Chronic myeloid Leukemia (cml) : study of the autophagy role in the erythroleuceic cells chemotherapy resistance

Alteraciones en un proceso normal de diferenciación y maduración, como es la hematopoyesis, pueden conducir a situaciones de sobreproducción de células hematopoyéticas, como las leucemias. La autofagia, es considerada como un mecanismo por el cual macromoléculas citosólicas e incluso organelas enteras, son secuestradas en estructuras membranosas que son transportadas a los lisosomas para su degradación. La autofagia ha sido asociada a la diferenciación de algunos tipos celulares, como los reticulocitos, ya que es necesario el remodelamiento y la eliminación de ciertas estructuras internas. Además, las células leucémicas poseen altos niveles de autofagia basal, lo que le permite sobrevivir en condiciones adversas e incluso generar resistencia a las drogas quimioterápicas. Resultados recientes, han demostrado que la estimulación de los mecanismos de maduración eritroide, por un compuesto natural como es la hemina, es capaz de estimular tanto la síntesis de hemoglobina, como así también la expresión de proteínas autofágicas, induciendo la autofagia en células K562 (línea celular eritroleucémica). La proteína LRP1, es un receptor transmembrana asociado principalmente con ligandos extracelulares. Su estímulo desencadena la endocitosis dependiente de clatrina, estando implicado en diferentes procesos celulares. Se ha demostrado que LRP1 es responsable de la eliminación del complejo hemina-hemopexina. Los niveles de LRP1 varía en los distintos tipos celulares, siendo prácticamente indetectables en el glóbulo rojo maduro, a diferencia de sus progenitores más inmaduros o incluso en células leucémicas. Nuestros resultados muestran que la incubación de eritroblastos leucémicos (células k562) en presencia de hemina o resveratrol (inductor farmacológico de la autofagia) producen un marcado aumento de los niveles de expresión de la proteína LRP1. Esto nos estaría sugiriendo fuertemente que LRP1 podría estar involucrado en la estimulación de la autofagia, por hemina, en células eritroleucémicas. Nuestro proyecto, busca establecer los mecanismos celulares y moleculares de la vía autofágica mediada por LRP1 que participan durante el proceso de maduración eritroide y la sobrevida de células leucémicas.Alterations in a normal process of differentiation and maturation, such as hematopoiesis, can lead to situations of overproduction of hematopoietic cells, such as leukemia. Autophagy is considered as a mechanism by which macromolecules and even whole organelles are sequestered in membranous structures which can fuse to lysosomes for degradation. Autophagy has been associated with the differentiation of some cell types, such as reticulocytes, which requires the remodeling and elimination of certain internal structures. In addition, leukemic cells are associated with high levels of autophagy, which allow them to survive in adverse conditions and even generate resistance to chemotherapeutic drugs. New results have shown that the stimulation of the mechanisms of maturation, by a natural compound such as hemin, is able to express both the synthesis of hemoglobin, as well as the expression of autophagic proteins, inducing autophagy in K562 cells (erythroleukemic cell line) . The LRP1 protein is a transmembrane receptor associated with extracellular ligands, which is involved in different cellular processes. It has been shown that LRP1 is responsible for the elimination of the heme-hemopexin complex. The levels of LRP1 differ in the different cell types, being undetectable in the mature blood cell network, unlike their immature progenitors or even in the leukemic cells. Our results show that incubation of leukemic erythroblasts (k562 cells) in the presence of hemin or resveratrol (pharmacological inducer of autophagy) produces a marked increase in the expression levels of LRP1 protein. This means that it could be involved in the estimation of autophagy, by hemin, in erythroleukemic cells. Our project aims to establish the cellular and molecular mechanisms of the autophagic pathway, mediated by LRP1, that participate during the process of erythroid maturation and the survival of leukemic cells

