第9期13卷 1160-1176页

作者： Alexia Nedel Sant'ana Anelise Bergmann Araújo Fabiany da Costa Gonçalves ana helena paz Laboratório de Células Tecidos e Genes Hospital de Clínicas de Porto AlegrePorto Alegre 90035-903RSBrazil Centro de Processamento Celular Hospital de Clínicas de Porto AlegrePorto Alegre 90035-903RSBrazil Department of Internal Medicine Erasmus Medical CenterRotterdam 3015 GDNetherlands Departamento de Ciências Morfológicas Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do SulPorto Alegre 90035-903RSBrazil

Mesenchymal stromal cells (MSCs) are multipotent and self-renewing stem cellsthat have great potential as cell therapy for autoimmune and inflammatorydisorders, as well as for other clinical conditions, due to their immunoregulatoryand regenerative properties. MSCs modulate the inflammatory milieu by releasingsoluble factors and acting through cell-to-cell mechanisms. MSCs switch theclassical inflammatory status of monocytes and macrophages towards a nonclassicaland anti-inflammatory phenotype. This is characterized by an increasedsecretion of anti-inflammatory cytokines, a decreased release of pro-inflammatorycytokines, and changes in the expression of cell membrane molecules and inmetabolic pathways. The MSC modulation of monocyte and macrophage phenotypesseems to be critical for therapy effectiveness in several disease models, sincewhen these cells are depleted, no immunoregulatory effects are observed. Here,we review the effects of living MSCs (metabolically active cells) and metabolicallyinactive MSCs (dead cells that lost metabolic activity by induced inactivation) andtheir derivatives (extracellular vesicles, soluble factors, extracts, and microparticles)on the profile of macrophages and monocytes and the implications forimmunoregulatory and reparative processes. This review includes mechanisms ofaction exhibited in these different therapeutic appro-aches, which induce the antiinflammatoryproperties of monocytes and macrophages. Finally, we overviewseveral possibilities of therapeutic applications of these cells and their derivatives,with results regarding monocytes and macrophages in animal model studies andsome clinical trials.

关键词： Mesenchymal stromal cells Macrophage Monocyte Immunomodulation Cell therapy Immunoregulation

Temporal clinical, proteomic, histological and cellular immune responses of dextran sulfate sodium-induced acute colitis

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World Journal of Gastroenterology 2018年第38期24卷 4341-4355页

作者： Natalia Schneider Nunes Saejeong Kim Maggie Sundby Parwathy Chandran Scott Robert Burks ana helena paz Joseph Alan Frank Frank Laboratory Radiology and Imaging Sciences Clinical Center National Institutes of Health Gastroenterology and Hepatology Sciences Graduate Program Universidade Federal do Rio Grande do Sul National Institute of Biomedical Imaging and Bioengineering National Institutes of Health

AIM To investigate the temporal clinical, proteomic, histological and cellular immune profiles of dextran sulfate sodium(DSS)-induced acute *** Acute colitis was induced in C57 BL/6 female mice by administration of 1%, 2% or 3% DSS in drinking water for 7 d. Animals were monitored daily for weight loss, stool consistency and blood in the stool, while spleens and colons were harvested on day 8. A time course analysis was performed in mice ingesting 3% DSS, which included colon proteomics through multiplex assay, colon histological scoring by a blinded investigator, and immune response through flow cytometry or immunohistochemistry of the spleen, mesenteric lymph node and *** Progressive worsening of clinical colitis was observed with increasing DSS from 1% to 3%. In mice ingesting 3% DSS, colon shortening and increase in proinflammatory factors starting at day 3 was observed, with increased spleen weights at day 6 and day 8. This coincided with cellular infiltration in the colon from day 2 to day 8, with progressive accumulation of macrophages F4/80^+, T helper CD4^+(Th), T cytotoxic CD8^+(Tcyt) and T regulatory CD25^+(Treg) cells, and progressive changes in colonic pathology including destruction of crypts, loss of goblet cells and depletion of the epithelial barrier. Starting on day 4, mesenteric lymph node and/or spleen presented with lower levels of Treg, Th and Tcyt cells, suggesting an immune cell tropism to the gut. CONCLUSION These results demonstrate that the severity of experimental colitis is dependent on DSS concentration, correlated with clinical, proteomic, histological and cellular immune response on 3% DSS.

