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Tumor microenvironment involvement in colorectal cancer progression via Wnt/β-catenin pathway:Providing understanding of the complex mechanisms of chemoresistance

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World Journal of Gastroenterology 2022年第26期28卷 3027-3046页

作者： María Belén novoa Díaz María julia martín Claudia Gentili Departamento de Biología Bioquímica y FarmaciaUniversidad Nacional del Sur(UNS)-INBIOSUR(CONICET-UNS)Bahía Blanca 8000Argentina Departamento de Química Universidad Nacional del Sur(UNS)-INQUISUR(CONICET-UNS)Bahía Blanca 8000Argentina

Colorectal cancer(CRC)continues to be one of the main causes of death from cancer because patients progress unfavorably due to resistance to current therapies.Dysregulation of the Wnt/β-catenin pathway plays a fundamental role in the genesis and progression of several types of cancer,including CRC.In many subtypes of CRC,hyperactivation of theβ-catenin pathway is associated with mutations of the adenomatous polyposis coli gene.However,it can also be associated with other causes.In recent years,studies of the tumor microenvironment(TME)have demonstrated its importance in the development and progression of CRC.In this tumor nest,several cell types,structures,and biomolecules interact with neoplastic cells to pave the way for the spread of the disease.Cross-communications between tumor cells and the TME are then established primarily through paracrine factors,which trigger the activation of numerous signaling pathways.Crucial advances in the field of oncology have been made in the last decade.This Minireview aims to actualize what is known about the central role of the Wnt/β-catenin pathway in CRC chemoresistance and aggressiveness,focusing on crosscommunication between CRC cells and the TME.Through this analysis,our main objective was to increase the understanding of this complex disease considering a more global context.Since many treatments for advanced CRC fail due to mechanisms involving chemoresistance,the data here exposed and analyzed are of great interest for the development of novel and effective therapies.

关键词： Colorectal cancer β-catenin pathway Tumor stroma Tumor microenvironment factors Cancer progression Drug resistance

Involvement of parathyroid hormone-related peptide in the aggressive phenotype of colorectal cancer cells

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World Journal of Gastroenterology 2021年第41期27卷 7025-7040页

作者： María Belén novoa Díaz Pedro Matías Carriere María julia martín natalia Calvo Claudia Gentili Departamento de Biología Bioquímica y FarmaciaUniversidad Nacional del Sur(UNS)-INBIOSUR(CONICET-UNS)Bahía Blanca 8000Buenos AiresArgentina Departamento de Química Universidad Nacional del Sur(UNS)-INQUISUR(CONICET-UNS)Bahía Blanca 8000Buenos AiresArgentina

Colorectal cancer(CRC)remains one of the leading causes of mortality from malignant diseases worldwide.In general terms,CRC presents high heterogeneity due to the influence of different genetic and environmental factors;also,the neoplastic cells are strongly influenced by the extracellular matrix and several surrounding cells,known together as the tumor microenvironment(TME).Bidirectional communication takes place between the tumor and the TME through the release of autocrine and paracrine factors.Parathyroid hormone-related peptide(PTHrP)is a cytokine secreted by a wide variety of tissues and is able to regulate several cellular functions both in physiological as well as in pathological processes.It exerts its effects as a paracrine/autocrine factor,although its mode of action is mainly paracrine.It has been shown that this peptide is expressed by several tumors and that the tumor secretion of PTHrP is responsible for the malignant humoral hypercalcemia.Eight years ago,when our research group started studying PTHrP effects in the experimental models derived from intestinal tumors,the literature available at the time addressing the effects of PTHrP on colorectal tumors was limited,and no articles had been published regarding to the paracrine action of PTHrP in CRC cells.Based on this and on our previous findings regarding the role of PTH in CRC cells,our purpose in recent years has been to explore the role of PTHrP in CRC.We analyzed the behavior of CRC cells treated with exogenous PTHrP,focalizing in the study of the following events:Survival,cell cycle progression and proliferation,migration,chemoresistance,tumor-associated angiogenesis,epithelial to mesenchymal transition program and other events also associated with invasion,such us the induction of cancer stem cells features.This work summarizes the major findings obtained by our investigation group using in vitro and in vivo CRC models that evidence the participation of PTHrP in the acquisition of an aggressive phenotype of CRC cells and the molecular mecha

关键词： Parathyroid hormone-related protein Colorectal cancer Tumor biomarkers neoplastic processes Drug resistance Tumor microenvironment

Mycobacterium tuberculosis in the aorta of a patient with takayasu’s arteritis. extra pulmonary tuberculosis

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Health 2011年第3期3卷 159-161页

作者： María Elena Soto Virgilia Soto julia Isela martín Sandría Ricardo Gamboa Claudia Huesca 不详

Takayasu’s arteritis (TA), of unknown etiology, has been related with Mycobacterium tuberculosis infection. The published cases are controversial. A 29- year-old man died, prolapse of the aortic valve and unspecific arteritis were demonstrated at necropsy. Our objective was to search in the fresh aortic tissues, the infectious agent of tuberculosis through culture, as well as by performing histopathology and searching by the molecular study, sequences of genes associated to micobacteria and Ziehl’s stain. Results. The bacillus of tuberculosis was observed by the Ziehl’s stain and the sequences of insertion IS6110 gene were identified. Our findings support the relation of TA with possible tuberculosis infection.Conclusion. The possibility that Takayasu’s arteritis is an extra pulmonary tu-berculosis must be explored.

关键词： Takayasu’s arteritis extrapulmonary tuberculosis IS6110 and HupB sequences

Beta-blocker therapy in elderly patients with renal dysfunction and heart failure

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Journal of Geriatric Cardiology 2021年第1期18卷 20-29页

作者： Juan martínez-Milla Marcelino Cortés García julia Anna Palfy Mikel Taibo Urquía marta López Castillo Ana Devesa Arbiol Ana Lucía Rivero Monteagudo María Luisa martín Mariscal Inés Jiménez-Varas Sem Briongos Figuero Juan Antonio Franco-Pelaéz JoséTuñón Department of Cardiology Hospital Universitario Fundación Jiménez Díaz-Quirónsalud Centro nacional de Investigaciones Cardiovasculares MadridSpain Department of Cardiology Hospital Central de Asturias Department of Cardiology Hospital Universitario Ruber-Quirónsalud Department of Cardiology Hospital Universitario Infanta Leonor Department of Endocrinology Hospital Clínico San Carlos Universidad Autónoma de Madrid CIBERCV MadridSpain

OBJECTIVE To assess the role of beta-blockers(BB)in patients with chronic kidney disease(CKD)aged≥75 years.METHODS AnD RESULTS From January 2008 to July 2014,we included 390 consecutive patients≥75 years of age with ejection fraction≤35%and glomerular filtration rate(GFR)≤60 m L/min per 1.73 m^2.We analyzed the relationship between treatment with BB and mortality or cardiovascular events.The mean age of our population was 82.6±4.1 years.Mean ejection fraction was 27.9%±6.5%.GFR was 60-45 m L/min per 1.73 m^2 in 50.3%of patients,45-30 m L/min per 1.73 m^2 in 37.4%,andn per 1.73 m^2 in 12.3%.At the conclusion of follow-up,67.4%of patients were receiving BB.The median follow-up was28.04(IR:19.41-36.67)months.During the study period,211 patients(54.1%)died and 257(65.9%)had a major cardiovascular event(death or hospitalization for heart failure).BB use was significantly associated with a reduced risk of death(HR=0.51,95%CI:0.35-0.74;Pnts receiving BB consistently showed a reduced risk of death across the different stages of CKD:stage IIIa(GFR=30-45 m L/min per 1.73 m^2;HR=0.47,95%CI:0.26-0.86,Pn per 1.73 m^2;HR=0.55,95%CI:0.26-1.06,P=0.007),and stages IV and V(GFRn per 1.73 m~2;HR=0.29,95%CI:0.11-0.76;P=0.047).COnCLUSIOnS The use of BB in elderly patients with HFr EF and renal impairment was associated with a better prognosis.Use of BB should be encouraged when possible.

关键词： CKD GFR Beta-blocker therapy in elderly patients with renal dysfunction and heart failure

Hepatic flow is an intraoperative predictor of early allograft dysfunction in whole-graft deceased donor liver transplantation: An observational cohort study

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World Journal of Hepatology 2019年第9期11卷 689-700页

作者： Pablo Lozano Lominchar Maitane Igone Orue-Echebarria Lorena martín Cristina julia Lisbona María Magdalena Salcedo Luis Olmedilla Hemant Sharma Jose Manuel Asencio JoséAngel López-Baena General Surgery Department Liver Transplant UnitHospital General Universitario Gregorio MaranonMadrid 28007Spain Anesthesiology Department Liver Transplant UnitHospital General Universitario Gregorio MaranonMadrid 28007Spain Hepatology Department Liver Transplant UnitHospital General Universitario Gregorio MaranonMadrid 28007Spain Department of Transplant Surgery Oschner Medical CenterNew OrleansLA 70816United States

BACKGROUnD Early allograft dysfunction(EAD)after liver transplantation(LT)is an important cause of morbidity and mortality.To ensure adequate graft function,a critical hepatocellular mass is required in addition to an appropriate blood supply.We hypothesized that intraoperative measurement of portal venous and hepatic arterial flow may serve as a predictor in the diagnosis of EAD.AIM To study whether hepatic flow is an independent predictor of EAD following LT.METHODS This is an observational cohort study in a single institution.Hepatic arterial blood flow and portal venous blood flow were measured intraoperatively by transit flow.EAD was defined using the Olthoff criteria.Univariate and multivariate analyses were used to determine the intraoperative predictors of EAD.Survival analysis and prognostic factor analysis were performed using the Kaplan-Meier and Cox regression models.RESULTS A total of 195 liver transplant procedures were performed between January 2008 and December 2014 in 188 patients.A total of 54(27.7%)patients developed EAD.The median follow-up was 39 mo.Portal venous flow,hepatic arterial flow(HAF)and total hepatic arterial flow were associated with EAD in both the univariate and multivariate analyses.HAF is an independent prognostic factor for 30-d patient mortality.COnCLUSIOn Intraoperative measurement of blood flow after reperfusion appears to be a predictor of EAD;Moreover,HAF should be considered a predictor of 30-d patient mortality.

关键词： Hepatic flow Early allograft dysfunction Liver transplant

8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases

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Acta Pharmaceutica Sinica B 2023年第5期13卷 2152-2175页

作者： Damijan Knez Daniel Diez-Iriepa Mourad Chioua Andrea Gottinger Milica Denic Fabien Chantegreil Florian nachon Xavier Brazzolotto Anna Skrzypczak-Wiercioch Ane Meden Anja Pilar Janko Kos Simon akelj Jure Stojan Kinga Saat julia Serrano Ana Patricia Fernández Aitana Sánchez-García Ricardo martínez-Murillo Claudia Binda Francisco López-Muoz Stanislav Gobec JoséMarco-Contelles University of Ljubljana Faculty of PharmacyLjubljana 1000Slovenia Laboratory of Medicinal Chemistry(Institute of Organic Chemistry CSIC)Madrid 28006Spain Departamento de Química Orgánicay Química Inorgánica Alcaláde HenaresMadrid 28871Spain Department of Biology and Biotechnology University of PaviaPavia 27100Italy Département de Toxicologie et Risques Chimiques Institut de Recherche Biomédicale des ArméesParis 91220France Department of Animal Anatomy and Preclinical Sciences University Centre of Veterinary Medicine JU-UAUniversity of Agriculture in KrakowKrakow 30-059Poland Institute of Biochemistry Faculty of MedicineUniversity of LjubljanaLjubljana 1000Slovenia Department of Pharmacodynamics Chair of PharmacodynamicsFaculty of PharmacyJagiellonian University Medical CollegeKrakow 30-688Poland Department of Translational neurobiology Neurovascular Research GroupCajal Institute(CSIC)Madrid 28002Spain Biotechnology and Vegetal Biology Department Escuela Técnica Superior de Ingeniería AgronómicaAlimentaria y de BiosistemasUniversidad Politécnica de MadridMadrid 28040Spain Faculty of Health Camilo JoséCela University of Madrid(UCJC)Neuropsychopharmacology Unit“Hospital 12 de Octubre”Research InstituteMadrid 28692Spain

We describe the development of quinolylnitrones(Qns)as multifunctional ligands inhibiting cholinesterases(ChEs:acetylcholinesterase and butyrylcholinesterase—h BChE)and monoamine oxidases(hMAO-A/B)for the therapy of neurodegenerative diseases.We identified Qn 19,a simple,low molecular weight nitrone,that is readily synthesized from commercially available 8-hydroxyquinoline-2-carbaldehyde.Quinolylnitrone 19 has no typical pharmacophoric element to suggest ChE or MAO inhibition,yet unexpectedly showed potent inhibition of h BChE(IC50=1.06±0.31 nmol/L)and h MAO-B(IC_(50)=4.46±0.18μmol/L).The crystal structures of 19 with hBChE and hMAO-B provided the structural basis for potent binding,which was further studied by enzyme kinetics.Compound 19 acted as a free radical scavenger and biometal chelator,crossed the blood—brain barrier,was not cytotoxic,and showed neuroprotective properties in a 6-hydroxydopamine cell model of Parkinson's disease.In addition,in vivo studies showed the anti-amnesic effect of 19 in the scopolamine-induced mouse model of AD without adverse effects on motoric function and coordination.Importantly,chronic treatment of double transgenic APPswe-PS1δE9 mice with 19 reduced amyloid plaque load in the hippocampus and cortex of female mice,underscoring the disease-modifying effect of Qn 19.

关键词： Quinolylnitrone Butyrylcholinesterase Monoamine oxidase B Alzheimer's disease Multifunctional ligands 6-Hydroxydopamine model Passive avoidance task novel object recognition

文化浸入在旅游业中的应用研究 ——以文化浸入旅行社TripDeep为例

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文化浸入在旅游业中的应用研究 ——以文化浸入旅行社TripDeep为例

作者： julia nú(?)ez martínez 上海外国语大学

学位级别：硕士

本论文以一家文化浸入旅行社TripDeep为例,探究了文化浸入在旅游业中的应用。本研究结合了目前西班牙市场的两个社会趋势:客户体验和国家文化遗产。本研究的对象为一家浸入式旅行社,该旅行社的第一阶段重点为西班牙市场。TripDeep希望... 详细信息

本论文以一家文化浸入旅行社TripDeep为例,探究了文化浸入在旅游业中的应用。本研究结合了目前西班牙市场的两个社会趋势:客户体验和国家文化遗产。本研究的对象为一家浸入式旅行社,该旅行社的第一阶段重点为西班牙市场。TripDeep希望借助西班牙的历史、音乐、体育、习惯、建筑、美食等文化遗产,提供在西班牙旅行的多种可能性。TripDeep旅行社不会采用常规旅行社通常提供的巴士旅行或常规旅游路线,它的目标客户是希望能体验不同的旅行方式、享受特殊旅行体验、对西班牙特色感兴趣的人群。旅行项目将由西班牙当地传统行业的相关从业者提供,涉及内容包括:缝制传统服装、弹奏传统乐器或从事摘橄榄等。本项目的成功基于对其可以满足市场真实需求的预期。此外,目前业内没有任何一家机构能够提供类似的旅游服务。在这样一个消费者需求日益增长的行业,TripDeep将提供一项全新的浸入式体验。

关键词：文化浸入体验经济营销策略旅游业

Diabetic gastroenteropathy:An underdiagnosed complication

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World Journal of Diabetes 2021年第6期12卷 794-809页

作者： Marcio JoséConcepción Zavaleta Jhean Gabriel Gonzáles Yovera Diego martín Moreno Marreros Luciana del Pilar Rafael Robles Kely Roxana Palomino Taype Karen nohelly Soto Gálvez Luis Fernando Arriola Torres julia Cristina Coronado Arroyo Luis Alberto Concepción Urteaga Division of Endocrinology Hospital Nacional Guillermo Almenara IrigoyenLima 12590Peru Division of Gastroenterology Hospital Nacional Guillermo Almenara IrigoyenLima 12590Peru Division of Medicine Universidad Nacional de TrujilloTrujillo 13011Peru Division of Endocrinology Hospital Nacional Dos de MayoLima 150101Peru Division of Endocrinology Instituto de Neurología y Endocrinología AvanzadaAndahuaylas 03700Peru Clinical Management Unit Hospital Nacional Guillermo Almenara IrigoyenLima 12590Peru Division of neurology Instituto de Neurología y Endocrinología AvanzadaAndahuaylas 03700Peru Division of Obstetrics and Gynaecology Clínica VesalioLima 15036Peru Division of neumology Hospital Regional Docente de TrujilloTrujillo 13011Peru