Platelet rich plasma (PRP) induces autophagy in osteoblast precursor 3T3-L1

Autophagy is an essential cellular homeostatic mechanism by which intracellular components are delivered into the lysosomes for degradation and recycling. Autophagy has been related with a diversity of pathological or physiological dentary processes such as bone remodeling, skeletal aging, osteoclastogenesis, osteoblastogenesis and different types of oral cancer. Platelet-rich plasma (PRP), isolated from autologous blood, is a plasma preparation containing a higher concentration of platelets which contains numerous different growth factors and cytokines that activate several cellular signaling cascades. The purpose of this study is to investigate the effect of PRP on autophagy stimulation in both osteoblast precursor 3T3-L1 and non-related osteoblastic cells. Our results showed that PRP can increase the number of autophagic structures in 3T3-L1 and HeLa (cervical cancer cells) cells. Moreover, we have determined by Western blot a rise in the lipidated form of the autophagic protein LC3 (i.e. LC3-II) upon PRP treatment. Taken together, our results suggest that PRP is able to induce a strongly autophagy response in osteoblast precursor and, to a lesser extent, in non-related osteoblastic cells, suggesting that PRP could be a potential therapeutic tool for some autophagy-related diseases associated with bone homeostasis.Fil: Carminati, Sergio Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Barbosa, María Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Fader Kaiser, Claudio Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentin

Chronic kidney disease and cardiovascular risk in six regions of the world (ISN-KDDC): a cross-sectional study

Background Chronic kidney disease is an important cause of global mortality and morbidity. Data for epidemiological features of chronic kidney disease and its risk factors are limited for low-income and middle-income countries. The International Society of Nephrology’s Kidney Disease Data Center (ISN-KDDC) aimed to assess the prevalence and awareness of chronic kidney disease and its risk factors, and to investigate the risk of cardiovascular disease, in countries of low and middle income. Methods We did a cross-sectional study in 12 countries from six world regions: Bangladesh, Bolivia, Bosnia and Herzegovina, China, Egypt, Georgia, India, Iran, Moldova, Mongolia, Nepal, and Nigeria. We analysed data from screening programmes in these countries, matching eight general and four high-risk population cohorts collected in the ISN-KDDC database. High-risk cohorts were individuals at risk of or with a diagnosis of either chronic kidney disease, hypertension, diabetes, or cardiovascular disease. Participants completed a self-report questionnaire, had their blood pressure measured, and blood and urine samples taken. We defi ned chronic kidney disease according to modifi ed KDIGO (Kidney Disease: Improving Global Outcomes) criteria; risk of cardiovascular disease development was estimated with the Framingham risk score. Findings 75 058 individuals were included in the study. The prevalence of chronic kidney disease was 14·3% (95% CI 14·0–14·5) in general populations and 36·1% (34·7–37·6) in high-risk populations. Overall awareness of chronic kidney disease was low, with 409 (6%) of 6631 individuals in general populations and 150 (10%) of 1524 participants from high-risk populations aware they had chronic kidney disease. Moreover, in the general population, 5600 (44%) of 12 751 individuals with hypertension did not know they had the disorder, and 973 (31%) of 3130 people with diabetes were unaware they had that disease. The number of participants at high risk of cardiovascular disease, according to the Framingham risk score, was underestimated compared with KDIGO guidelines. For example, all individuals with chronic kidney disease should be considered at high risk of cardiovascular disease, but the Framingham risk score detects only 23% in the general population, and only 38% in high-risk cohorts. Interpretation Prevalence of chronic kidney disease was high in general and high-risk populations from countries of low and middle income. Moreover, awareness of chronic kidney disease and other non-communicable diseases was low, and a substantial number of individuals who knew they were ill did not receive treatment. Prospective programmes with repeat testing are needed to confi rm the diagnosis of chronic kidney disease and its risk factors. Furthermore, in general, health-care workforces in countries of low and middle income need strengthening

Saliva - Blood groups

Fil: Ruiz, Ana María. Universidad Nacional de Cuyo. Facultad de OdontologíaFil: Fader, Claudio. Universidad Nacional de Cuyo. Facultad de OdontologíaFil: Biscaro de Massa, Amalia. Universidad Nacional de Cuyo. Facultad de OdontologíaFil: Bravo, Mónica. Universidad Nacional de Cuyo. Facultad de OdontologíaFil: Carminati, Sergio. Universidad Nacional de Cuyo. Facultad de OdontologíaFil: Fernández, María Elizabeth. Universidad Nacional de Cuyo. Facultad de OdontologíaFil: Gil Lorenzo, Andrea. Universidad Nacional de Cuyo. Facultad de Odontologí

Cortactin Is Involved in the Entry of Coxiella burnetii into Non-Phagocytic Cells