关键词： Ulcerative colitis Dextran sulfate sodium Proteomics Inflammatory bowel diseases Inflammation

Intravenous vs intraperitoneal mesenchymal stem cells administration:What is the best route for treating experimental colitis?

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World Journal of Gastroenterology 2014年第48期20卷 18228-18239页

作者： Fabiany da Costa Goncalves Natália Schneider Fernanda Otesbelgue Pinto Fabíola Schons Meyer Fernanda Visioli Bianca Pfaffenseller Patrícia Luciana da Costa Lopez Eduardo Pandolfi Passos Elizabeth Obino Cirne-Lima Luíse Meurer ana helena paz Centro de Pesquisa Experimental do Hospital de Clínicas de Porto Alegre Porto Alegre 90035-903Rio Grande do SulBrazil Programa de Pós-Gradua??o:Ciências em Gastroenterologia e Hepatologia Universidade Federal do Rio Grande do SulPorto Alegre 90035-903Rio Grande do SulBrazil Faculdade de Odontologia Universidade Federado Rio Grande do SulPorto Alegre 90035-003Rio Grande doSulBrazil

AIM:To investigate the therapeutic effects of mesenchymal stem cells(MSCs)transplanted intraperitoneally andintravenously in a murine model of ***:MSCs were isolated from C57BL/6 mouse adipose *** cultures were analyzed according to morphology,cellular differentiation potential,and surface molecular *** acute colitis was induced in C57BL/6 mice by oral administration of2%dextran sulfate sodium(DSS)in drinking water ad libitum from days 0 to *** mice were treated with1×106 MSCs via intraperitoneal or intravenous injection on days 2 and *** disease activity index was determined daily based on the following parameters:weight loss,stool consistency and presence of blood in the feces and *** compare morphological and functional differences in tissue regeneration between different MSC injection modalities,mice were euthanized on day 8,and their colons were examined for length,weight,and histopathological *** responses were determined by measuring the levels of different serum cytokines using a CBA Th1/Th2/Th17 *** rates were evaluated by terminal deoxynucleotidyl transferase-mediated d UDPbiotin nick end labeling ***:Intravenous infusion of MSCs was more effective than intraperitoneal treatment(P<0.001)in reducing the clinical and histopathologic severity of colitis,which includes weight loss,diarrhea and *** histological evaluation demonstrated decreased colonic inflammation based on reduced crypt loss and reduced infiltration of inflammatory *** therapeutic effect was most likely mediated by the down-regulation of pro-inflammatory cytokines[interleukin(IL)-6 and tumor necrosis factor(TNF)];and by the up-regulation of anti-inflammatory cytokines(IL-10 and IL-4).Intravenous transplantation alsoinduced high levels of IFN that lead to activation of the immunosuppressive activity of the MSCs,which did not occur with intraperitoneal transplantation(P=0.006).An increase in a

关键词： Ulcerative colitis Dextran sulfate sodium Inflammatory bowel disease Mesenchymal stem cell Cell transplantation Intravenous injection Immunomodulation

Clinical use of estimating glomerular filtration rate equ-ations during pregnancy

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Health 2011年第1期3卷 32-36页

作者： Luiz Paulo José Marques Regina Rocco Maria helena Victor Benedita Calheiros de Novaes ana Luiza Batista de Carvalho Omar da rosa Santos 不详

