72 results on '"Pineda JR"'
Search Results
2. Analyzing the Effectiveness of Property Developers' In-house-Developed Versus Outsourced Systems on Procurement Efficiency
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Beloy, Julianne Cyrose D., Garcia, Shirley D., Pigao, Kevin Jamir F., Rosauro C. Pineda Jr., Beloy, Julianne Cyrose D., Garcia, Shirley D., Pigao, Kevin Jamir F., and Rosauro C. Pineda Jr.
- Abstract
Digital solutions have greatly progressed the automation of procurement functions across industries, including real estate. This study focused on analyzing the effectiveness of in-house-developed applications compared to outsourced systems on the procurement efficiency of property developers. Regardless of the company size, procurement involves several steps to obtain the goods and services needed for the business. One of the distinct functions of the procurement department is to ensure that purchased materials, or services conform to specified requirements at the most economical but good quality and in favorable terms. Streamlining systems, procedures, and processes, overcoming operational challenges, and establishing a sound business culture with well-integrated solutions are the objectives of digitization. This research study aims to ascertain the efficacy of internally developed systems versus externally obtained software for procurement efficiency of real estate developers in Makati City, Philippines, with 65 respondents. The researchers aim to examine the respondents’ perception of the perceived usefulness and perceived ease of use of in-house-developed systems compared to outsourced applications in achieving procurement efficiency with consideration of the company size and users’ age group. The researchers made use of descriptive and explanatory research methods for the investigation of the significant relationship and differences between the two digital platforms. The results of the study show several significant implications. The demographic profile of the respondents plays a relevant role in the assessment of the effectiveness of internally developed software versus outsourcing for procurement efficiency. Distinct differences were observed in terms of perceived usefulness and perceived ease of use between in-house-developed systems and outsourced systems. The findings indicate that individuals who utilize outsourced systems tend to exhibit a greater inclin
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- 2023
3. EXPLORING CULTURAL FORMATION THROUGH COMMUNICATION PRACTICES IN EDUCATIONAL INSTITUTIONS: IDENTIFYING PRACTICES, OVERCOMING BARRIERS, AND IMPLEMENTING SOLUTIONS
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Florentino G. Pineda, Jr.
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Microbiology (medical) ,Immunology ,Immunology and Allergy - Abstract
The current paper focuses on the qualitative method used that examines the cultural formation in the educational institution, its practices, barriers, and solution. The use of qualitative research in this study reveals insights into how communication becomes an integral part of the culture-shaping process through its focus on the emerging themes and patterns developed over time. Among the methods used included a collection of notes and interviews from three generational participants; and an analysis of the Focus Discussion Group (FGD). FGD were classified on the nature of their inputs as indicated in the foreshadowed problems that seek to identify the characteristics of a culture-shaping process, experiences of communicators, and challenges encountered by members of the organizations in the aspect of behavior, satisfaction, and engagement. The obtained data demonstrate that organizational culture has a significant influence on the performance of the members. Many of the responses reflect the involvement of “cultured” individual perspectives that emerged from their daily work experiences and communication practices that leads to the formation of subgroups. Furthermore, the inclusion of the management, diversity of cultural backgrounds, and expectations also emerged. Based on the findings, the identified pieces of evidence in the approaches of both the management and members towards communicated rules policy have led to the formulation of a long-term sustainable adjustment in culture formation that mainly impacts motivation, communication, improving organizational values, decision-making, and solving conflicts. Article visualizations
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- 2023
4. SPEAKING ENGLISH POLICY: IMPACT ON THE ENGLISH LANGUAGE PROFICIENCY OF THE ESL
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Franzine Leighan V. Chee, Alexis Joyce S. Cruz, Joanna Marie R. Lorenzo, Bethel Grace C. Nicodemus, and Florentino G. Pineda, Jr.
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General Medicine - Abstract
Learning English for different purposes, especially in the workplace has drastically changed. English increases the chances of getting a good job in any local or multinational company. It is also the language of communication, it is used in the media and the internet community, so learning English is important for socializing and entertainment as well as work. It is essential for individuals and future professionals to have profound knowledge and understanding of the English language that is used in any respective field. The study was conducted to weigh up the English language proficiency skills of a selected private school in the City of Malolos, particularly the grade ten (10) students who implement the English Only Policy and another secondary government school in the same city of Bulacan who do not implement the English Only Policy. The impact and factors of the English-Only Policy on students were measured and identified. The researcher utilized an English proficiency test from Cambridge University as the research instrument, which was given to the 80 respondents. The study is comparative that utilized an independent t-test in analyzing the data gathered. The results showed that there is a significant difference in the English language proficiency skills of the students who come from schools that have an English-only policy and those students who come from a school that does not implement the said policy. The research recommends that the students be more engaged and motivated to increase their English language proficiency skills. The teachers should also motivate their students to not only use the English language but also encourage them to use their L1. Article visualizations
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- 2023
5. SITUATIONAL FACTORS: BASES FOR IMPROVING THE ATTITUDE AND MOTIVATION OF ESL LEARNERS’ SPEAKING SKILLS IN THE COLLEGE OF ARTS AND LETTERS
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Florentino G. Pineda, Jr. and Issachar A. Dela Cerna
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General Medicine - Abstract
This paper highlights the importance of enhancing the speaking skills among ESL freshmen in the College of Arts and Letters of Bulacan State University. The respondents in this study were Bachelor of Arts in Mass Communication Major in Broadcasting Sections A to D. Although this course requires oral communication proficiency for global competitiveness, only a few students participate actively in classroom discussions. Many of them lag behind in terms of speaking skills. The ability to speak English has become the norm in the country and around the world. Graduates who possess such a skill can have better opportunities locally or internationally compared with those who cannot speak fluently. Hence, the researchers looked into the role of attitude and motivation in enhancing speaking skills among the respondents in terms of the following: demographics, the attitude of students toward English, situational factors affecting the attitude of students toward English, the motivation of students in learning English, and students’ beliefs about learning English. The research instrument was administered to the respondents via Google Forms. The 32-item questionnaire was designed to determine the attitudes and motivation of ESL students toward learning English. Each of the respondents was scored from 1-5 on a Likert Scale. Through the use of the Pearson Correlation Coefficient, Fisher Z-test, and P-Value in testing the hypotheses, data were analyzed and interpreted. The Likert Scales show the participants had an incredibly positive attitude and behavior toward English in general. Among all motivation items, the top factors affecting students to learn more in English are the Student’s Practical Purpose, Correction of the Teacher during Class, Communication Focused Class Activities, and Positive Atmosphere during class. Based on the findings of the study, language teachers should take advantage of motivation to foster a positive attitude among the students when it comes to speaking skills through the use of authentic materials such as audio, video, printed, and softcopies. Factors such as activities, environment, and teachers’ attitudes should be the point of reference in determining which learning materials work best in enhancing the speaking skills of the students. Article visualizations
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- 2023
6. The addition of intravenous, high dose, bolus of methyl-prednisolone increases the early clinical response to oral corticosteroids in moderately active ulcerative colitis. Preliminary results of a prospective, controlled, multicentre, randomised, open-label study
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Moral, ED, Llao, J, Manosa, M, Martin-Arranz, E, Zabana, Y, Navarro-Llavat, M, Garcia-Planella, E, Busquets, D, Pineda, JR, Monfort, D, Gutierrez, A, Garcia-Alonso, FJ, Menchen, LA, and Villoria, A
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- 2022
7. ACCEPTABILITY OF E-COURSEWARE IN THE TEACHING OF ARTS: INPUTS TO ACTION PLAN TOWARDS DEPED’S COMPUTERIZATION PROGRAM
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Adulfo S. Amit, Reynaldo S. Pineda Jr, Adulfo S. Amit, and Reynaldo S. Pineda Jr
- Abstract
This study aimed to determine the Acceptability of e-Courseware in the Teaching of Arts: Inputs to Action Plan Towards DepEd’s Computerization in the Division of City Schools, Manila, that will provide teachers and learners with the 21st century skills which involve the Technological Pedagogical Content Knowledge (TPACK) framework attuned to the needs of the learners. The respondents of the study were selected Grade 3 teachers from Districts I – VI in the Division of City Schools, Manila. This study employed the quantitative descriptive method of research. Frequency and percentage, Weighted Mean and Test of Difference were used to answer the problem of the study. Based on the findings of the study, the respondents rated all the five indicators; content, pedagogy, usability, adaptability, design and layout as “Highly Acceptable”. In the light of the significant findings and conclusions of the study, the following recommendations are hereby offered: 1.) It is highly recommended that the eCourseware should be adopted by the Department of Education and utilized this Learning Management System (LMS) toward teaching arts subject among grade 3 learners in the country during and after pandemic time. 2.) A mixed-method design of research through focus group discussion including the stakeholders like administrators, parents and education technology specialists/experts can be conducted by future researcher/s towards enhancement of the e-Courseware material. 3.) Further validation, evaluation and enhancement of the eCourseware must be done in order to come up with exemplary, efficiency standards for learning and teaching art lessons. 4.) Valid and reliable technological, pedagogical, content knowledge research tool that can be used by the future researcher/s in assessing and modifying the content, pedagogy, usability, adaptability, layout and design. 5.) Create another version of eCourseware which can give more features to enhance the interest of the learners. 6.) Create an Act
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- 2021
8. Evolution After Anti-TNF Discontinuation in Patients With Inflammatory Bowel Disease: A Multicenter Long-Term Follow-Up Study
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Casanova MJ, Chaparro M, García-Sánchez V, Nantes O, Leo E, Rojas-Feria M, Jauregui-Amezaga A, García-López S, Huguet JM, Arguelles-Arias F, Aicart M, Marín-Jiménez I, Gómez-García M, Muñoz F, Esteve M, Bujanda L, Cortés X, Tosca J, Pineda JR, Mañosa M, Llaó J, Guardiola J, Pérez-Martínez I, Muñoz C, González-Lama Y, Hinojosa J, Vázquez JM, Martinez-Montiel MP, Rodríguez GE, Pajares R, García-Sepulcre MF, Hernández-Martínez A, Pérez-Calle JL, Beltrán B, Busquets D, Ramos L, Bermejo F, Barrio J, Barreiro-de Acosta M, Roncedo O, Calvet X, Hervías D, Gomollón F, Domínguez-Antonaya M, Alcaín G, Sicilia B, Dueñas C, Gutiérrez A, Lorente-Poyatos R, Domínguez M, Khorrami S, Taxonera C, Rodríguez-Pérez A, Ponferrada A, Van Domselaar M, Arias-Rivera ML, Merino O, Castro E, Marrero JM, Martín-Arranz M, Botella B, Fernández-Salazar L, Monfort D, Opio V, García-Herola A, Menacho M, Ramírez-de la Piscina P, Ceballos D, Almela P, Navarro-Llavat M, Robles-Alonso V, Vega-López AB, Moraleja I, Novella MT, Castaño-Milla C, Sánchez-Torres A, Benítez JM, Rodríguez C, Castro L, Garrido E, Domènech E, García-Planella E, and Gisbert JP
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Male ,Constriction, Pathologic ,Inflammatory bowel disease ,Gastroenterology ,Deprescriptions ,0302 clinical medicine ,Crohn Disease ,Recurrence ,Risk Factors ,Medicine ,Young adult ,Mesalamine ,Aged, 80 and over ,Incidence ,Incidence (epidemiology) ,Remission Induction ,Age Factors ,Middle Aged ,Antirheumatic Agents ,030220 oncology & carcinogenesis ,Retreatment ,Disease Progression ,Female ,030211 gastroenterology & hepatology ,Tumor necrosis factor alpha ,Adult ,medicine.medical_specialty ,Adolescent ,Drug-Related Side Effects and Adverse Reactions ,Colon ,Young Adult ,03 medical and health sciences ,Ileum ,Internal medicine ,Humans ,Immunologic Factors ,Colitis ,Aged ,Proportional Hazards Models ,Retrospective Studies ,Hepatology ,Tumor Necrosis Factor-alpha ,business.industry ,Proportional hazards model ,Adalimumab ,Retrospective cohort study ,Protective Factors ,Inflammatory Bowel Diseases ,medicine.disease ,Infliximab ,Discontinuation ,Methotrexate ,Colitis, Ulcerative ,business ,Follow-Up Studies - Abstract
OBJECTIVES: The aims of this study were to assess the risk of relapse after discontinuation of anti-tumor necrosis factor (anti-TNF) drugs in patients with inflammatory bowel disease (IBD), to identify the factors associated with relapse, and to evaluate the overcome after retreatment with the same anti-TNF in those who relapsed. METHODS: This was a retrospective, observational, multicenter study. IBD patients who had been treated with anti-TNFs and in whom these drugs were discontinued after clinical remission was achieved were included. RESULTS: A total of 1,055 patients were included. The incidence rate of relapse was 19% and 17% per patient-year in Crohn's disease and ulcerative colitis patients, respectively. In both Crohn's disease and ulcerative colitis patients in deep remission, the incidence rate of relapse was 19% per patient-year. The treatment with adalimumab vs. infliximab (hazard ratio (HR)=1.29; 95% confi dence interval (CI)= 1.01-1.66), elective discontinuation of anti-TNFs (HR=1.90; 95% CI= 1.07-3.37) or discontinuation because of adverse events (HR= 2.33; 95% CI= 1.27-2.02) vs. a top-down strategy, colonic localization (HR= 1.51; 95% CI= 1.13-2.02) vs. ileal, and stricturing behavior (HR= 1.5; 95% CI= 1.09-2.05) vs. inflammatory were associated with a higher risk of relapse in Crohn's disease patients, whereas treatment with immunomodulators after discontinuation (HR= 0.67; 95% CI= 0.51-0.87) and age (HR= 0.98; 95% CI= 0.97-0.99) were protective factors. None of the factors were predictive in ulcerative colitis patients. Retreatment of relapse with the same anti-TNF was effective (80% responded) and safe. CONCLUSIONS: The incidence rate of infl ammatory bowel disease relapse after anti-TNF discontinuation is relevant. Some predictive factors of relapse after anti-TNF withdrawal have been identifi ed. Retreatment with the same anti-TNF drug was effective and safe.