BACKGROUND: Cortactin is a key regulator of the actin cytoskeleton and is involved in pathogen-host cell interactions. Numerous pathogens exploit the phagocytic process and actin cytoskeleton to infect host cells. Coxiella burnetii, the etiologic agent of Q fever, is internalized by host cells through a molecular mechanism that is poorly understood. METHODOLOGY/PRINCIPAL FINDING: Here we analyzed the role of different cortactin motifs in the internalization of C. burnetii by non-phagocytic cells. C. burnetii internalization into HeLa cells was significantly reduced when the cells expressed GFP-cortactin W525K, which carries a mutation in the SH3 domain that renders the protein unable to bind targets such as N-WASP. However, internalization was unaffected when the cells expressed the W22A mutant, which has a mutation in the N-terminal acidic region that destroys the protein's ability to bind and activate Arp2/3. We also determined whether the phosphorylation status of cortactin is important for internalization. Expression of GFP-cortactin 3F, which lacks phosphorylatable tyrosines, significantly increased internalization of C. burnetii, while expression of GFP-cortactin 3D, a phosphotyrosine mimic, did not affect it. In contrast, expression of GFP-cortactin 2A, which lacks phosphorylatable serines, inhibited C. burnetii internalization, while expression of GFP-cortactin SD, a phosphoserine mimic, did not affect it. Interestingly, inhibitors of Src kinase and the MEK-ERK kinase pathway blocked internalization. In fact, both kinases reached maximal activity at 15 min of C. burnetii infection, after which activity decreased to basal levels. Despite the decrease in kinase activity, cortactin phosphorylation at Tyr421 reached a peak at 1 h of infection. CONCLUSIONS/SIGNIFICANCE: Our results suggest that the SH3 domain of cortactin is implicated in C. burnetii entry into HeLa cells. Furthermore, cortactin phosphorylation at serine and dephosphorylation at tyrosine favor C. burnetii internalization. We present evidence that ERK and Src kinases play a role early in infection by this pathogen

Methodology of umbilical cord stem cells obtention and their potential use in dentistry and hematology

Las posibles aplicaciones terapéuticas de las células madre estromales mesenquimales (MSC) han despertado un gran interés en el campo de la ingeniería biomédica como terapia regenerativa. Las MSC son células madre adultas multipotentes que poseen un alto potencial de diferenciación, baja inmunogenicidad, propiedades inmunomoduladoras y capacidad de expansión in vitro eficiente. Las células madre derivadas de cordón umbilical humano (hUC-MSC) pueden diferenciarse a otros tipos celulares y ser utilizadas con fines terapéuticos. En este trabajo mostramos la metodología a través de la cual obtuvimos hUC-MSC, con la finalidad de diferenciarlas dentro del linaje eritropoyético. Así mismo, evaluamos y discutimos el potencial de estas hUC-MSC, en la diferenciación osteoblástica y su aplicación en la práctica odontológica.The possible therapeutic applications of mesenchymal stromal stem cells (MSC) have aroused great interest in the field of biomedical engineering, such as regenerative therapy. MSC´s are multipotent adult stem cells that have a high potential for differentiation, low immunogenicity, immunomodulatory properties and efficient in vitro expandability. Stem cells derived from human umbilical cord (hUC-MSC) can be differentiated into other cell types and may be used for therapeutic purposes. In this work we show the methodology by which we obtained hUC-MSC, in order to differentiate them within the erythropoietic lineage. Likewise, we evaluate and discuss the potential of these hUC-MSC, in osteoblastic differentiation and its application in dental practice.Fil: García Sanmartino, Clara. Universidad Nacional de Cuyo. Facultad de OdontologíaFil: Carminati, Sergio Andrés . Universidad Nacional de Cuyo. Facultad de Ciencias MédicasFil: Aguilera, Milton Osmar. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histologia y Embriología Mendoza. "Dr. Mario H. Burgos"Fil: Moras, M.. Paris Diderot University (France). Integrated Biology of Red Blood CellsFil: Ostuni, M. A.. Paris Diderot University (France). Integrated Biology of Red Blood CellsFil: Fader Kaiser, Claudio. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histologia y Embriología Mendoza. "Dr. Mario H. Burgos

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements