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Stem cell therapy for faecal incontinence: Current state and future perspectives

World Journal of Stem Cells 2018年第7期10卷 82-105页

作者： Jacobo Trébol Ana Carabias-Orgaz mariano garcía-arranz Damián garcía-Olmo General and Digestive Tract Surgery Department Salamanca University Healthcare Centre Anaesthesiology Department Complejo Asistencial de ávila New Therapies Laboratory Instituto de Investigación Sanitaria-Fundación Jiménez Díaz General and Digestive Tract Surgery Department Quiron-Salud Hospitals Surgery Department Universidad AutónomaMadrid

Faecal continence is a complex function involving different organs and systems. Faecal incontinence is a common disorder with different pathogeneses, disabling consequences and high repercussions for quality of life. Current management modalities are not ideal, and the development of new treatments is needed. Since 2008, stem cell therapies have been validated, 36 publications have appeared(29 in preclinical models and seven in clinical settings), and six registered clinical trials are currently ongoing. Some publications have combined stem cells with bioengineering technologies. The aim of this review is to identify and summarise the existing published knowledge of stem cell utilization as a treatment for faecal incontinence. A narrative or descriptive review is presented. Preclinical studies have demonstrated that cellular therapy, mainly in the form of local injections of muscle-derived(muscle derived stem cells or myoblasts derived from them) or mesenchymal(bone-marrow-or adipose-derived) stem cells, is safe. Cellular therapy has also been shown to stimulate the repair of both acute and subacute anal sphincter injuries, and some encouraging functional results have been obtained. Stem cells combined with normal cells on bioengineered scaffolds have achieved the successful creation and implantation of intrinsically-innervated anal sphincter constructs. The clinical evidence, based on adipose-derived stem cells and myoblasts, is extremely limited yet has yielded some promising results, and appears to be safe. Further investigation in both animal models and clinical settings is necessary to drawing conclusions. Nevertheless, if the preliminary results are confirmed, stem cell therapy for faecal incontinence may well become a clinical reality in the near future.

关键词： Faecal incontinence Anal sphincter Cell implantation Tissue engineering Cell therapy Stem cells

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Stem cell therapy applied for digestive anastomosis: Current state and future perspectives

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World Journal of Stem Cells 2022年第1期14卷 117-141页

作者： Jacobo Trébol Tihomir Georgiev-Hristov Isabel Pascual-Miguelañez Hector Guadalajara mariano garcía-arranz Damian garcía-Olmo Servicio de Cirugía General y del Aparato Digestivo Complejo Asistencial Universitario de SalamancaSalamanca 37007Spain Departamento de Anatomía e Histología Humanas Universidad de SalamancaSalamanca 37007Spain Servicio de Cirugía General y del Aparato Digestivo Hospital General Universitario de VillalbaMadrid 28400Spain Servicio de Cirugía General y del Aparato Digestivo Hospital Universitario La PazMadrid 28046Spain Servicio de Cirugía General y del Aparato Digestivo Hospital Universitario Fundación Jiménez DíazMadrid 28040Spain Grupo de Investigación en Nuevas Terapias Instituto de Investigación Sanitaria-Fundación Jiménez DíazMadrid 28040Spain Damian garcía-Olmo Departamento de CirugíaUniversidad Autónoma de MadridMadrid 28029Spain Servicio de Cirugía General y del Aparato Digestivo Hospital Universitario Fundación Jiménez Díaz y Grupo Quiron-Salud MadridMadrid 28040Spain

BACKGROUND Digestive tract resections are usually followed by an *** leakage,normally due to failed healing,is the most feared complication in digestive surgery because it is associated with high morbidity and *** technical and technological advances and focused research,its rates have remained almost unchanged the last *** the last two decades,stem cells(SCs)have been shown to enhance healing in animal and human studies;hence,SCs have emerged since 2008 as an alternative to improve anastomoses *** To summarise the published knowledge of SC utilisation as a preventative tool for hollow digestive viscera anastomotic or suture *** PubMed,Science Direct,Scopus and Cochrane searches were performed using the key words“anastomosis”,“colorectal/colonic anastomoses”,“anastomotic leak”,“stem cells”,“progenitor cells”,“cellular therapy”and“cell therapy”in order to identify relevant articles published in English and Spanish during the years of 2000 to *** employing SCs,performing digestive anastomoses in hollow viscera or digestive perforation sutures and monitoring healing were finally *** lists from the selected articles were reviewed to identify additional pertinent *** Given the great variability in the study designs,anastomotic models,interventions(SCs,doses and vehicles)and outcome measures,performing a reliable meta-analysis was considered impossible,so we present the studies,their results and *** Eighteen preclinical studies and three review papers were identified;no clinical studies have been published and there are no registered clinical *** studies,mainly in rat and porcine models and occasionally in very adverse conditions such as ischaemia or colitis,have been demonstrated SCs as safe and have shown some encouraging morphological,functional and even clinical *** SCs are mostly employed,and delivery routes are mainly local

关键词： Surgical anastomosis Anastomotic leak Digestive system surgical procedure Cell transplantation Cell therapy Stem cells Tissue engineering

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Rat model of anal sphincter injury and two approaches for stem cell administration

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World Journal of Stem Cells 2018年第1期10卷 1-14页

作者： Jacobo Trébol Tihomir Georgiev-Hristov Luz Vega-Clemente Ignacio garcía-Gómez Ana Carabias-Orgaz mariano garcía-arranz Damián garcía-Olmo Department of General and Digestive Tract Surgery University Hospital“La Paz”Madrid 28046Spain Department of General and Digestive Tract Surgery Villalba General HospitalMadrid 28400Spain New Therapies Laboratory Instituto de Investigación Sanitaria-Fundación Jiménez DíazMadrid 28040Spain Hektoen Institute of Medicine ChicagoIL 60612United States Department of Anaesthesiology Complejo Asistencial deávilaávila 05004Spain New Therapies Laboratory Instituto de Investigación Sanitaria-Fundación Jiménez DíazMadrid 28040Spain Department of General and Digestive Tract Surgery Quiron-Salud HospitalsMadrid 28040Spain Department of Surgery Madrid Autonomous UniversityMadrid 28029Spain

AIM To establish a rat model of anal sphincter injury and test different systems to provide stem cells to injured *** Adipose-derived stem cells(ASCs) were isolated from BDIX rats and were transfected with green fluorescent protein(GFP) for cell tracking. Biosutures(sutures covered with ASCs) were prepared with 1.5 × 10~6 GFPASCs, and solutions of 10~6 GFP-ASCs in normal saline were prepared for injection. Anorectal normal anatomy was studied on Wistar and BDIX female rats. Then, we designed an anal sphincter injury model consisting of a 1-cm extra-mucosal miotomy beginning at the anal verge in the anterior middle line. The sphincter lesion was confirmed with conventional histology(hematoxylin and eosin) and immunofluorescence with 4', 6-diamidino-2-phenylindole(commonly known as DAPI), GFP and α-actin. Functional effect was assessed with basal anal manometry, prior to and after injury. After sphincter damage, 36 BDIX rats were randomized to three groups for:(1) Cell injection without repair;(2) biosuture repair; and(3) conventional suture repair and cell injection. Functional and safety studies were conducted on all the animals. Rats were sacrificed after 1, 4 or 7 d. Then, histological and immunofluorescence studies were performed on the surgical *** With the described protocol, biosutures had been covered with at least 820000-860000 ASCs, with 100% viability. Our studies demonstrated that some ASCs remained adhered after suture passage through the muscle. Morphological assessment showed that the rat anal anatomy is comparable with human anatomy; two sphincters are present, but the external sphincter is poorly developed. Anal sphincter pressure data showed spontaneous, consistent, rhythmic anal contractions, taking the form of "plateaus" with multiple twitches(peaks) in each pressure wave. These basal contractions were very heterogeneous; their frequency was 0.91-4.17 per min(mean 1.6980, SD 0.57698), their mean duration was 26.67 s and mean numb

关键词： Fecal incontinence Experimental rat model Anal sphincter Cell implantation Cell therapy Stem cells Mesenchymal stem cell

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Stem cell therapy in the management of shoulder rotator cuff disorders

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World Journal of Stem Cells 2015年第4期7卷 691-699页

作者： Maria Valencia Mora Miguel A Ruiz Ibán Jorge Díaz Heredia Raul Barco Laakso Ricardo Cuéllar mariano garcía arranz Unidad de Hombro y Codo Hospital Universitario Ramón y Cajal Hospital Universitario La Paz Departamento de Traumatología y Cirugía Ortopédica Hospital Universitario Donostia Instituto de Investigación Sanitaria Fundación Jiménez Diaz Departamento de Cirugía Universidad Autónoma de Madrid

Rotator cuff tears are frequent shoulder problems that are usually dealt with surgical repair. Despite improved surgical techniques, the tendon-to-bone healing rate is unsatisfactory due to difficulties in restoring the delicate transitional tissue between bone and tendon. It is essential to understand the molecular mechanisms that determine this failure. The study of the molecular environment during embryogenesis and during normal healing after injury is key in devising strategies to get a successful repair. Mesenchymal stem cells(MSC) can differentiate into different mesodermal tissues and have a strong paracrine, anti-inflammatory, immunoregulatory and angiogenic potential. Stem cell therapy is thus a potentially effective therapy to enhance rotator cuff healing. Promising results have been reported with the use of autologous MSC of different origins in animal studies: they have shown to have better healing properties, increasing the amount of fibrocartilage formation and improving the orientation of fibrocartilage fibers with less immunologic response and reduced lymphocyte infiltration. All these changes lead to an increase in biomechanical strength. However, animal research is still inconclusive and more experimental studies are needed before human application. Future directions include expanded stem cell therapy in combination with growth factors or different scaffolds as well as new stem cell types and gene therapy.

关键词： Rotator cuff Enthesis Biologic Stem cells

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Detection of KRAS G12D in colorectal cancer stool by droplet digital PCR

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World Journal of Gastroenterology 2017年第39期23卷 7087-7097页

作者： Susana Olmedillas-López Dennis César Lévano-Linares Carmen Laura Aúz Alexandre Luz Vega-Clemente Edurne León Sánchez Alejandro Villagrasa Jaime Ruíz-Tovar mariano garcía-arranz Damián garcía-Olmo Foundation Health Research Institute-Fundación Jiménez Díaz University Hospital Department of Surgery School of Medicine Universidad Autónoma de Madrid Department of Surgery Rey Juan Carlos University Hospital Department of Pathology Fundación Jiménez Díaz University Hospital Department of Biomedicine and Biotechnology Universidad de Alcalá Department of Surgery Fundación Jiménez Díaz University Hospital

AIMTo assess KRAS G12D mutation detection by droplet digital PCR (ddPCR) in stool-derived DNA from colorectal cancer (CRC) *** this study, tumor tissue and stool samples were collected from 70 patients with stage I-IV CRC diagnosed by preoperative biopsy. KRAS mutational status was determined by pyrosequencing analysis of DNA obtained from formalin-fixed paraffin-embedded (FFPE) tumor tissues. The KRAS G12D mutation was then analyzed by ddPCR in FFPE tumors and stool-derived DNA from patients with this point mutation. Wild-type (WT) tumors, as determined by pyrosequencing, were included as controls; analysis of FFPE tissue and stool-derived DNA by ddPCR was performed for these patients as *** the total 70 patients included, KRAS mutations were detected by pyrosequencing in 32 (45.71%), whereas 38 (54.29%) had WT tumors. The frequency of KRAS mutations was higher in left-sided tumors (11 located in the right colon, 15 in the left, and 6 in the rectum). The predominant point mutation was KRAS G12D (14.29%, n = 10), which was more frequent in early-stage tumors (I-IIA, n = 7). In agreement with pyrosequencing results, the KRAS G12D mutation was detected by ddPCR in FFPE tumor-derived DNA, and only a residual number of mutated copies was found in WT controls. The KRAS G12D mutation was also detected in stool-derived DNA in 80% of all fecal samples from CRC patients with this point *** is a reliable and sensitive method to analyze KRAS G12D mutation in stool-derived DNA from CRC patients, especially at early stages. This non-invasive approach is potentially applicable to other relevant biomarkers for CRC management.

关键词： Droplet digital PCR KRAS Stool Formalin-fixed paraffin-embedded Pyrosequencing Colorectal cancer

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Kinetics of the reaction of OH radical with ethylfluoroacetate,ethyl 4,4,4-trifluorobutyrate,and butylfluoroacetate

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Journal of Environmental Sciences 2025年第5期151卷 273-283页

作者： Pedro L.Lugo Vianni Straccia mariano A.Teruel María B.Blanco Laboratorio Universitario de Química y Contaminación del Aire(L.U.Q.C.A) Institute for Research in Physical Chemistry of Córdoba(I.N.F.I.Q.C.)Department of Physical ChemistryFaculty of Chemical SciencesNational University of CórdobaUniversity CityCórdoba 5000Argentina Institute for Atmospheric and Environmental Research University of WuppertalWuppertal DE-42097Germany

Kinetics of the gas-phase reactions of•OH radicals with a series of fluoroesters were studied for the first time at 298±3 K and atmospheric *** rate coefficients were determined by in situ FTIR spectroscopy in nitrogen and GC-FID in air to monitor the decay of reactants and *** following coefficient values(in 10^(−12)cm^(3)/(molecule•sec))were obtained for ethyl fluoroacetate(EFA),ethyl 4,4,4-trifluorobutyrate(ETB),and butyl fluoroacetate(BFA),respectively:k_(1)(EFA+OH)=1.15±0.25 by FTIR and 1.34±0.23 by GC-FID;k_(2)(ETB+OH)=1.61±0.36 by FTIR and 2.02±0.30 by GC-FID;k_(3)(BFA+OH)=2.24±0.37 by *** trends were developed and correlated with the number of CH_(3)and F substituents in the fluoroester,and structure-activity relationships(SARs)calculations were *** addition,the tropospheric lifetimes of EFA,ETB,and BFA upon degradation by OH radicals were calculated to be 9,6,and 5 days,respectively,indicating that these fluorinated compounds could have a possible regional effect from the emission *** small photochemical ozone creation potentials of 9,7,and 19 were estimated for EFA,ETB,and BFA,*** GlobalWarming Potentials(GWPs)for EFA,ETB,and BFA were calculated for different time *** a 20-year time horizon,the GWPs were 1.393,0.063,and 0.062,*** the case of a 100-year time horizon,the GWPs were 0.379,0.017,and 0.017,and for a 500-year time horizon,the GWPs were 0.108,0.005,and 0.005 for EFA,ETB,and BFA.

关键词： CFC replacements sinks in situ FTIR SAR Acidification potentials Greenhouse gases

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Beyond neurodegeneration:engineering amyloids for biocatalysis

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Neural Regeneration Research 2025年第10期20卷 2915-2916页

作者： Andrea Bartolomé-Nafría Javier garcía-Pardo Salvador Ventura Institut de Biotecnologia i de Biomedicina(IBB)and Departament de Bioquímica i Biologia Molecular Universitat Autònoma de BarcelonaBellaterraBarcelonaSpain Hospital Universitari Parc Taulí Institut d’Investigaciói InnovacióParc Taulí(I3PT-CERCA)Universitat Autònoma de BarcelonaSabadellSpain

Amyloid fibrils are highly organized protein or peptide aggregates,often characterized by a distinctive supramolecular cross-β-sheet *** formation and accumulation of these structures have been traditionally associated with neural or systemic human diseases,such as Alzheimer’s disease,Parkinson’s disease,type-2 diabetes,or amyotrophic lateral sclerosis(Wei et al.,2017;Wittung-Stafshede,2023).

关键词： structure amyloid

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Atmospheric chemistry of trifluorodicarbonyls initiated by Cl atoms:Reactivity trends,mechanism,and acid formation yields

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Journal of Environmental Sciences 2025年第5期151卷 12-25页

作者： Pedro L.Lugo Vianni G.Straccia Cynthia B.Rivela mariano A.Teruel María B.Blanco Laboratorio Universitario de Química y Contaminación del Aire(L.U.Q.C.A) Instituto de Investigaciones en Fisicoquímica de Córdoba(I.N.F.I.Q.C.)Dpto.de Fisicoquímica.Facultad de Ciencias QuímicasUniversidad Nacional de Córdoba.Ciudad Universitaria5000 CórdobaArgentina Institute for Atmospheric and Environmental Research University of WuppertalDE-42097 WuppertalGermany

Rate coefficients of the gas-phase reactions of Cl atoms with a series of fluorinated diketones(FDKs):CF_(3)C(O)CH_(2)C(O)CH_(3)(TFP),CF_(3)C(O)CH_(2)C(O)CH_(2)CH_(3)(TFH)and CF_(3)C(O)CH_(2)C(O)CH(CH_(3))2(TFMH),have been measured at(298±2)K and under atmospheric *** experiments were performed using the relative-rate method with a GC-FID detection *** different determinations and references used,the following rate coefficients were obtained(in cm3/(molecule·sec)):k_(4)(TFP+Cl)=(1.75±0.21)×10^(−10),k_(5)(TFH+Cl)=(2.05±0.23)×10^(−10),k_(6)(TFMH+Cl)=(2.71±0.34)×10^(−10).Reactivity trends of FDKs were discussed and Free Energy Relationships analysis was *** expression lgkOH=1.68 lgkCl+5.71 was obtained for the reactivity of the studied FDKs together with similar unsaturated VOCs with Cl and OH radicals Additionally,acetic acid(CH_(3)C(O)OH)and trifluoroacetic acid(CF_(3)C(O)OH)were positively identified and quantified as degradation products using in situ FTIR *** to the identified products,atmospheric chemical mechanisms were *** atmospheric implications of the studied reactions were assessed by the estimation of the tropospheric lifetimes of TFP,TFH,and TFMH concerning their reaction with Cl atoms to be 48,41,and 31 hours,*** relatively short residence in the atmosphere of the fluorocarbons studied will have a local/regional impact with restricted *** warming potential(GWP(20 yr))calculated for the studied fluoro diketones were 0.014,0.003 and 0.001 for TFP,TFH and TFMH,respectively with a negligible contribution to the greenhouse effect.

关键词： Fluorinated diketones Kinetics SPME-GC-FID FTIR in situ SAR Free energy relationships

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The emerging role of mesenchymal stem cell-derived extracellular vesicles to ameliorate hippocampal NLRP3 inflammation induced by binge-like ethanol treatment in adolescence

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Neural Regeneration Research 2025年第4期20卷 1153-1163页

作者： Susana Mellado María JoséMorillo-Bargues Carla Perpiñá-Clérigues Francisco garcía-garcía Victoria Moreno-Manzano Consuelo Guerri María Pascual Department of Physiology School of Medicine and DentistryUniversity of ValenciaValenciaSpain Bioinformatics and Biostatistics Unit Príncipe Felipe Research CenterValenciaSpain Neuronal and Tissue Regeneration Laboratory Príncipe Felipe Research CenterValenciaSpain

Our previous studies have reported that activation of the NLRP3(NOD-,LRR-and pyrin domain-containing protein 3)-inflammasome complex in ethanol-treated astrocytes and chronic alcohol-fed mice could be associated with neuroinflammation and brain *** stem cell-derived extracellular vesicles(MSC-EVs)have been shown to restore the neuroinflammatory response,along with myelin and synaptic structural alterations in the prefrontal cortex,and alleviate cognitive and memory dysfunctions induced by binge-like ethanol treatment in adolescent *** the therapeutic role of the molecules contained in mesenchymal stem cell-derived extracellular vesicles,the present study analyzed whether the administration of mesenchymal stem cell-derived extracellular vesicles isolated from adipose tissue,which inhibited the activation of the NLRP3 inflammasome,was capable of reducing hippocampal neuroinflammation in adolescent mice treated with binge *** demonstrated that the administration of mesenchymal stem cell-derived extracellular vesicles ameliorated the activation of the hippocampal NLRP3 inflammasome complex and other NLRs inflammasomes(e.g.,pyrin domain-containing 1,caspase recruitment domain-containing 4,and absent in melanoma 2,as well as the alterations in inflammatory genes(interleukin-1β,interleukin-18,inducible nitric oxide synthase,nuclear factor-kappa B,monocyte chemoattractant protein-1,and C–X3–C motif chemokine ligand 1)and miRNAs(miR-21a-5p,miR-146a-5p,and miR-141-5p)induced by binge-like ethanol treatment in adolescent *** analysis further revealed the involvement of miR-21a-5p and miR-146a-5p with inflammatory target genes and NOD-like receptor signaling *** together,these findings provide novel evidence of the therapeutic potential of MSC-derived EVs to ameliorate the hippocampal neuroinflammatory response associated with NLRP3 inflammasome activation induced by binge drinking in adolescence.

关键词： adolescence binge-like ethanol treatment extracellular vesicles hippocampus mesenchymal stem cells neuroinflammation NOD-,LRR-and pyrin domain-containing protein 3(NLRP3)

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Reassessing the AMPK-MTORC1 balance in autophagy in the central nervous system

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Neural Regeneration Research 2025年第11期20卷 3209-3210页

作者： Marta garcía-Juan Mario Villa Irene Benito-Cuesta Lara Ordónez-Gutiérrez Francisco Wandosell Centro de Biología Molecular“Severo Ochoa”(CSIC-UAM) Nicolas Cabrera 1Universidad Autónoma de MadridMadridSpain Fisiología Animal Departamento de BiologíaFacultad de CienciasUniversidad Autónoma de MadridMadridSpain Department of Clinical Neuroscience CMM Karolinska Universitetssjukhuset SolnaStockholmSweden Departamento de Bioquímica y Biología Molecular Universidad Complutense de MadridMadridSpain Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas(CIBERNED) MadridSpain

Autophagy is a cellular degradation and recycling system,indispensable for cellular and organ development,homeostasis,and *** cellular process is evolutionarily highly conserved to quality control of many proteins and dysfunctional organelles,which finally recycle components as amino *** process is effective during normal physiology as part of anabolism and plays an additional important role during starvation(Dikic and Elazar,2018).Different types of autophagy have been chara cterized based on their dynamic,mechanism of action,target substrates,and protein *** of them are macroautophagy(hereafter called"autophagy"),microa utophagy,and chape rone-media ted autophagy(Fleming et al.,2022).

关键词： homeostasis system hereafter

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