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- 2017
9. Modelo Analítico del Vuelo de Dispersión del Aquenio de Triplaris Caracasana Cham
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Ladera, Celso L., Pineda Jr, Pedro A., Alcalá, Gustavo, Ladera, Celso L., Pineda Jr, Pedro A., and Alcalá, Gustavo
- Abstract
Se presenta un modelo físico del movimiento vertical de dispersión de los aquenios (frutos alados) de Triplaris caracasana Cham, especie de árbol autóctono de la región Norte de Venezuela, y que crece en selvas tropicales de vientos alisios. Hemos encontrado que estos aquenios inician su “vuelo” de dispersión con un régimen transitorio no-lineal de rotación y traslación simultáneas, que luego es seguido por un régimen terminal. Nuestro modelo teórico del aquenio proporciona dos ecuaciones diferenciales no-lineales que representan con buena exactitud ambos regímenes de rotación y traslación de un espécimen real. Basado en formalismos de mecánica analítica, el modelo predice un descenso inicial con una rapidez que tiene dependencia temporal tangente-hiperbólica, y luego el régimen terminal con rapidez de traslación vertical y rapidez angular de rotación constantes. Los resultados experimentales, obtenidos mediante localización ultrasónica y estroboscopía electrónica, confirman la validez de nuestro modelo. En el régimen uniforme la rapidez de descenso alcanza entre 0,9 y 1,2 m/s, mientras que la rapidez angular alcanza un valor entre 95 y 125 rad/s. Esta sucesión de regímenes cinemáticos, no-lineal y lineal, para traslación y rotación, y los torques que actúan sobre el aquenio, permiten a Triplaris maximizar su proceso de dispersión
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- 2009
10. Organization of the gene for an invertebrate mitochondrial creatine kinase: comparisons with genes of higher forms and correlation of exon boundaries with functional domains
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Pineda Jr., Agustin O, primary and Ellington, W.Ross, additional
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- 2001
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11. Structural and functional implications of the amino acid sequences of dimeric, cytoplasmic and octameric mitochondrial creatine kinases from a protostome invertebrate.
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Pineda Jr., Agustin O. and Ellington, W. Ross
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CHAETOPTERUS , *CREATININE - Abstract
Studies the cDNA and deduced amino acid sequences of dimeric and octameric creatinine kinase (CK) from Chaetopterus variopedatus. Evolutionary pathway for CK; CK isoenzymes contained in Chaetopterus; Structure/function relationships of residues.
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- 1999
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12. HB-EGF activates EGFR to induce reactive neural stem cells in the mouse hippocampus after seizures.
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Pastor-Alonso O, Durá I, Bernardo-Castro S, Varea E, Muro-García T, Martín-Suárez S, Encinas-Pérez JM, and Pineda JR
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- Animals, Mice, Male, Disease Models, Animal, Gefitinib pharmacology, Epilepsy, Temporal Lobe metabolism, Cell Differentiation drug effects, Kainic Acid pharmacology, Mice, Inbred C57BL, ErbB Receptors metabolism, Neural Stem Cells metabolism, Neural Stem Cells drug effects, Hippocampus metabolism, Heparin-binding EGF-like Growth Factor metabolism, Seizures metabolism, Neurogenesis drug effects, Signal Transduction drug effects
- Abstract
Hippocampal seizures mimicking mesial temporal lobe epilepsy cause a profound disruption of the adult neurogenic niche in mice. Seizures provoke neural stem cells to switch to a reactive phenotype (reactive neural stem cells, React-NSCs) characterized by multibranched hypertrophic morphology, massive activation to enter mitosis, symmetric division, and final differentiation into reactive astrocytes. As a result, neurogenesis is chronically impaired. Here, using a mouse model of mesial temporal lobe epilepsy, we show that the epidermal growth factor receptor (EGFR) signaling pathway is key for the induction of React-NSCs and that its inhibition exerts a beneficial effect on the neurogenic niche. We show that during the initial days after the induction of seizures by a single intrahippocampal injection of kainic acid, a strong release of zinc and heparin-binding epidermal growth factor, both activators of the EGFR signaling pathway in neural stem cells, is produced. Administration of the EGFR inhibitor gefitinib, a chemotherapeutic in clinical phase IV, prevents the induction of React-NSCs and preserves neurogenesis., (© 2024 Pastor-Alonso et al.)
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- 2024
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13. Editorial: Tumor accommodation: the importance of the niche in neurological tumors.
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Azzarelli R, Gauthier LR, Pineda JR, and Marques-Torrejon MA
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Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
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- 2024
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14. Clinical and treatment outcomes of a second subcutaneous or intravenous anti-TNF in patients with ulcerative colitis treated with two consecutive anti-TNF agents: data from the ENEIDA registry.
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Calafat M, Torres P, Tosca-Cuquerella J, Sánchez-Aldehuelo R, Rivero M, Iborra M, González-Vivo M, Vera I, de Castro L, Bujanda L, Barreiro-de Acosta M, González-Muñoza C, Calvet X, Benítez JM, Llorente-Barrio M, Surís G, Cañete F, Arias-García L, Monfort D, Castaño-García A, Garcia-Alonso FJ, Huguet JM, Marín-Jímenez I, Lorente R, Martín-Cardona A, Ferrer JÁ, Camo P, Gisbert JP, Pajares R, Gomollón F, Castro-Poceiro J, Morales-Alvarado J, Llaó J, Rodríguez A, Rodríguez C, Pérez-Galindo P, Navarro M, Jiménez-García N, Carrillo-Palau M, Blázquez-Gómez I, Sesé E, Almela P, Ramírez de la Piscina P, Taxonera C, Rodríguez-Lago I, Cabrinety L, Vela M, Mínguez M, Mesonero F, García MJ, Aguas M, Márquez L, Silva Porto M, Pineda JR, García-Etxebarría K, Bertoletti F, Brunet E, Mañosa M, and Domènech E
- Abstract
Background: Infliximab seems to be the most efficacious of the three available anti-TNF agents for ulcerative colitis (UC) but little is known when it is used as the second anti-TNF., Objectives: To compare the clinical and treatment outcomes of a second subcutaneous or intravenous anti-TNF in UC patients., Design: Retrospective observational study., Methods: Patients from the ENEIDA registry treated consecutively with infliximab and a subcutaneous anti-TNF (or vice versa), naïve to other biological agents, were identified and grouped according to the administration route of the first anti-TNF into IVi (intravenous initially) or SCi (subcutaneous initially)., Results: Overall, 473 UC patients were included (330 IVi and 143 SCi). Clinical response at week 14 was 42.7% and 48.3% in the IVi and SCi groups (non-statistically significant), respectively. Clinical remission rates at week 52 were 32.8% and 31.4% in the IVi and SCi groups (nonsignificant differences), respectively. A propensity-matched score analysis showed a higher clinical response rate at week 14 in the SCi group and higher treatment persistence in the IVi group. Regarding long-term outcomes, dose escalation and discontinuation due to the primary failure of the first anti-TNF and more severe disease activity at the beginning of the second anti-TNF were inversely associated with clinical remission., Conclusion: The use of a second anti-TNF for UC seems to be reasonable in terms of efficacy, although it is particularly reduced in the case of the primary failure of the first anti-TNF. Whether the second anti-TNF is infliximab or subcutaneous does not seem to affect efficacy., Competing Interests: MC has served as a speaker for Takeda, Janssen, Faes Farma, and MSD; FC has served as a speaker or has received educational grants from Takeda, Janssen, MSD, and Ferring; MR has served as a speaker or has received research or educational funding or advisory fees from MSD, Abbvie, Pfizer, Takeda, and Janssen; MI has served as a speaker or has received research or educational funding or advisory fees from MSD, Janssen, Adacyte, and Takeda; LC has served as a speaker or has received research or educational funding or advisory fees from Abbvie, Dr. Falk Pharma, and Tillots Pharma; LB has served as a speaker or has received research or educational funding or advisory fees from Ikan Biotech; MBA has served as a speaker or has received research or educational funding or advisory fees from MSD, AbbVie, Janssen, Kern Pharma, Celltrion, Takeda, Gillead, Celgene, Pfizer, Sandoz, Biogen, Fresenius, Ferring, Faes Farma, Dr. Falk Pharma, Chiesi, Gebro Pharma, Adacyte, and Vifor Pharma; CG-M has received educational funding fees from AbbVie, Janssen, Pfizer, Ferring, Kern Pharma, Norgine, and Tillots Pharma; JMH has served as a speaker or has received research or educational funding or advisory fees from Merck Sharp & Dohme, Ferring, Abbvie, Janssen, Biogen, Sandoz, Kern Pharma, Faes Farma, Vifor Pharma, and Takeda; RL has served as a speaker or has received research or educational funding or advisory fees from MSD, Abbvie, Pfizer, Takeda, Janssen, and Dr. Falk; AM-C has received research or educational funding from Abbvie, Biogen, Ferring, Janssen, MSD, Takeda, Dr. Falk Pharma, and Tillotts; JPG has served as a speaker or has received research or educational funding or advisory fees from MSD, Abbvie, Pfizer, Kern Pharma, Biogen, Mylan, Takeda, Janssen, Roche, Sandoz, Celgene/Bristol Myers, Gilead/Galapagos, Lilly, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical, Norgine, and Vifor Pharma; FG has served as a speaker or has received research or educational funding or advisory fees from Faes-Farma, Galápagos, Takeda, Pfizer, Janssen, and Abbvie; PA has served as a speaker or has received research or educational funding or advisory fees from MSD, Abbvie, Takeda, Janssen, Gebro Pharma, Tillotts Pharma, and Biogen; CT has served as a speaker or has received research or educational funding or advisory fees from MSD, AbbVie, Pfizer, Takeda, Janssen, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Galapagos, and Tillots; IR-L has served as a speaker or has received research or educational funding or advisory fees from MSD, Pfizer, Abbvie, Takeda, Janssen, Tillotts Pharma, Kern, Celltrion, Roche, Ferring, Dr. Falk Pharma, Galapagos, Otsuka Pharmaceutical, and Adacyte; MM has served as a speaker and has received research or educational funding from MSD, AbbVie, Takeda, Janssen, Ferring, and Pfizer; ED has served as a speaker or has received research or educational funding or advisory fees from AbbVie, Adacyte Therapeutics, Biogen, Celltrion, Galapagos, Gilead, Janssen, Kern Pharma, MSD, Pfizer, Roche, Samsung, Takeda, and Tillots; MJG has served as a speaker or has received research or educational funding or advisory fees from Janssen, Pfizer, Abbvie, Takeda, Kern Pharma, and Ferring; MA has served as a speaker or has received research or educational funding or advisory fees from Faes, Ferring, and Janssen, and received educational grants from Janssen; JRP has served as a speaker or has received research or educational funding or advisory fees from MSD, AbbVie, and Tillots Pharma; FB received educational funding fees from AbbVie, Janssen, Pfizer, Ferring, Kern Pharma, Norgine, and Tillots Pharma. The remaining authors declared no conflicts of interest., (© The Author(s), 2024.)
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- 2024
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15. Hospital Outcomes of Spontaneous Coronary Artery Dissection With Concurrent Ventricular Arrhythmias.
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Tan MC, Yeo YH, Ang QX, Lee JZ, Yang EH, Mazzarelli JK, Pineda JE, Su W, and Lee KS
- Abstract
Background: While patients with spontaneous coronary artery dissection (SCAD) occasionally present with concurrent ventricular arrhythmias (VA), the impact of VA on in-hospital outcomes in the United States (US) is not well-established. This study aims to analyze in-hospital outcomes of patients with SCAD and concurrent VA and to determine the factors associated with VA occurrence in this high-risk population in the US., Methods: Using the Nationwide Readmissions Database, our study included patients age 18 years or older who had SCAD between 2017 and 2020. We categorized the cohort into 2 groups depending on the presence of VA during hospitalization. In-hospital outcomes were assessed between SCAD patients with VA and those without. Weighted analysis was performed. We analyzed the independent factors associated with VA occurring among SCAD patients through univariable and multivariable analyses., Results: Eight hundred seventy-seven SCAD patients were included in the study: 118 (13.5%) with VA and 759 (86.6%) without. SCAD patients with concurrent VA were associated with higher rates of early mortality (10.2% vs 2.0%; P < .01), prolonged index hospital stay (≥7 days) (33.1% vs 11.7%; P < .01), and non-home discharge (21.2% vs 5.9%; P < .01). The length of hospital stay was longer in the SCAD with concurrent VA group (7.39 days vs 3.58 days; P < .01), and the median cumulative cost of hospitalization was also higher in this group ($31,451 vs $13,802; P < .01). SCAD patients with concurrent VA had increased in-hospital adverse events: acute heart failure, cardiac arrest, cardiogenic shock, cerebral infarction, pulmonary edema, and acute kidney injury. In multivariable analysis, the independent factors associated with VA occurrence among SCAD patients were chronic liver disease (aOR, 3.42; 95% CI, 1.43-8.20; P < .01) and heart failure (aOR, 5.63; 95% CI, 3.36-9.42; P < .01)., Conclusions: Concurrence of VA among SCAD patients was associated with poorer in-hospital outcomes. Heart failure and chronic liver disease were the independent factors associated with VA occurrence in SCAD patients., (© 2023 The Author(s).)
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- 2023
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16. Notch and Wnt Signaling Modulation to Enhance DPSC Stemness and Therapeutic Potential.
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Uribe-Etxebarria V, Pineda JR, García-Gallastegi P, Agliano A, Unda F, and Ibarretxe G
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- Humans, Cell Differentiation physiology, Cells, Cultured, Epigenesis, Genetic, Dental Pulp, Wnt Signaling Pathway, Pluripotent Stem Cells metabolism
- Abstract
The Dental Pulp of permanent human teeth is home to stem cells with remarkable multilineage differentiation ability: human Dental Pulp Stem Cells (DPSCs). These cells display a very notorious expression of pluripotency core factors, and the ability to give rise to mature cell lineages belonging to the three embryonic layers. For these reasons, several researchers in the field have long considered human DPSCs as pluripotent-like cells. Notably, some signaling pathways such as Notch and Wnt contribute to maintaining the stemness of these cells through a complex network involving metabolic and epigenetic regulatory mechanisms. The use of recombinant proteins and selective pharmacological modulators of Notch and Wnt pathways, together with serum-free media and appropriate scaffolds that allow the maintenance of the non-differentiated state of hDPSC cultures could be an interesting approach to optimize the potency of these stem cells, without a need for genetic modification. In this review, we describe and integrate findings that shed light on the mechanisms responsible for stemness maintenance of hDPSCs, and how these are regulated by Notch/Wnt activation, drawing some interesting parallelisms with pluripotent stem cells. We summarize previous work on the stem cell field that includes interactions between epigenetics, metabolic regulations, and pluripotency core factor expression in hDPSCs and other stem cell types.
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- 2023
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17. Editorial: Tumor microenvironment in primary brain cancers.
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Niechi I and Pineda JR
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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- 2023
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18. Semisynthetic Abietic and Dehydroabietic Acid Derivatives and Triptoquinone Epimers Interfere with LPS-Triggered Activation of Dendritic Cells.
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Sierra JA, Gilchrist K, Tabares-Guevara JH, Betancur-Galvis L, Ramirez-Pineda JR, and González-Cardenete MA
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- Anti-Inflammatory Agents metabolism, Anti-Inflammatory Agents pharmacology, Cytokines metabolism, Dendritic Cells, Esters pharmacology, Interleukin-12 metabolism, Interleukin-6 metabolism, Lipopolysaccharides metabolism, Lipopolysaccharides pharmacology, Abietanes metabolism, Abietanes pharmacology, Tumor Necrosis Factor-alpha metabolism
- Abstract
Abietic acid (AA), dehydroabietic acid (DHA) and triptoquinones (TQs) are bioactive abietane-type diterpenoids, which are present in many edible vegetables and medicinal herbs with health-promoting properties. Evidence suggests that beneficial effects of diterpenes operate, at least in part, through effects on cells in the immune system. Dendritic cells (DCs) are a key type of leukocyte involved in the initiation and regulation of the immune/inflammatory response and natural or synthetic compounds that modulate DC functions could be potential anti-inflammatory/immunomodulatory agents. Herein, we report the screening of 23 known semisynthetic AA and DHA derivatives, and TQs, synthesized previously by us, in a multi-analyte DC-based assay that detects inhibition of pro-inflammatory cytokine production. Based on the magnitude of the inhibitory effect observed and the number of cytokines inhibited, a variety of activities among compounds were observed, ranging from inactive/weak to very potent inhibitors. Structurally, either alcohol or methyl ester substituents on ring A along with the introduction of aromaticity and oxidation in ring C in the abietane skeleton were found in compounds with higher inhibitory properties. Two DHA derivatives and two TQs exhibited a significant inhibition in all pro-inflammatory cytokines tested and were further investigated. The results confirmed their ability to inhibit, dose dependently, LPS-stimulated expression of the co-stimulatory molecules CD40 and/or CD86 and the production of the pro-inflammatory cytokines IL-1β, IL-6, IL-12 and TNFα. Our results demonstrate that DC maturation process can be targeted by semisynthetic DHA derivatives and TQ epimers and indicate the potential of these compounds as optimizable anti-inflammatory/immunomodulatory agents.
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- 2022
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19. Enhanced Adipogenic Differentiation of Human Dental Pulp Stem Cells in Enzymatically Decellularized Adipose Tissue Solid Foams.
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Garcia-Urkia N, Luzuriaga J, Uribe-Etxebarria V, Irastorza I, Fernandez-San-Argimiro FJ, Olalde B, Briz N, Unda F, Ibarretxe G, Madarieta I, and Pineda JR
- Abstract
Engineered 3D human adipose tissue models and the development of physiological human 3D in vitro models to test new therapeutic compounds and advance in the study of pathophysiological mechanisms of disease is still technically challenging and expensive. To reduce costs and develop new technologies to study human adipogenesis and stem cell differentiation in a controlled in vitro system, here we report the design, characterization, and validation of extracellular matrix (ECM)-based materials of decellularized human adipose tissue (hDAT) or bovine collagen-I (bCOL-I) for 3D adipogenic stem cell culture. We aimed at recapitulating the dynamics, composition, and structure of the native ECM to optimize the adipogenic differentiation of human mesenchymal stem cells. hDAT was obtained by a two-enzymatic step decellularization protocol and post-processed by freeze-drying to produce 3D solid foams. These solid foams were employed either as pure hDAT, or combined with bCOL-I in a 3:1 proportion, to recreate a microenvironment compatible with stem cell survival and differentiation. We sought to investigate the effect of the adipogenic inductive extracellular 3D-microenvironment on human multipotent dental pulp stem cells (hDPSCs). We found that solid foams supported hDPSC viability and proliferation. Incubation of hDPSCs with adipogenic medium in hDAT-based solid foams increased the expression of mature adipocyte LPL and c/EBP gene markers as determined by RT-qPCR, with respect to bCOL-I solid foams. Moreover, hDPSC capability to differentiate towards adipocytes was assessed by PPAR-γ immunostaining and Oil-red lipid droplet staining. We found out that both hDAT and mixed 3:1 hDAT-COL-I solid foams could support adipogenesis in 3D-hDPSC stem cell cultures significantly more efficiently than solid foams of bCOL-I, opening the possibility to obtain hDAT-based solid foams with customized properties. The combination of human-derived ECM biomaterials with synthetic proteins can, thus, be envisaged to reduce fabrication costs, thus facilitating the widespread use of autologous stem cells and biomaterials for personalized medicine.
- Published
- 2022
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20. A Mouse Model of Ulcerative Cutaneous Leishmaniasis by Leishmania (Viannia) panamensis to Investigate Infection, Pathogenesis, Immunity, and Therapeutics.
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Muñoz-Durango N, Gómez A, García-Valencia N, Roldán M, Ochoa M, Bautista-Erazo DE, and Ramírez-Pineda JR
- Abstract
A mouse model of cutaneous leishmaniasis (CL) by Leishmania (Viannia) panamensis (L(V)p) that reproduces the characteristics of the human disease remains elusive. Here we report the development of a CL model that uses a mouse-adapted L(V)p isolate to reproducibly induce a dermal disease with a remarkable similarity to human CL. BALB/c mice infected intradermally in the ear with 10
5 stationary UA-946 L(V)p promastigotes develop a progressive cutaneous disease that exhibits the typical ulcerated lesions with indurated borders observed in CL patients. Although most of parasites in the inoculum die within the first week of infection, the survivors vigorously multiply at the infection site during the following weeks, paralleling disease appearance and aggravation. Regional lymphadenopathy as well as lymphatic dissemination of parasites to draining lymph nodes (dLN) was evidenced early after infection. Viable parasites were also isolated from spleen at later timepoints indicating systemic parasitic dissemination, but, strikingly, no signs of systemic disease were observed. Increasing numbers of myeloid cells and T lymphocytes producing IFNγ and IL-4 were observed in the dLN as disease progressed. A mixed adaptive L(V)p -specific T cell-mediated response was induced, since ex vivo recall experiments using dLN cells and splenocytes revealed the production of type 1 (IFNγ, IL-2), type 2 (IL-4, IL-13), regulatory (IL-10), and inflammatory (GM-CSF, IL-3) cytokines. Humoral adaptive response was characterized by early production of IgG1- followed by IgG2a-type of L(V)p -specific antibodies. IFNγ/IL-4 and IgG2a/IgG1 ratios indicated that the initial non-protective Th2 response was redirected toward a protective Th1 response. In situ studies revealed a profuse recruitment of myeloid cells and of IFNγ- and IL-4-producing T lymphocytes to the site of infection, and the typical histopathological changes induced by dermotropic Leishmania species. Evidence that this model is suitable to investigate pharmacological and immunomodulatory interventions, as well as for antigen discovery and vaccine development, is also presented. Altogether, these results support the validity and utility of this novel mouse model to study the pathogenesis, immunity, and therapeutics of L(V)p infections., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Muñoz-Durango, Gómez, García-Valencia, Roldán, Ochoa, Bautista-Erazo and Ramírez-Pineda.)- Published
- 2022
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21. A Comparative Study of Cell Culture Conditions during Conversion from Primed to Naive Human Pluripotent Stem Cells.
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Romayor I, Herrera L, Burón M, Martin-Inaraja M, Prieto L, Etxaniz J, Inglés-Ferrándiz M, Pineda JR, and Eguizabal C
- Abstract
The successful reprogramming of human somatic cells into induced pluripotent stem cells (hiPSCs) represented a turning point in the stem cell research field, owing to their ability to differentiate into any cell type with fewer ethical issues than human embryonic stem cells (hESCs). In mice, PSCs are thought to exist in a naive state, the cell culture equivalent of the immature pre-implantation embryo, whereas in humans, PSCs are in a primed state, which is a more committed pluripotent state than a naive state. Recent studies have focused on capturing a similar cell stage in human cells. Given their earlier developmental stage and therefore lack of cell-of-origin epigenetic memory, these cells would be better candidates for further re-differentiation, use in disease modeling, regenerative medicine and drug discovery. In this study, we used primed hiPSCs and hESCs to evaluate the successful establishment and maintenance of a naive cell stage using three different naive-conversion media, both in the feeder and feeder-free cells conditions. In addition, we compared the directed differentiation capacity of primed and naive cells into the three germ layers and characterized these different cell stages with commonly used pluripotent and lineage-specific markers. Our results show that, in general, naive culture NHSM medium (in both feeder and feeder-free systems) confers greater hiPSCs and hESCs viability and the highest naive pluripotency markers expression. This medium also allows better cell differentiation cells toward endoderm and mesoderm.
- Published
- 2022
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22. Osteogenic differentiation of human dental pulp stem cells in decellularised adipose tissue solid foams.
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Luzuriaga J, García-Gallastegui P, García-Urkia N, Pineda JR, Irastorza I, Fernandez-San-Argimiro FJ, Briz N, Olalde B, Unda F, Madarieta I, and Ibarretxe G
- Subjects
- Adipose Tissue, Animals, Cell Differentiation, Cells, Cultured, Dental Pulp, Humans, Stem Cells, Swine, Tissue Engineering, Tissue Scaffolds, Collagen Type I, Osteogenesis
- Abstract
3D cell culture systems based on biological scaffold materials obtainable from both animal and human tissues constitute very interesting tools for cell therapy and personalised medicine applications. The white adipose tissue (AT) extracellular matrix (ECM) is a very promising biomaterial for tissue engineering due to its easy accessibility, malleability and proven biological activity. In the present study, human dental pulp stem cells (hDPSCs) were combined in vitro with ECM scaffolds from porcine and human decellularised adipose tissues (pDAT, hDAT) processed as 3D solid foams, to investigate their effects on the osteogenic differentiation capacity and bone matrix production of hDPSCs, compared to single-protein-based 3D solid foams of collagen type I and conventional 2D tissue-culture-treated polystyrene plates. pDAT solid foams supported the osteogenic differentiation of hDPSCs to similar levels to collagen type I, as assessed by alkaline phosphatase and alizarin red stainings, reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) and osteocalcin/bone gamma-carboxyglutamate protein (BGLAP) immunostaining. Interestingly, hDAT solid foams showed a markedly lower capacity to sustain hDPSC osteogenic differentiation and matrix calcification and a higher capacity to support adipogenesis, as assessed by RT-qPCR and oil red O staining. White ATs from both human and porcine origins are relatively abundant and available sources of raw material to obtain high quality ECM-derived biomedical products. These biomaterials could have promising applications in tissue engineering and personalised clinical therapy for the healing and regeneration of lesions involving not only a loss of calcified bone but also its associated soft non-calcified tissues.
- Published
- 2022
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23. Incidence of inflammatory bowel disease and phenotype at diagnosis in 2011: results of the Epi-IBD 2011 study in the Vigo area.
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Hernández V, de Castro ML, Salinas-Rojo M, Fernández A, Martínez-Ares D, Sanromán L, Pineda JR, Carmona A, Salgado-Álvarez C, Martínez-Cadilla J, Pereira S, García-Burriel JI, González-Portela C, Vázquez S, and Rodríguez-Prada JI
- Subjects
- Cohort Studies, Humans, Incidence, Phenotype, Prospective Studies, Colitis, Ulcerative diagnosis, Colitis, Ulcerative epidemiology, Crohn Disease diagnosis, Crohn Disease epidemiology, Inflammatory Bowel Diseases diagnosis, Inflammatory Bowel Diseases epidemiology
- Abstract
Objective: to validate the incidence of inflammatory bowel disease (IBD) reported in Vigo in 2010 within the Epi-IBD study, which was the highest incidence reported so far in Spain., Methods: an epidemiological, prospective, population-based inception cohort study. All incident cases of IBD living in the Vigo area at diagnosis from January 1 to December 31, 2011 were included., Results: one hundred patients were diagnosed (62 % men; median age, 43.27 years): 49 with ulcerative colitis (UC), 34 with Crohn's disease (CD), and 17 with IBD unclassified (IBDU). The incidence (per 100,000 inhabitants/year) was 17.56 (CD: 5.97; UC: 8.60; IBDU: 2.98), similar to that reported in 2010. The incidence in the non-pediatric population was 19.66 (CD: 6.89, UC: 9.52; IBDU: 3.04). CD and UC phenotype was similar in 2010 and 2011., Conclusion: this study supports the increased incidence of EII in the Vigo area reported in 2010.
- Published
- 2022
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24. shinyCurves, a shiny web application to analyse multisource qPCR amplification data: a COVID-19 case study.
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Olaechea-Lázaro S, García-Santisteban I, Pineda JR, Badiola I, Alonso S, Bilbao JR, and Fernandez-Jimenez N
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- Data Analysis, Humans, Pandemics, Real-Time Polymerase Chain Reaction, SARS-CoV-2, COVID-19
- Abstract
Background: Quantitative, reverse transcription PCR (qRT-PCR) is currently the gold-standard for SARS-CoV-2 detection and it is also used for detection of other virus. Manual data analysis of a small number of qRT-PCR plates per day is a relatively simple task, but automated, integrative strategies are needed if a laboratory is dealing with hundreds of plates per day, as is being the case in the COVID-19 pandemic., Results: Here we present shinyCurves, an online shiny-based, free software to analyze qRT-PCR amplification data from multi-plate and multi-platform formats. Our shiny application does not require any programming experience and is able to call samples Positive, Negative or Undetermined for viral infection according to a number of user-defined settings, apart from providing a complete set of melting and amplification curve plots for the visual inspection of results., Conclusions: shinyCurves is a flexible, integrative and user-friendly software that speeds-up the analysis of massive qRT-PCR data from different sources, with the possibility of automatically producing and evaluating melting and amplification curve plots., (© 2021. The Author(s).)
- Published
- 2021
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25. IL-10-Dependent Amelioration of Chronic Inflammatory Disease by Microdose Subcutaneous Delivery of a Prototypic Immunoregulatory Small Molecule.
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Tabares-Guevara JH, Jaramillo JC, Ospina-Quintero L, Piedrahíta-Ochoa CA, García-Valencia N, Bautista-Erazo DE, Caro-Gómez E, Covián C, Retamal-Díaz A, Duarte LF, González PA, Bueno SM, Riedel CA, Kalergis AM, and Ramírez-Pineda JR
- Subjects
- Animals, Apolipoproteins E physiology, Atherosclerosis prevention & control, Chronic Disease, Curcumin pharmacology, Lipids blood, Mice, Mice, Inbred C57BL, Neuroprotection, Curcumin administration & dosage, Immunomodulating Agents administration & dosage, Inflammation prevention & control, Interleukin-10 physiology
- Abstract
One of the interventional strategies to reestablish the immune effector/regulatory balance, that is typically altered in chronic inflammatory diseases (CID), is the reinforcement of endogenous immunomodulatory pathways as the one triggered by interleukin (IL)-10. In a recent work, we demonstrated that the subcutaneous (sc) administration of an IL-10/Treg-inducing small molecule-based formulation, using a repetitive microdose (REMID) treatment strategy to preferentially direct the effects to the regional immune system, delays the progression of atherosclerosis. Here we investigated whether the same approach using other IL-10-inducing small molecule, such as the safe, inexpensive, and widely available polyphenol curcumin, could induce a similar protective effect in two different CID models. We found that, in apolipoprotein E deficient mice, sc treatment with curcumin following the REMID strategy induced atheroprotection that was not consequence of its direct systemic lipid-modifying or antioxidant activity, but instead paralleled immunomodulatory effects, such as reduced proatherogenic IFNγ/TNFα-producing cells and increased atheroprotective FOXP3
+ Tregs and IL-10-producing dendritic and B cells. Remarkably, when a similar strategy was used in the neuroinflammatory model of experimental autoimmune encephalomyelitis (EAE), significant clinical and histopathological protective effects were evidenced, and these were related to an improved effector/regulatory cytokine balance in restimulated splenocytes. The essential role of curcumin-induced IL-10 for neuroprotection was confirmed by the complete abrogation of the clinical effects in IL-10-deficient mice. Finally, the translational therapeutic prospection of this strategy was evidenced by the neuroprotection observed in mice starting the treatment one week after disease triggering. Collectively, results demonstrate the power of a simple natural IL-10-inducing small molecule to tackle chronic inflammation, when its classical systemic and direct pharmacological view is shifted towards the targeting of regional immune cells, in order to rationally harness its immunopharmacological potential. This shift implies that many well-known IL-10-inducing small molecules could be easily reformulated and repurposed to develop safe, innovative, and accessible immune-based interventions for CID., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tabares-Guevara, Jaramillo, Ospina-Quintero, Piedrahíta-Ochoa, García-Valencia, Bautista-Erazo, Caro-Gómez, Covián, Retamal-Díaz, Duarte, González, Bueno, Riedel, Kalergis and Ramírez-Pineda.)- Published
- 2021
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26. Advances and Perspectives in Dental Pulp Stem Cell Based Neuroregeneration Therapies.
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Luzuriaga J, Polo Y, Pastor-Alonso O, Pardo-Rodríguez B, Larrañaga A, Unda F, Sarasua JR, Pineda JR, and Ibarretxe G
- Subjects
- Cell Differentiation, Extracellular Vesicles physiology, Humans, Neuroglia cytology, Stem Cell Transplantation, Stem Cells physiology, Tissue Engineering methods, Tissue Scaffolds, Cell- and Tissue-Based Therapy methods, Dental Pulp cytology, Nerve Regeneration physiology, Stem Cells cytology
- Abstract
Human dental pulp stem cells (hDPSCs) are some of the most promising stem cell types for regenerative therapies given their ability to grow in the absence of serum and their realistic possibility to be used in autologous grafts. In this review, we describe the particular advantages of hDPSCs for neuroregenerative cell therapies. We thoroughly discuss the knowledge about their embryonic origin and characteristics of their postnatal niche, as well as the current status of cell culture protocols to maximize their multilineage differentiation potential, highlighting some common issues when assessing neuronal differentiation fates of hDPSCs. We also review the recent progress on neuroprotective and immunomodulatory capacity of hDPSCs and their secreted extracellular vesicles, as well as their combination with scaffold materials to improve their functional integration on the injured central nervous system (CNS) and peripheral nervous system (PNS). Finally, we offer some perspectives on the current and possible future applications of hDPSCs in neuroregenerative cell therapies., Competing Interests: The authors declare no conflicts of interest.
- Published
- 2021
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27. Stem and Cancer Stem Cell Identities, Cellular Markers, Niche Environment and Response to Treatments to Unravel New Therapeutic Targets.
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Pineda JR, Badiola I, and Ibarretxe G
- Abstract
Adult stem cells are a partially quiescent cell population responsible for natural cell renewal and are found in many different regions of the body, including the brain, teeth, bones, muscles, skin, and diverse epithelia, such as the epidermal or intestinal epithelium, among others [...].
- Published
- 2021
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28. Is There Such a Thing as a Genuine Cancer Stem Cell Marker? Perspectives from the Gut, the Brain and the Dental Pulp.
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Crende O, García-Gallastegui P, Luzuriaga J, Badiola I, de la Hoz C, Unda F, Ibarretxe G, and Pineda JR
- Abstract
The conversion of healthy stem cells into cancer stem cells (CSCs) is believed to underlie tumor relapse after surgical removal and fuel tumor growth and invasiveness. CSCs often arise from the malignant transformation of resident multipotent stem cells, which are present in most human tissues. Some organs, such as the gut and the brain, can give rise to very aggressive types of cancers, contrary to the dental pulp, which is a tissue with a very remarkable resistance to oncogenesis. In this review, we focus on the similarities and differences between gut, brain and dental pulp stem cells and their related CSCs, placing a particular emphasis on both their shared and distinctive cell markers, including the expression of pluripotency core factors. We discuss some of their similarities and differences with regard to oncogenic signaling, telomerase activity and their intrinsic propensity to degenerate to CSCs. We also explore the characteristics of the events and mutations leading to malignant transformation in each case. Importantly, healthy dental pulp stem cells (DPSCs) share a great deal of features with many of the so far reported CSC phenotypes found in malignant neoplasms. However, there exist literally no reports about the contribution of DPSCs to malignant tumors. This raises the question about the particularities of the dental pulp and what specific barriers to malignancy might be present in the case of this tissue. These notable differences warrant further research to decipher the singular properties of DPSCs that make them resistant to transformation, and to unravel new therapeutic targets to treat deadly tumors.
- Published
- 2020
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29. Vasculogenesis from Human Dental Pulp Stem Cells Grown in Matrigel with Fully Defined Serum-Free Culture Media.
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Luzuriaga J, Irurzun J, Irastorza I, Unda F, Ibarretxe G, and Pineda JR
- Abstract
The generation of vasculature is one of the most important challenges in tissue engineering and regeneration. Human dental pulp stem cells (hDPSCs) are some of the most promising stem cell types to induce vasculogenesis and angiogenesis as they not only secrete vascular endothelial growth factor (VEGF) but can also differentiate in vitro into both endotheliocytes and pericytes in serum-free culture media. Moreover, hDPSCs can generate complete blood vessels containing both endothelial and mural layers in vivo, upon transplantation into the adult brain. However, many of the serum free media employed for the growth of hDPSCs contain supplements of an undisclosed composition. This generates uncertainty as to which of its precise components are necessary and which are dispensable for the vascular differentiation of hDPSCs, and also hinders the transfer of basic research findings to clinical cell therapy. In this work, we designed and tested new endothelial differentiation media with a fully defined composition using standard basal culture media supplemented with a mixture of B27, heparin and growth factors, including VEGF-A165 at different concentrations. We also optimized an in vitro Matrigel assay to characterize both the ability of hDPSCs to differentiate to vascular cells and their capacity to generate vascular tubules in 3D cultures. The description of a fully defined serum-free culture medium for the induction of vasculogenesis using human adult stem cells highlights its potential as a relevant innovation for tissue engineering applications. In conclusion, we achieved efficient vasculogenesis starting from hDPSCs using serum-free culture media with a fully defined composition, which is applicable for human cell therapy purposes.
- Published
- 2020
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30. The HIF1α/JMY pathway promotes glioblastoma stem-like cell invasiveness after irradiation.
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Gauthier LR, Saati M, Bensalah-Pigeon H, Ben M'Barek K, Gitton-Quent O, Bertrand R, Busso D, Mouthon MA, Collura A, Junier MP, Chneiweiss H, Pineda JR, and Boussin FD
- Subjects
- Cell Line, Tumor, Cell Movement genetics, Cell Movement radiation effects, Cell Nucleus metabolism, Cell Nucleus radiation effects, Cytoplasm metabolism, Cytoplasm radiation effects, Humans, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Nuclear Proteins genetics, Radiation, Ionizing, Signal Transduction genetics, Signal Transduction radiation effects, Trans-Activators genetics, Glioblastoma metabolism, Glioblastoma pathology, Glioma metabolism, Glioma pathology, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Nuclear Proteins metabolism, Trans-Activators metabolism
- Abstract
Human glioblastoma (GBM) is the most common primary malignant brain tumor. A minor subpopulation of cancer cells, known as glioma stem-like cells (GSCs), are thought to play a major role in tumor relapse due to their stem cell-like properties, their high resistance to conventional treatments and their high invasion capacity. We show that ionizing radiation specifically enhances the motility and invasiveness of human GSCs through the stabilization and nuclear accumulation of the hypoxia-inducible factor 1α (HIF1α), which in turn transcriptionally activates the Junction-mediating and regulatory protein (JMY). Finally, JMY accumulates in the cytoplasm where it stimulates GSC migration via its actin nucleation-promoting activity. Targeting JMY could thus open the way to the development of new therapeutic strategies to improve the efficacy of radiotherapy and prevent glioma recurrence.
- Published
- 2020
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31. Reformulating Small Molecules for Cardiovascular Disease Immune Intervention: Low-Dose Combined Vitamin D/Dexamethasone Promotes IL-10 Production and Atheroprotection in Dyslipidemic Mice.
- Author
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Ospina-Quintero L, Jaramillo JC, Tabares-Guevara JH, and Ramírez-Pineda JR
- Subjects
- Animals, Apolipoproteins E deficiency, CD8-Positive T-Lymphocytes metabolism, Cardiovascular Diseases metabolism, Interferon-gamma metabolism, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, T-Lymphocytes, Regulatory metabolism, Atherosclerosis prevention & control, Cardiovascular Diseases immunology, Cardiovascular Diseases therapy, Dexamethasone pharmacology, Interleukin-10 metabolism, Vitamin D pharmacology
- Abstract
The targeting of proinflammatory pathways has a prophylactic and therapeutic potential on atherosclerotic cardiovascular diseases (CVD). An alternative/complementary strategy is the promotion of endogenous atheroprotective mechanisms that are impaired during atherosclerosis progression, such as the activity of tolerogenic dendritic cells (tolDC) and regulatory T cells (Treg). There is a need to develop novel low cost, safe and effective tolDC/Treg-inducing formulations that are atheroprotective and that can be of easy translation into clinical settings. We found that apolipoprotein E-deficient (ApoE
-/- ) mice treated with a low-dose combined formulation of Vitamin D and Dexamethasone (VitD/Dexa), delivered repetitively and subcutaneously (sc) promoted interleukin-10 (IL-10) production by dendritic cells and other antigen presenting cells in the lymph nodes draining the site of injection and the spleens. Expectedly, the treatment also increased the numbers of IL-10-producing CD4+ T cells. Concomitantly, the frequency of IFNγ-producing CD4+ and CD8+ T cells in the spleen, and the IFNγ response of splenocytes to polyclonal stimulation ex vivo were lower after VitD/Dexa treatment, indicating a reduced proatherogenic Th1 response. Interestingly, VitD/Dexa-treated mice had smaller atherosclerotic lesions, with reduced lipid content and lower inflammatory infiltrate of macrophages and T cells in the aortic root. No hypolipidemic or antioxidant effect could be detected, suggesting that a dominantly immunomodulatory mechanism of atheroprotection was engaged under the low-dose sc VitD/Dexa conditions used. Finally, no evidence of clinical, biochemical or immune toxicity was observed in treated ApoE-/- mice and, most importantly, C57BL/6 mice latently infected with Leishmania parasites and treated with an identical VitD/Dexa dose/scheme showed no clinical or microbiological signs of disease reactivation, suggesting the absence of general immunosuppression. Altogether, these results indicate that a non-toxic, non-immunosuppressive, low-dose of VitD/Dexa, administered subcutaneously and repetitively, exerts atheroprotective effects in dyslipidemic mice, apparently due to the induction of an IL-10-producing network of lymphoid and myeloid immune cells. These well known, widely available, and inexpensive small molecules can be easily co-formulated into a simple and accessible agent with a potential use as a prophylactic or therapeutic immune intervention for CVD and other chronic inflammatory diseases., (Copyright © 2020 Ospina-Quintero, Jaramillo, Tabares-Guevara and Ramírez-Pineda.)- Published
- 2020
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32. Serjanic Acid Improves Immunometabolic Markers in a Diet-Induced Obesity Mouse Model.
- Author
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Gutiérrez G, Giraldo-Dávila D, Combariza MY, Holzgrabe U, Tabares-Guevara JH, Ramírez-Pineda JR, Acín S, Muñoz DL, Montoya G, and Balcazar N
- Subjects
- Adipose Tissue metabolism, Animals, Body Weight drug effects, Carbohydrate Metabolism drug effects, Diet, High-Fat, Disease Models, Animal, Gene Expression Regulation drug effects, Insulin Secretion drug effects, Liver drug effects, Liver pathology, Mice, Obesity blood, Obesity drug therapy, Organ Size drug effects, Triterpenes chemistry, Triterpenes isolation & purification, Triterpenes pharmacology, Biomarkers metabolism, Obesity immunology, Obesity metabolism, Triterpenes therapeutic use
- Abstract
Plant extracts from Cecropia genus have been used by Latin-American traditional medicine to treat metabolic disorders and diabetes. Previous reports have shown that roots of Cecropia telenitida that contains serjanic acid as one of the most prominent and representative pentacyclic triterpenes. The study aimed to isolate serjanic acid and evaluate its effect in a prediabetic murine model by oral administration. A semi-pilot scale extraction was established and serjanic acid purification was followed using direct MALDI-TOF analysis. A diet induced obesity mouse model was used to determine the impact of serjanic acid over selected immunometabolic markers. Mice treated with serjanic acid showed decreased levels of cholesterol and triacylglycerols, increased blood insulin levels, decreased fasting blood glucose and improved glucose tolerance, and insulin sensitivity. At transcriptional level, the reduction of inflammation markers related to adipocyte differentiation is reported., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
- Published
- 2020
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33. Human Dental Pulp Stem Cells Grown in Neurogenic Media Differentiate Into Endothelial Cells and Promote Neovasculogenesis in the Mouse Brain.
- Author
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Luzuriaga J, Pastor-Alonso O, Encinas JM, Unda F, Ibarretxe G, and Pineda JR
- Abstract
Dental pulp stem cells (DPSCs) have the capacity to give rise to cells with neuronal-like phenotypes, suggesting their use in brain cell therapies. In the present work, we wanted to address the phenotypic fate of adult genetically unmodified human DPSCs cultured in Neurocult
TM (Stem Cell Technologies), a cell culture medium without serum which can be alternatively supplemented for the expansion and/or differentiation of adult neural stem cells (NSCs). Our results show that non-genetically modified human adult DPSCs cultured with Neurocult NS-A proliferation supplement generated neurosphere-like dentospheres expressing the NSC markers Nestin and glial fibrillary acidic protein (GFAP), but also the vascular endothelial cell marker CD31. Remarkably, 1 month after intracranial graft into athymic nude mice, human CD31+/CD146+ and Nestin+ DPSC-derived cells were found tightly associated with both the endothelial and pericyte layers of brain vasculature, forming full blood vessels of human origin which showed an increased laminin staining. These results are the first demonstration that DPSC-derived cells contributed to the generation of neovasculature within brain tissue, and that Neurocult and other related serum-free cell culture media may constitute a fast and efficient way to obtain endothelial cells from human DPSCs.- Published
- 2019
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34. Green Coffee Extract Improves Cardiometabolic Parameters and Modulates Gut Microbiota in High-Fat-Diet-Fed ApoE -/- Mice.
- Author
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Caro-Gómez E, Sierra JA, Escobar JS, Álvarez-Quintero R, Naranjo M, Medina S, Velásquez-Mejía EP, Tabares-Guevara JH, Jaramillo JC, León-Varela YM, Muñoz-Durango K, and Ramírez-Pineda JR
- Subjects
- Adipose Tissue drug effects, Adipose Tissue microbiology, Animals, Apolipoproteins E genetics, Atherosclerosis, Energy Metabolism drug effects, Gene Expression Regulation drug effects, Insulin Resistance, Liver drug effects, Liver microbiology, Liver Cirrhosis prevention & control, Mice, Mice, Knockout, Non-alcoholic Fatty Liver Disease prevention & control, Plant Extracts chemistry, Apolipoproteins E metabolism, Coffea chemistry, Diet, High-Fat adverse effects, Gastrointestinal Microbiome drug effects, Plant Extracts pharmacology
- Abstract
Chlorogenic acids (CGA) are the most abundant phenolic compounds in green coffee beans and in the human diet and have been suggested to mitigate several cardiometabolic risk factors. Here, we aimed to evaluate the effect of a water-based standardized green coffee extract (GCE) on cardiometabolic parameters in ApoE
-/- mice and to explore the potential underlying mechanisms. Mice were fed an atherogenic diet without (vehicle) or with GCE by gavage (equivalent to 220 mg/kg of CGA) for 14 weeks. We assessed several metabolic, pathological, and inflammatory parameters and inferred gut microbiota composition, diversity, and functional potential. Although GCE did not reduce atherosclerotic lesion progression or plasma lipid levels, it induced important favorable changes. Specifically, improved metabolic parameters, including fasting glucose, insulin resistance, serum leptin, urinary catecholamines, and liver triglycerides, were observed. These changes were accompanied by reduced weight gain, decreased adiposity, lower inflammatory infiltrate in adipose tissue, and protection against liver damage. Interestingly, GCE also modulated hepatic IL-6 and total serum IgM and induced shifts in gut microbiota. Altogether, our results reveal the cooccurrence of these beneficial cardiometabolic effects in response to GCE in the same experimental model and suggest potential mediators and pathways involved.- Published
- 2019
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35. BDNF and NT3 Reprogram Human Ectomesenchymal Dental Pulp Stem Cells to Neurogenic and Gliogenic Neural Crest Progenitors Cultured in Serum-Free Medium.
- Author
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Luzuriaga J, Pineda JR, Irastorza I, Uribe-Etxebarria V, García-Gallastegui P, Encinas JM, Chamero P, Unda F, and Ibarretxe G
- Subjects
- Adolescent, Adult, CD57 Antigens metabolism, Cell Differentiation drug effects, Cell Proliferation drug effects, Cells, Cultured, Dental Pulp cytology, Humans, Ion Channels genetics, Ion Channels metabolism, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Neural Crest cytology, Neurogenesis drug effects, Neurotrophin 3, Receptor, trkA genetics, Receptor, trkA metabolism, Receptors, Nerve Growth Factor genetics, Receptors, Nerve Growth Factor metabolism, SOXB1 Transcription Factors genetics, SOXB1 Transcription Factors metabolism, Stem Cells cytology, Stem Cells metabolism, Young Adult, Brain-Derived Neurotrophic Factor pharmacology, Cellular Reprogramming drug effects, Culture Media, Serum-Free pharmacology, Nerve Growth Factors pharmacology
- Abstract
Background/aims: Human Dental Pulp Stem Cells (hDPSCs) are one of the most promising types of cells to regenerate nerve tissues. Standard DMEM+10% fetal bovine serum (FBS) culture medium allows a fast expansion of hDPSC as a surface-adherent cell monolayer. However, the use of FBS also compromises the clinical use of these protocols, and its longterm presence favors hDPSCs differentiation toward mesenchymal cell-derived lineages, at the expense of a reduced capability to generate neural cells. The objective of this work was to characterize the role of neurotrophin signaling on hDPSCs using a serum-free culture protocol, and to assess the neurogenic and gliogenic capacity of hDPSCs for future nerve tissue bioengineering and regeneration., Methods: We compared the different expression of neurotrophin receptors by RT-PCR, Q-PCR, and IF of hDPSCs cultured with different growth media in the presence or absence of serum. Moreover, we assessed the response of hDPSCs to stimulation of neurotransmitter receptors by live cell calcium imaging under these different media. Finally, we compared the osteogenic potential of hDPSCs by Alizarin red staining, and the differentiation to gliogenic/neurogenic fates by immunostaining for Schwann lineage and neuronal lineage markers. We tested a commercial serum-free medium designed for the growth of mesenchymal stem cells: StemPro MSCTM (STP)., Results: hDPSCs cultured in STP generated small non-adherent floating dentospheres that showed very low proliferation rates, in contrast to standard FBS-containing medium. We found that hDPSCs grown in STP conditions overexpressed neurotrophin receptor genes NTRK2 (TrkB) and NTRK3 (TrkC). Interestingly, the stimulation of these receptors by adding their respective ligands BDNF and NT-3 to STP medium enhanced the neural crest (NC) progenitor features of cultured hDPSCs. We observed a 10 to 100-fold increase of migratory NC cell markers HNK1 and P75
NTR , and a significant overexpression of pluripotency core factors SOX2, OCT4 and NANOG. Moreover, hDPSCs cultured in BDNF/NT-3 supplemented STP showed a largely increased potential to differentiate towards neuronal and Schwann glial lineage cells, assessed by positive immunostaining for DCX, NeuN and S100ß, p75NTR markers, respectively., Conclusion: Our results demonstrate that the use of BDNF and NT-3 combined with STP induced the partial reprogramming of ectomesenchymal hDPSCs to generate early NC progenitor cells, which are far more competent for neuronal and glial differentiation than hDPSCs grown in the presence of FBS., Competing Interests: The authors have no conflicts of interest to declare., (© Copyright by the Author(s). Published by Cell Physiol Biochem Press.)- Published
- 2019
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36. Genomic Analysis of Colombian Leishmania panamensis strains with different level of virulence.
- Author
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Urrea DA, Duitama J, Imamura H, Álzate JF, Gil J, Muñoz N, Villa JA, Dujardin JC, Ramirez-Pineda JR, and Triana-Chavez O
- Subjects
- Animals, Colombia, DNA Copy Number Variations, Female, Genome, Protozoan, Leishmania braziliensis genetics, Leishmaniasis, Mucocutaneous parasitology, Machine Learning, Mice, Inbred BALB C, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Leishmania guyanensis genetics, Leishmania guyanensis pathogenicity
- Abstract
The establishment of Leishmania infection in mammalian hosts and the subsequent manifestation of clinical symptoms require internalization into macrophages, immune evasion and parasite survival and replication. Although many of the genes involved in these processes have been described, the genetic and genomic variability associated to differences in virulence is largely unknown. Here we present the genomic variation of four Leishmania (Viannia) panamensis strains exhibiting different levels of virulence in BALB/c mice and its application to predict novel genes related to virulence. De novo DNA sequencing and assembly of the most virulent strain allowed comparative genomics analysis with sequenced L. (Viannia) panamensis and L. (Viannia) braziliensis strains, and showed important variations at intra and interspecific levels. Moreover, the mutation detection and a CNV search revealed both base and structural genomic variation within the species. Interestingly, we found differences in the copy number and protein diversity of some genes previously related to virulence. Several machine-learning approaches were applied to combine previous knowledge with features derived from genomic variation and predict a curated set of 66 novel genes related to virulence. These genes can be prioritized for validation experiments and could potentially become promising drug and immune targets for the development of novel prophylactic and therapeutic interventions.
- Published
- 2018
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37. Natural Biflavonoids Modulate Macrophage-Oxidized LDL Interaction In Vitro and Promote Atheroprotection In Vivo .
- Author
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Tabares-Guevara JH, Lara-Guzmán OJ, Londoño-Londoño JA, Sierra JA, León-Varela YM, Álvarez-Quintero RM, Osorio EJ, and Ramirez-Pineda JR
- Abstract
The accumulation of oxidized ApoB-100-containing lipoproteins in the vascular intima and its subsequent recognition by macrophages results in foam cell formation and inflammation, key events during atherosclerosis development. Agents targeting this process are considered potentially atheroprotective. Since natural biflavonoids exert antioxidant and anti-inflammatory effects, we evaluated the atheroprotective effect of biflavonoids obtained from the tropical fruit tree Garcinia madruno . To this end, the pure biflavonoid aglycones morelloflavone (Mo) and volkensiflavone (Vo), as well as the morelloflavone's glycoside fukugiside (Fu) were tested in vitro in primary macrophages, whereas a biflavonoid fraction with defined composition (85% Mo, 10% Vo, and 5% Amentoflavone) was tested in vitro and in vivo . All biflavonoid preparations were potent reactive oxygen species (ROS) scavengers in the oxygen radical absorbance capacity assay, and most importantly, protected low-density lipoprotein particle from both lipid and protein oxidation. In biflavonoid-treated macrophages, the surface expression of the oxidized LDL (oxLDL) receptor CD36 was significantly lower than in vehicle-treated macrophages. Uptake of fluorescently labeled oxLDL and cholesterol accumulation were also attenuated in biflavonoid-treated macrophages and followed a pattern that paralleled that of CD36 surface expression. Fu and Vo inhibited oxLDL-induced ROS production and interleukin (IL)-6 secretion, respectively, whereas all aglycones, but not the glucoside Fu, inhibited the secretion of one or more of the cytokines IL-1β, IL-12p70, and monocyte chemotactic protein-1 (MCP-1) in lipopolysaccharide (LPS)-stimulated macrophages. Interestingly, in macrophages primed with low-dose LPS and stimulated with cholesterol crystals, IL-1β secretion was significantly and comparably inhibited by all biflavonoid preparations. Intraperitoneal administration of the defined biflavonoid fraction into ApoE
-/- mice was atheroprotective, as evidenced by the reduction of the atheromatous lesion size and the density of T cells and macrophages infiltrating the aortic root; moreover, this treatment also lowered the circulating levels of cholesterol and the lipid peroxidation product malondialdehyde. These results reveal the potent atheroprotective effects exerted by biflavonoids on key events of the oxLDL-macrophage interphase: (i) atheroligand formation, (ii) atheroreceptor expression, (iii) foam cell transformation, and (iv) prooxidant/proinflammatory macrophage response. Furthermore, our results also evidence the antioxidant, anti-inflammatory, hypolipemiant, and atheroprotective effects of Garcinia madruno 's biflavonoids in vivo .- Published
- 2017
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38. Assessing medication adherence in inflammatory bowel diseases. A comparison between a self-administered scale and a pharmacy refill index.
- Author
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de Castro ML, Sanromán L, Martín A, Figueira M, Martínez N, Hernández V, Del Campo V, Pineda JR, Martínez-Cadilla J, Pereira S, and Rodríguez Prada JI
- Subjects
- Adult, Age Factors, Aged, Colitis, Ulcerative drug therapy, Crohn Disease drug therapy, Female, Humans, Male, Middle Aged, Reproducibility of Results, Surveys and Questionnaires, Young Adult, Drug Prescriptions statistics & numerical data, Inflammatory Bowel Diseases drug therapy, Medication Adherence statistics & numerical data, Pharmacies statistics & numerical data, Self Report
- Abstract
Background: Medication non-adherence in inflammatory bowel disease (IBD) has a negative impact on disease outcome. Different tools have been proposed to assess non-adherence. We aimed to compare a self-administered scale and a pharmacy refill index as a reliable measure of medication adherence and to determine what factors are related to adherence., Methods: Consecutive non-active IBD outpatients were asked to fill in the self-reported Morisky Medication Adherence Scale (MMAS-8) and the Beliefs about Medication Questionnaire (BMQ). Pharmacy refill data were reviewed from the previous three or six months and the medication possession ratio (MPR) was calculated. Non-adherence was defined as MMAS-8 scores < 6 or MPR < 0.8., Results: Two-hundred and three patients were enrolled (60% ulcerative colitis, 40% Crohn's disease); 51% were men, and the mean age was 46.3 (14) years. Seventy-four per cent of patients were on monotherapy and 26% on combination therapy; altogether, 65% received mesalazine, 46% thiopurines and 16% anti-tumor necrosis factor alfa. Non-adherence rate assessed by MPR was 37% and 22.4% by MMAS-8. Receiver operator curve analysis using a MMAS-8 cut-off of six gave an area under the curve of 0.6 (95% CI 0.5-0.7), p = 0.001. This score had an 85% sensitivity and 34% specificity to predict medication non-adherence, with negative and positive predictive values of 57% and 70% respectively. High scores in the BMQ potential for harm of medication were significantly associated with MPR non-adherence (p = 0.01)., Conclusion: The accuracy of MMAS-8 to identify medication non-adherence in inactive IBD outpatients in our setting is poor due to a low specificity and a negative predictive value. Psychosocial factors such as beliefs about medication seem to be related to IBD non-adherence.
- Published
- 2017
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39. Opposite effects of GCN5 and PCAF knockdowns on the alternative mechanism of telomere maintenance.
- Author
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Jeitany M, Bakhos-Douaihy D, Silvestre DC, Pineda JR, Ugolin N, Moussa A, Gauthier LR, Busso D, Junier MP, Chneiweiss H, Chevillard S, Desmaze C, and Boussin FD
- Subjects
- Cell Cycle genetics, Cell Line, Tumor, Cell Proliferation, Gene Expression, Gene Knockdown Techniques, Genomic Instability, Humans, Intranuclear Inclusion Bodies genetics, Intranuclear Inclusion Bodies metabolism, Leukemia, Promyelocytic, Acute genetics, Leukemia, Promyelocytic, Acute metabolism, Leukemia, Promyelocytic, Acute pathology, Protein Binding, Sister Chromatid Exchange, Translocation, Genetic, Genetic Association Studies, Telomere genetics, Telomere Homeostasis genetics, p300-CBP Transcription Factors genetics
- Abstract
Cancer cells can use a telomerase-independent mechanism, known as alternative lengthening of telomeres (ALT), to elongate their telomeres. General control non-derepressible 5 (GCN5) and P300/CBP-associated factor (PCAF) are two homologous acetyltransferases that are mutually exclusive subunits in SAGA-like complexes. Here, we reveal that down regulation of GCN5 and PCAF had differential effects on some phenotypic characteristics of ALT cells. Our results suggest that GCN5 is present at telomeres and opposes telomere recombination, in contrast to PCAF that may indirectly favour them in ALT cells.
- Published
- 2017
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40. Increase of Frequency and Modulation of Phenotype of Regulatory T Cells by Atorvastatin Is Associated with Decreased Lung Inflammatory Cell Infiltration in a Murine Model of Acute Allergic Asthma.
- Author
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Blanquiceth Y, Rodríguez-Perea AL, Tabares Guevara JH, Correa LA, Sánchez MD, Ramírez-Pineda JR, and Velilla PA
- Abstract
Regulatory T cells (Tregs) play an important role by controlling allergic inflammation of airways. Recently, it has been shown that statins have immunomodulatory properties, probably mediated by their effects on Tregs. Therefore, we evaluated the in vivo effect of atorvastatin (ATV) on Tregs and its association with the inflammatory process in a model of allergic asthma. BALB/c mice were sensitized with ovalbumin (OVA) and then challenged with intranasal OVA. ATV (40 mg/kg) was delivered by daily intraperitoneal injection for 7 or 15 days before each OVA challenge. ATV treatment for 7 days increased the frequency of Tregs in mediastinal lymph nodes (MLN) and the interleukin (IL)-10 in lungs. After 15 days of treatment, ATV increased the percentage of glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR+) and programmed cell death protein 1 (PD-1+) Tregs in the lung, without enhancing their suppressive activity, but also increased the percentage of conventional T cells expressing GITR+, PD1+, and OX-40 (tumor necrosis factor receptor superfamily member 4). Although no significant changes were observed in the number of inflammatory cells in the bronchoalveolar lavage (BAL), OVA-specific immunoglobulin E in the serum, and type 2 helper (Th2) cytokines in the lungs, there was a significant decrease of peribronchial inflammation that negatively correlated with the Tregs in MLN and the concentration of IL-10 in the lung. These results suggest that ATV has an immunomodulatory role possibly mediated by their effects on Tregs, which could contribute to the control of inflammation during allergic asthma. Further studies are necessary to elucidate the contribution of Treg to immunomodulatory action of statins in the context of allergic asthma.
- Published
- 2016
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41. Data in support of dyslipidemia-associated alterations in B cell subpopulations frequency and phenotype during experimental atherosclerosis.
- Author
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Rincón-Arévalo H, Castaño D, Villa-Pulgarín J, Rojas M, Vásquez G, Correa LA, Ramírez-Pineda JR, and Yassin LM
- Abstract
Cardiovascular diseases are the most common cause of death in the world, atherosclerosis being its main underlying disease. Information about the role of B cells during atherosclerotic process is scarce, but both proatherogenic and atheroprotective properties have been described in the immunopathology of this disease. Frequency and phenotype of B cell subpopulations were studied in wild type and apolipoprotein-E-deficient (apoE (-/-) ) mice fed or not with high-fat diet (HFD), by flow cytometry. Here, we provide the information about the materials, methods, analysis and additional information related to our study published in Atherosclerosis (DOI: 10.1016/j.atherosclerosis.2015.12.022, article reference: ATH14410) [1]. The data contained in this article shows and supports that mice with advanced atherosclerosis have a variety of alterations in frequency and phenotype of B cell subsets, most of which associated with dyslipidemia.
- Published
- 2016
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42. The Contradictory Effects of Neuronal Hyperexcitation on Adult Hippocampal Neurogenesis.
- Author
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Pineda JR and Encinas JM
- Abstract
Adult hippocampal neurogenesis is a highly plastic process that responds swiftly to neuronal activity. Adult hippocampal neurogenesis can be regulated at the level of neural stem cell recruitment and activation, progenitor proliferation, as well as newborn cell survival and differentiation. An "excitation-neurogenesis" rule was proposed after the demonstration of the capability of cultured neural stem and progenitor cells to intrinsically sense neuronal excitatory activity. In vivo, this property has remained elusive although recently the direct response of neural stem cells to GABA in the hippocampus via GABAA receptors has evidenced a mechanism for a direct talk between neurons and neural stem cells. As it is pro-neurogenic, the effect of excitatory neuronal activity has been generally considered beneficial. But what happens in situations of neuronal hyperactivity in which neurogenesis can be dramatically boosted? In animal models, electroconvulsive shock markedly increases neurogenesis. On the contrary, in epilepsy rodent models, seizures induce the generation of misplaced neurons with abnormal morphological and electrophysiological properties, namely aberrant neurogenesis. We will herein discuss what is known about the mechanisms of influence of neurons on neural stem cells, as well as the severe effects of neuronal hyperexcitation on hippocampal neurogenesis.
- Published
- 2016
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43. Encephalitozoon intestinalis Inhibits Dendritic Cell Differentiation through an IL-6-Dependent Mechanism.
- Author
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Bernal CE, Zorro MM, Sierra J, Gilchrist K, Botero JH, Baena A, and Ramirez-Pineda JR
- Subjects
- Animals, B7-2 Antigen biosynthesis, CD4-Positive T-Lymphocytes immunology, CD40 Antigens biosynthesis, CD8-Positive T-Lymphocytes immunology, Cell Differentiation immunology, Cells, Cultured, Encephalitozoonosis microbiology, Interferon-gamma immunology, Interferon-gamma metabolism, Interleukin-12 Subunit p35 immunology, Lymphocyte Activation immunology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Spores, Bacterial immunology, Dendritic Cells cytology, Dendritic Cells immunology, Encephalitozoon immunology, Encephalitozoonosis immunology, Immune Evasion immunology, Interleukin-6 immunology
- Abstract
Microsporidia are a group of intracellular pathogens causing self-limited and severe diseases in immunocompetent and immunocompromised individuals, respectively. A cellular type 1 adaptive response, mediated by IL-12, IFNγ, CD4+, and CD8+ T cells has been shown to be essential for host resistance, and dendritic cells (DC) play a key role at eliciting anti-microsporidial immunity. We investigated the in vitro response of DC and DC precursors/progenitors to infection with Encephalitozoon intestinalis (Ei), a common agent of human microsporidosis. Ei-exposed DC cultures up-regulated the surface expression of MHC class II and the costimulatory molecules CD86 and CD40, only when high loads of spores were used. A vigorous secretion of IL-6 but not of IL-1β or IL-12p70 was also observed in these cultures. Ei-exposed DC cultures consisted of immature infected and mature bystander DC, as assessed by MHC class II and costimulatory molecules expression, suggesting that intracellular Ei spores deliver inhibitory signals in DC. Moreover, Ei selectively inhibited the secretion of IL-12p70 in LPS-stimulated DC. Whereas Ei-exposed DC promoted allogeneic naïve T cell proliferation and IL-2 and IFNγ secretion in DC-CD4+ T cell co-cultures, separated co-cultures with bystander or infected DCs showed stimulation or inhibition of IFNγ secretion, respectively. When DC precursors/progenitors were exposed to Ei spores, a significant inhibition of DC differentiation was observed without shifting the development toward cells phenotypically or functionally compatible with myeloid-derived suppressor cells. Neutralization experiments demonstrated that this inhibitory effect is IL-6-dependent. Altogether this investigation reveals a novel potential mechanism of immune escape of microsporidian parasites through the modulation of DC differentiation and maturation.
- Published
- 2016
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44. TGFβ lengthens the G1 phase of stem cells in aged mouse brain.
- Author
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Daynac M, Pineda JR, Chicheportiche A, Gauthier LR, Morizur L, Boussin FD, and Mouthon MA
- Subjects
- Animals, Cell Proliferation physiology, Mice, Inbred C57BL, Stem Cell Niche physiology, Aging physiology, Brain cytology, Cell Differentiation physiology, G1 Phase genetics, Neurogenesis physiology, Stem Cells cytology, Transforming Growth Factor beta metabolism
- Abstract
Neurogenesis decreases during aging causing a progressive cognitive decline but it is still controversial whether proliferation defects in neurogenic niches result from a loss of neural stem cells or from an impairment of their progression through the cell cycle. Using an accurate fluorescence-activated cell sorting technique, we show that the pool of neural stem cells is maintained in the subventricular zone of middle-aged mice while they have a reduced proliferative potential eventually leading to the subsequent decrease of their progeny. In addition, we demonstrate that the G1 phase is lengthened during aging specifically in activated stem cells, but not in transit-amplifying cells, and directly impacts on neurogenesis. Finally, we report that inhibition of TGFβ signaling restores cell cycle progression defects in stem cells. Our data highlight the significance of cell cycle dysregulation in stem cells in the aged brain and provide an attractive foundation for the development of anti-TGFβ regenerative therapies based on stimulating endogenous neural stem cells., (© 2014 AlphaMed Press.)
- Published
- 2014
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45. Safety and effectiveness of gastric balloons associated with hypocaloric diet for the treatment of obesity.
- Author
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de Castro ML, Morales MJ, Martínez-Olmos MA, Pineda JR, Cid L, Estévez P, del-Campo V, and Rodríguez-Prada JI
- Subjects
- Adolescent, Adult, Aged, Cohort Studies, Female, Humans, Male, Middle Aged, Obesity diet therapy, Prospective Studies, Safety, Treatment Outcome, Young Adult, Diet, Reducing adverse effects, Gastric Balloon adverse effects, Obesity therapy
- Abstract
Introduction: intragastric balloons provide early satiety and thereby induce short-term weight loss. The aim of this study was to evaluate safety and short and medium-term effectiveness of gastric balloons associated to hypocaloric diet in obesity., Material and Methods: from May 2004 to June 2011 91 obese patients, body mass index (BMI) 45.2 +/- 7.2 kg/m2 were prospectively followed after endoscopic implantation of a gastric balloon associated to restricted diet. Successful therapy was defined as percent loss of total weight (%LTW) > or = 5 % at six months after balloon placement and 6 and 12 months after their withdrawal. All analyses followed intention-to treat principles considering significant p-values < 0.05., Results: we placed 73 fluid-filled balloons (80.2 %) and 18 air-filled ones (19.8 %). Compared to baseline values, at 6-month 73.7 % subjects succeeded, showing significant reductions in weight (13.3 +/- 8.8 kg), BMI (5 +/- 3.4 kg/m2) (p < 0.0001), with % LTW 11 +/- 7 %. Six and twelve months after retrieval 45.1 % and 28.6 % patients reached % LTW > or = 5 %. Short-term and medium-term effectiveness was negatively associated to obesity in first-grade relatives (p = 0.003 and p = 0.04). Higher weight loss 6 months after balloon placement independently predicted medium-term effectiveness (p = 0.0001). Mortality was absent but there were two spontaneous deflations of air-filled balloons and severe withdrawal difficulties in 8 patients, leading to surgery in one case. Retrieval complications associated to air-filled balloons (p = 0.0005)., Conclusions: in obesity, effectiveness of gastric balloons associated to hypocaloric diet decreases over time.Complications occurred mainly in the retrieval endoscopic procedure and related to air-filled balloons.
- Published
- 2013
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46. Quiescent neural stem cells exit dormancy upon alteration of GABAAR signaling following radiation damage.
- Author
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Daynac M, Chicheportiche A, Pineda JR, Gauthier LR, Boussin FD, and Mouthon MA
- Subjects
- Animals, Cell Culture Techniques, Cell Differentiation, Cell Proliferation, Mice, Mice, Inbred C57BL, Neural Stem Cells metabolism, Neurons metabolism, Receptors, GABA-A genetics, Signal Transduction, Neural Stem Cells cytology, Neurons cytology, Receptors, GABA-A metabolism
- Abstract
Quiescent neural stem cells (NSCs) are considered the reservoir for adult neurogenesis, generating new neurons throughout life. Until now, their isolation has not been reported, which has hampered studies of their regulatory mechanisms. We sorted by FACS quiescent NSCs and their progeny from the subventricular zone (SVZ) of adult mice according to the expression of the NSC marker LeX/CD15, the EGF receptor (EGFR) and the CD24 in combination with the vital DNA marker Hoechst 33342. Characterization of sorted cells showed that the LeX(bright)/EGFR-negative population was enriched in quiescent cells having an NSC phenotype. In contrast to proliferating NSCs and progenitors, the LeX(bright)/EGFR-negative cells, i.e. quiescent NSCs, resisted to a moderate dose of gamma-radiation (4Gy), entered the cell cycle two days after irradiation prior to EGFR acquisition and ultimately repopulated the SVZ. We further show that the GABAAR signaling regulates their cell cycle entry by using specific GABAAR agonists/antagonists and that the radiation-induced depletion of neuroblasts, the major GABA source, provoked their proliferation in the irradiated SVZ. Our study demonstrates that quiescent NSCs are specifically enriched in the LeX(bright)/EGFR-negative population, and identifies the GABAAR signaling as a regulator of the SVZ niche size by modulating the quiescence of NSCs., (Copyright © 2013 Elsevier B.V. All rights reserved.)
- Published
- 2013
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47. [TGFβ, a troublemaker in the adult neural stem cell niche].
- Author
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Pineda JR, Boussin FD, and Mouthon MA
- Subjects
- Animals, Humans, Neural Stem Cells physiology, Stem Cell Niche, Transforming Growth Factor beta physiology
- Published
- 2013
- Full Text
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48. Vascular-derived TGF-β increases in the stem cell niche and perturbs neurogenesis during aging and following irradiation in the adult mouse brain.
- Author
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Pineda JR, Daynac M, Chicheportiche A, Cebrian-Silla A, Sii Felice K, Garcia-Verdugo JM, Boussin FD, and Mouthon MA
- Subjects
- Aging radiation effects, Animals, Brain cytology, Brain metabolism, Cell Proliferation, Humans, Male, Mice, Mice, Inbred C57BL, Neural Stem Cells cytology, Neural Stem Cells radiation effects, Signal Transduction radiation effects, Aging metabolism, Brain growth & development, Brain radiation effects, Endothelial Cells metabolism, Neural Stem Cells metabolism, Neurogenesis radiation effects, Stem Cell Niche, Transforming Growth Factor beta metabolism
- Abstract
Neurogenesis decreases during aging and following cranial radiotherapy, causing a progressive cognitive decline that is currently untreatable. However, functional neural stem cells remained present in the subventricular zone of high dose-irradiated and aged mouse brains. We therefore investigated whether alterations in the neurogenic niches are perhaps responsible for the neurogenesis decline. This hypothesis was supported by the absence of proliferation of neural stem cells that were engrafted into the vascular niches of irradiated host brains. Moreover, we observed a marked increase in TGF-β1 production by endothelial cells in the stem cell niche in both middle-aged and irradiated mice. In co-cultures, irradiated brain endothelial cells induced the apoptosis of neural stem/progenitor cells via TGF-β/Smad3 signalling. Strikingly, the blockade of TGF-β signalling in vivo using a neutralizing antibody or the selective inhibitor SB-505124 significantly improved neurogenesis in aged and irradiated mice, prevented apoptosis and increased the proliferation of neural stem/progenitor cells. These findings suggest that anti-TGF-β-based therapy may be used for future interventions to prevent neurogenic collapse following radiotherapy or during aging., (Copyright © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.)
- Published
- 2013
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49. Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease.
- Author
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Keryer G, Pineda JR, Liot G, Kim J, Dietrich P, Benstaali C, Smith K, Cordelières FP, Spassky N, Ferrante RJ, Dragatsis I, and Saudou F
- Subjects
- Animals, Brain metabolism, Brain pathology, Centrosome metabolism, Cilia genetics, Cilia metabolism, Cilia pathology, Disease Models, Animal, Humans, Huntingtin Protein, Huntington Disease pathology, Mice, Mice, Knockout, Microtubules metabolism, Peptides genetics, Signal Transduction, Trinucleotide Repeat Expansion, Autoantigens genetics, Autoantigens metabolism, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Huntington Disease genetics, Huntington Disease metabolism, Mutant Proteins genetics, Mutant Proteins metabolism, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Nuclear Proteins genetics, Nuclear Proteins metabolism
- Abstract
Huntington disease (HD) is a devastating autosomal-dominant neurodegenerative disorder. It is caused by expansion of a CAG repeat in the first exon of the huntingtin (HTT) gene that encodes a mutant HTT protein with a polyglutamine (polyQ) expansion at the amino terminus. Here, we demonstrate that WT HTT regulates ciliogenesis by interacting through huntingtin-associated protein 1 (HAP1) with pericentriolar material 1 protein (PCM1). Loss of Htt in mouse cells impaired the retrograde trafficking of PCM1 and thereby reduced primary cilia formation. In mice, deletion of Htt in ependymal cells led to PCM1 mislocalization, alteration of the cilia layer, and hydrocephalus. Pathogenic polyQ expansion led to centrosomal accumulation of PCM1 and abnormally long primary cilia in mouse striatal cells. PCM1 accumulation in ependymal cells was associated with longer cilia and disorganized cilia layers in a mouse model of HD and in HD patients. Longer cilia resulted in alteration of the cerebrospinal fluid flow. Thus, our data indicate that WT HTT is essential for protein trafficking to the centrosome and normal ciliogenesis. In HD, hypermorphic ciliogenesis may affect signaling and neuroblast migration so as to dysregulate brain homeostasis and exacerbate disease progression.
- Published
- 2011
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50. Diagnostic accuracy and potential clinical value of the LightCycler SeptiFast assay in the management of bloodstream infections occurring in neutropenic and critically ill patients.
- Author
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Bravo D, Blanquer J, Tormo M, Aguilar G, Borrás R, Solano C, Clari MA, Costa E, Muñoz-Cobo B, Argüeso M, Pineda JR, and Navarro D
- Subjects
- Adult, Aged, Aged, 80 and over, Bacteremia drug therapy, Cohort Studies, Communicable Diseases drug therapy, DNA, Bacterial blood, DNA, Fungal blood, Female, Fever, Fungemia drug therapy, Humans, Intensive Care Units, Male, Middle Aged, Neutropenia diagnosis, Polymerase Chain Reaction economics, Polymerase Chain Reaction instrumentation, Reagent Kits, Diagnostic, Retrospective Studies, Sensitivity and Specificity, Spain, Bacteremia diagnosis, Critical Illness, Fungemia diagnosis, Molecular Diagnostic Techniques methods, Neutropenia complications, Polymerase Chain Reaction methods
- Abstract
Objectives: The objectives of this study were to compare the performance of the LightCycler SeptiFast Test MGRADE and conventional blood culture in the etiological diagnosis of febrile episodes occurring in neutropenic and critically ill patients (in the intensive care unit; ICU), and to assess the potential clinical value of the SeptiFast test in patient management., Methods: A total of 86 febrile episodes occurring in 33 neutropenic patients and 53 ICU patients were analyzed. Blood samples for blood culture and SeptiFast testing were obtained at the onset of fever, before the implementation of empirical antimicrobial therapy., Results: The overall microorganism-to-isolate agreement between the SeptiFast test and blood culture was 69% (κ=0.37) in neutropenic patients and 75% (κ=0.56) in ICU patients. The sensitivity of the SeptiFast assay for clinically relevant episodes of bacteremia and fungemia was 62% in neutropenic patients and 70% in ICU patients. Based on SeptiFast results, empirical treatments were deemed adequate in all but one of the febrile episodes. Nevertheless, early antibiotic treatment readjustment was judged feasible in most of clinically significant episodes overall., Conclusions: The SeptiFast assay is a valuable ancillary method for the diagnosis of bloodstream infections in neutropenic and ICU patients. In these clinical settings, results of the SeptiFast assay may lead to a more targeted antibiotic therapy early after the onset of fever., (Copyright © 2011 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2011
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