Background: Kidney disease, even when mild, was once considered so major an impediment to successful pregnancy and so dangerous to the mother’s wellbeing. High-risk pregnancy mainly associated to renal impairment may occur in 10-20% of gestations and it is very important that renal function is closely monitored to prevent or minimize maternal and fetal complications. This study was designed to investigate the performance of Cockcroft-Gault CGeq and the simplified MDRDeq equations in healthy pregnant women to assess renal function. Methods: We studied 167 normal ambulatory pregnant women and kidney function was contemporaneously estimated through the CGeq and the simplified MDRDeq and calculated through the creatinine clearance (Ccr). Serum and urinary creatinine were assayed using Jaffé reaction method in the same Autoanalyser. Results: When we compared calculated and estimated clearences for measurement of kidney function we observed that CGeq overestimated renal function (CGeq = 168.41 ± 38.80 ml/ min/1.73 m2, Ccr = 146.27 ± 30.49 ml/min / 1.73 m2, p < 0.001), MDRDeq underestimated renal function (Ccr = 146.27 ± 30.49 ml/min / 1.73 m2, MDRDeq = 129.15 ± 29.28 ml/min / 1.73m2, p < 0.001). Conclusions: Our results demonstrated that CGeq overestimated, MDRDeq underestimated significantly kidney function during gestation in healthy women and cannot be recommended to assess renal function in obstetric practice. Ccr remains a useful clinical tool in pregnant women until the development of a specific equation that considers the several important maternal renal physiological alterations and provides the measure of GFR the most unbiased and precise as possible.

关键词： Pregnancy Kidney function Glomerular Filtration Rate MDRD equation Cockcroft-Gault equation.

An opportunity for improvement with a medication reconciliation programme

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Open Journal of Internal Medicine 2013年第4期3卷 129-134页

作者： ana Belén Jiménez-Munoz ana Clara Zoni Esther Duran-Garcia paz Rodriguez Pérez Maria Sanjurjo Saez rosa Pla-Mestre Preventive Medicine Hospital Universitario Severo OchoaMadridSpain Preventive Medicine and Quality Management Department Hospital General Universitario Gregorio MaranonC/Doctor EsquerdoMadridSpain

Medication reconciliation is priority in safety. Between 54% and 67% of hospitalized patients have at least one unintended discrepancies (UDs) between pharmacological treatment of a hospital inpatient and treatment that they were previously taking at home. Quasi-experimental pre-post study performed. The objective is to assess the impact of an intervention aimed at decreasing UDs between medication prescribed on admission and patient’s regular treatment. Patients who were hospitalised for more than 24 hours and were undergoing treatment prior to admission which involved taking three or more medicines were included. The number of patients included was 331 and 3781 medicines were reconciled. The incidence of UDs decreased significantly from 7.24% to 4.18%. Omission was the most common UD, with a significant decrease from 5.8% to 3.4%. Respect to clinical impact, we observed that error type C (error reached patient without causing harm) predominates, how- ever, experienced a statistically significant decrease from 5.3% to 2.4%.

关键词： Medication Reconciliation Admission Unintended Discrepancies

Exosomal glypican-1 is elevated in pancreatic cancer precursors and can signal genetic predisposition in the absence of endoscopic ultrasound abnormalities

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World Journal of Gastroenterology 2022年第31期28卷 4310-4327页

作者： Pedro Moutinho-Ribeiro Ines A Batista Sofia T Quintas Bárbara Adem Marco Silva Rui Morais Armando Peixoto rosa Coelho Pedro Costa-Moreira Renato Medas Susana Lopes Filipe Vilas-Boas Manuela Baptista Diogo Dias-Silva ana L Esteves Filipa Martins Joanne Lopes helena Barroca Fátima Carneiro Guilherme Macedo Sonia A Melo Serviço de Gastrenterologia Centro Hospitalar Universitário de Sao JoaoPorto 4200Portugal Faculty of Medicine University of PortoPorto 4200Portugal Instituto de Investigacao e Inovacao em Saúde(i3S) Universidade do PortoPorto 4200Portugal IPATIMUP-Institute of Molecular Pathology and Immunology University of PortoPorto 4200Portugal Instituto de Ciencias Biomédicas Abel Salazar(ICBAS) University of PortoPorto 4050Portugal Servico de Cirurgia Geral Centro Hospitalar Universitário de Sao JoaoPorto 4200Portugal Unidade de Saúde Familiar Serpa Pinto ACeS Porto OcidentalPorto 4250Portugal Serviço de anatomia Patológica Centro Hospitalar Universitário de Sao JoaoPorto 4200Portugal

BACKGROUND Individuals within specific risk groups for pancreatic ductal adenocarcinoma(PdaC)[mucinous cystic lesions(MCLs),hereditary risk(HR),and new-late onset diabetes mellitus(NLOD)]represent an opportunity for early cancer *** ultrasound(EUS)is a premium image modality for PdaC screening and precursor lesion *** no specific biomarker is currently clinically available for this purpose,glypican-1(GPC1)is overexpressed in the circulating exosomes(crExos)of patients with PdaC compared with healthy subjects or those harboring benign pancreatic *** To evaluate the capacity of GPC1+crExos to identify individuals at higher risk within these specific groups,all characterized by *** This cross-sectional study with a prospective unicentric cohort included 88 subjects:40 patients with MCL,20 individuals with HR,and 20 patients with NLOD.A control group(CG)was submitted to EUS for other reasons than pancreatic pathology,with normal pancreas and absence of hereditary risk factors(n=8).The inclusion period was between October 2016 and January 2019,and the study was approved by the Ethics Committee of Centro Hospitalar Universitário de São João,Porto,*** patients provided written informed *** and blood tests for quantification of GPC1+crExos by flow cytometry and carbohydrate antigen 19-9(CA 19-9)levels by ELISA were performed in all ***-guided tissue acquisition was done whenever *** statistical analysis,SPSS®27.0(IBM Corp.,Armonk,NY,United States)version was *** graphs were created using GraphPad Prism 7.00(GraphPad Software,San Diego,CA,United States).RESULTS Half of MCLs harbored worrisome features(WF)or high-risk stigmata(HRS).Pancreatic abnormalities were detected by EUS in 10.0%and 35.0%in HR and NLOD individuals,respectively,all considered non-malignant and“harmless.”Median levels of GPC1+crExos were statistically different:MCL[99.4%,interquartile range(IQR):94.9%-99.8%],HR(8

关键词： Glypican-1 Circulating exosomes Endoscopic ultrasound Pancreatic cancer risk groups Pancreatic cancer precursor lesions Genetic predisposition

Clinical-pathological and molecular characterization of long-term survivors with advanced non-small cell lung cancer

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Cancer Biology & Medicine 2020年第2期17卷 444-457页

作者： Juan Moreno-Rubio Santiago Ponce rosa Alvarez Maria Eugenia Olmedo Sandra Falagan Xabier Mielgo Fatima Navarro Patricia Cruz Luis Cabezon-Gutierrez Carlos Aguado Gonzalo Colmenarejo Marta Munoz-Fernandez de Leglaria ana Belen Enguita Maria Cebollero Amparo Benito Isabel Alemany Carolina del Castillo Ricardo Ramos ana Ramirez de Molina Enrique Casado Maria Sereno ana Ramirez de Molina1 Enrique Casado5Maria Sereno5 XIMDEA Food InstituteCEI UAM+CSICMadrid 28702Spain 12 de Octubre University Hospital Madrid 28041Spain Gregorio Maranon University Hospital Madrid 28009Spain Ramon y Cajal University Hospital Madrid 28034Spain Infanta Sofia University Hospital San Sebastian De Los ReyesMadrid 28702Spain Fundacion Alcorcon University Hospital AlcorconMadrid 28922Spain Prlncipe de Asturias University Hospital Alcala De HenaresMadrid 28805Spain La paz University Hospital Madrid 28046Spain University Hospital of Torrejon Torrejon De ArdozMadrid 28850Spain Clinico San Carlos University Hospital Madrid 28040Spain Parque Cientifico de Madrid Foundation Madrid 28049Spain