This article is an extensive review that provides an update on the pathophysiology,symptoms,diagnosis,and treatment of diabetic gastroenteropathy.There is no reported prevalence,but it has been described that patients with type 1 diabetes have a cumulative incidence at 10 years of 5.2%,and type 2 patients,1%.Also,in the group of type 1 diabetes,it has been observed that women are more likely to present this condition(5.8%vs 3.5%).Many factors are associate with its development(e.g.,hyperglycemia,vagal dysfunction,loss of expression of neural nitric oxide synthase in the myenteric plexus,alterations in the Cajal interstitial cell network,and oxidative stress).Gastrointestinal discomfort could be perceived 70% higher in diabetic patients,describing that 25%of diabetic patients experience gastrointestinal symptoms.Diabetic enteropathy could affect any portion of the gastrointestinal tract,but esophageal alterations were described in more than 60% of diabetic patients,also 60% of them present constipation,and 20%,diarrhea.Gastric emptying scintigraphy is useful to evaluate gastroparesis,therefore,gastric retention of more than 60%at 2 h has a sensitivity of 100% and specificity of 20% for diagnosis;however,other studies such as breath tests,with a sensitivity of 89% and a specificity of 80%,or the endoscopic capsule contribute to the diagnosis.There is no cure;however,management must be multidisciplinary,focused on slowing the progression of diabetic gastroenteropathy,reducing symptoms,and restoring function;that includes nutritional recommendation,maintain glucose levels kept below 180 mg/dL,use of prokinetics,anti-emetics;nowadays,it has been special interest in surgical treatment,such as pyloroplasty,also gastric electrical stimulation appears to be another alternative.

关键词： Gastroenteropathy Gastroparesis Diabetes mellitus Complication Gastrointestinal disease Treatment

Validation of CFD-DEM simulation of a liquid-solid fluidized bed by dynamic analysis of time series

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Particuology 2022年第9期20卷 75-87页

作者： julia Picabea Mauricio Maestri Miryan Cassanello Gabriel Salierno Cataldo De Blasio María Angélica Cardona Daniel Hojman Héctor Somacal Departamento de Industrias Facultad de Ciencias Exactas y NaturalesUniversidad de Buenos AiresCiudad UniversitariaIntendente Güiraldes 2160C1428EGABuenos AiresArgentina COnICET-Universidad de Buenos Aires Instituto de Tecnología de Alimentos y Procesos Químicos-ITAPROQCiudad UniversitariaIntendente Güiraldes 2160 C1428EGABuenos AiresArgentina Faculty of Science and Engineering Abo Akademi UniversityRantakatu 265100 VaasaFinland Laboratorio de Diagnósticos por Radiaciones Dep.Física ExperimentalComisión Nacional de Energía AtómicaBKNA1650 San MartínBuenos AiresArgentina COnICET C1033AAJ Buenos AiresArgentina Escuela de Ciencia y Tecnología Universidad de San MartínBKNA 1650 San MartínBuenos AiresArgentina

Liquid-solid fluidized beds(LSFB)modeling validation is crucial for establishing design rules and monitor-ing tools.However,it generally relies on comparing global variables,which overlook dynamic features that influence reaction outputs.This work aims to implement time series analysis tools to compare Radioactive Particle Tracking data with a simulation consisting of Computational Fluid Dynamics cou-pled with Discrete-Element Method.Experiments have been performed in a pilot-scale LSFB of calcium alginate spheres fluidized with a calcium chloride solution.The Diks'test indicates that the simulation can capture the LSFB behavior.It also allows diagnosing flow regime transitions from the simulation.Trends of solid dispersion coefficients and mixing times predicted by the simulation are in good agreement with the experiments.

关键词： Liquid-solid fluidization CFD-DEM Dynamic comparison Radioactive particle tracking