Objective:Long-term survivors(LS)of non-small cell lung cancer(NSCLC)without driver alterations,displaying an overall survival(OS)of more than 3 years,comprise around 10%of cases in several series treated with *** are classical prognosis factors for these cases[stage,Eastern Cooperative Oncology Group(ECOG),etc.],but more data are required in the *** this multi-center study,we focused on LS of advanced NSCLC with OS above 36 months to perform a clinical-pathological and molecular ***:In the first step,we conducted a clinical-pathological characterization of the ***,we carried out a genetic analysis by comparing LS to a sample of short-term survivors(SS)(with an OS less than 9 months).We initially used whole-genome RNA-seq to identify differentiating profiles of LS and SS,and later confirmed these with reverse transcription-polymerase chain reaction(RT-PCR)for the rest of the ***:A total of 94 patients were included,who were mainly men,former smokers,having adenocarcinoma(AC)-type NSCLC with an ECOG of *** obtained an initial differential transcriptome expression,displaying 5 over-and 33 under-expressed genes involved in different pathways:namely,the secretin receptor,surfactant protein,trefoil factor 1(T FF1),serpin,Ca-channels,and Tolllike receptor(TLRs)***,RT-PCR analysis of 40(20 LS/20 SS)samples confirmed that four genes(surfactant proteins and SFTP)were significantly down-regulated in SS compared to LS by using an analysis of covariance(ANCOVA)model:SFTPA1(P=0.023),SFTPA2(P=0.027),SFTPB{P=0.02),and SFT PC(P=0.047).Conclusions:We present a sequential genetic analysis of a sample of NSCLCLS with no driver alterations,obtaining a differential RNA-seq/RT-PCR profile showing an abnormal expression of SF genes.

关键词： Long-term survivors non-small cell lung cancer surfactant proteins

Cardiovascular prevention in elderly patients

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Journal of Geriatric Cardiology 2022年第5期19卷 377-392页

作者： Clara Bonanad rosa Fernández-Olmo Sergio García-Blas Jose Antonio Alarcon Pablo Díez-Villanueva Carmen Rus Mansilla Héctor García-Pardo Pablo Toledo ana Ayesta Eva Pereira Antoni Carol Almudena Castro-Conde Carmen de Pablo-Zarzoso Manuel Martínez-Sellés Vicente Arrarte Raquel Campuzano Albert Ariza-Solé Servicio de Cardiología Hospital Clínico Universitario de ValenciaValenciaSpain Instituto de Investigación Sanitaria INCLIVA ValenciaSpain Servicio Cardiología Hospital Universitario de Jaén Spain Servicio Cardiología Hospital de Donosti Spain Servicio de Cardiología Hospital Universitario La Princesa de MadridSpain Servicio de Cardiología Hospital Alto Gudalquivir de AndújarJaénSpain Servicio de Cardiología Hospital Rio Hortega de ValladolidSpain Servicio Cardiología Hospital Clínico San Cecilio de Granada Spain Servicio de Cardiología Hospital Universitario Central de AsturiasSpain Servicio de Cardiologia Hospital de LugoSpain Servicio de Cardiología Hospital Moisés Broggi de BarcelonaSpain Servicio de Cardiología Hospital Universitario de la paz de Madrid Spain Servicio de Cardiología Hospital Ramón y Cajal de MadridSpain Department of Cardiology.Hospital Universitario Gregorio Marañón CIBERCV.Universidad EuropeaUniversidad Compluten Servicio de Cardiología del Hospital General de Alicante Spain Servicio de Cardiología Hospital Universitario Fundación de Alcorcón de MadridSpain Servicio de Cardiología Hospital Bellvitge de BarcelonaBioheartGrup de Malalties CardiovascularsInstitut d’InvestigacióBiomèdica de BellvitgeIDIBELLL’Hospitalet de LlobregatBarcelonaSpain

In recent decades,life expectancy has been increasing *** this scenario,health interventions are ne-cessary to improve prognosis and quality of life of elderly with cardiovascular risk factors and cardiovascular ***,the number of elderly patients included in clinical trials is low,thus current clinical practice guidelines do not include specific *** document aims to review prevention recommendations focused in patients≥75 years with high or very high cardiovascular risk,regarding objectives,medical treatment options and also including physical exercise and their inclusion in cardiac rehabilitation ***,we will show why geriatric syndromes such as frailty,dependence,cognitive impair-ment,and nutritional status,as well as comorbidities,ought to be considered in this population regarding their important pro-gnostic impact.

关键词： prevention patients cardiovascular