ABSTRACT
The nuclear export receptor, Exportin 1 (XPO1), mediates transport of growth-regulatory proteins, including tumor suppressors, and is overactive in many cancers, including chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML) and aggressive lymphomas. Oral selective inhibitor of nuclear export (SINE) compounds that block XPO1 function were recently identified and hold promise as a new therapeutic paradigm in many neoplasms. One of these compounds, KPT-330 (selinexor), has made progress in Phase I/II clinical trials, but systemic toxicities limit its administration to twice-per-week and requiring supportive care. We designed a new generation SINE compound, KPT-8602, with a similar mechanism of XPO1 inhibition and potency but considerably improved tolerability. Efficacy of KPT-8602 was evaluated in preclinical animal models of hematological malignancies, including CLL and AML. KPT-8602 shows similar in vitro potency compared with KPT-330 but lower central nervous system penetration, which resulted in enhanced tolerability, even when dosed daily, and improved survival in CLL and AML murine models compared with KPT-330. KPT-8602 is a promising compound for further development in hematological malignancies and other cancers in which upregulation of XPO1 is seen. The wider therapeutic window of KPT-8602 may also allow increased on-target efficacy leading to even more efficacious combinations with other targeted anticancer therapies.
Subject(s)
Antineoplastic Agents/therapeutic use , Hematologic Neoplasms/drug therapy , Karyopherins/antagonists & inhibitors , Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors , Animals , Hematologic Neoplasms/mortality , Hematologic Neoplasms/pathology , Heterografts , Humans , Mice , Neoplasm Invasiveness , Survival Rate , Treatment Outcome , Exportin 1 ProteinABSTRACT
Changes in the enzymatic activity of protein arginine methyltransferase (PRMT) 5 have been associated with cancer; however, the protein's role in acute myeloid leukemia (AML) has not been fully evaluated. Here, we show that increased PRMT5 activity enhanced AML growth in vitro and in vivo while PRMT5 downregulation reduced it. In AML cells, PRMT5 interacted with Sp1 in a transcription repressor complex and silenced miR-29b preferentially via dimethylation of histone 4 arginine residue H4R3. As Sp1 is also a bona fide target of miR-29b, the miR silencing resulted in increased Sp1. This event in turn led to transcription activation of FLT3, a gene that encodes a receptor tyrosine kinase. Inhibition of PRMT5 via sh/siRNA or a first-in-class small-molecule inhibitor (HLCL-61) resulted in significantly increased expression of miR-29b and consequent suppression of Sp1 and FLT3 in AML cells. As a result, significant antileukemic activity was achieved. Collectively, our data support a novel leukemogenic mechanism in AML where PRMT5 mediates both silencing and transcription of genes that participate in a 'yin-yang' functional network supporting leukemia growth. As FLT3 is often mutated in AML and pharmacologic inhibition of PRMT5 appears feasible, the PRMT5-miR-29b-FLT3 network should be further explored as a novel therapeutic target for AML.
Subject(s)
Arginine/chemistry , DNA Methylation , Epigenesis, Genetic/genetics , Epigenomics , Histones/chemistry , Leukemia, Myeloid, Acute/genetics , MicroRNAs/genetics , Protein-Arginine N-Methyltransferases/genetics , Animals , Apoptosis , Blotting, Western , Cell Proliferation , Chromatin Immunoprecipitation , Down-Regulation , Flow Cytometry , Gene Expression Regulation, Leukemic , Humans , Immunoenzyme Techniques , Leukemia, Myeloid, Acute/pathology , Mice , Mice, Inbred NOD , Mice, SCID , Protein-Arginine N-Methyltransferases/antagonists & inhibitors , RNA, Messenger/genetics , RNA, Small Interfering/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Transcriptional Activation , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Current treatments for acute myeloid leukemia (AML) are designed to target rapidly dividing blast populations with limited success in eradicating the functionally distinct leukemia stem cell (LSC) population, which is postulated to be responsible for disease resistance and relapse. We have previously reported high miR-126 expression levels to be associated with a LSC-gene expression profile. Therefore, we hypothesized that miR-126 contributes to 'stemness' and is a viable target for eliminating the LSC in AML. Here we first validate the clinical relevance of miR-126 expression in AML by showing that higher expression of this microRNA (miR) is associated with worse outcome in a large cohort of older (⩾60 years) cytogenetically normal AML patients treated with conventional chemotherapy. We then show that miR-126 overexpression characterizes AML LSC-enriched cell subpopulations and contributes to LSC long-term maintenance and self-renewal. Finally, we demonstrate the feasibility of therapeutic targeting of miR-126 in LSCs with novel targeting nanoparticles containing antagomiR-126 resulting in in vivo reduction of LSCs likely by depletion of the quiescent cell subpopulation. Our findings suggest that by targeting a single miR, that is, miR-126, it is possible to interfere with LSC activity, thereby opening potentially novel therapeutic approaches to treat AML patients.
Subject(s)
Leukemia, Myeloid, Acute/therapy , MicroRNAs/antagonists & inhibitors , Nanoparticles/administration & dosage , Neoplastic Stem Cells/physiology , Animals , DNA Methylation , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Leukocyte Common Antigens/antagonists & inhibitors , Mice , Mice, Inbred C57BL , MicroRNAs/physiology , Neoplastic Stem Cells/drug effectsABSTRACT
High levels of microRNA-155 (miR-155) are associated with poor outcome in acute myeloid leukemia (AML). In AML, miR-155 is regulated by NF-κB, the activity of which is, in part, controlled by the NEDD8-dependent ubiquitin ligases. We demonstrate that MLN4924, an inhibitor of NEDD8-activating enzyme presently being evaluated in clinical trials, decreases binding of NF-κB to the miR-155 promoter and downregulates miR-155 in AML cells. This results in the upregulation of the miR-155 targets SHIP1, an inhibitor of the PI3K/Akt pathway, and PU.1, a transcription factor important for myeloid differentiation, leading to monocytic differentiation and apoptosis. Consistent with these results, overexpression of miR-155 diminishes MLN4924-induced antileukemic effects. In vivo, MLN4924 reduces miR-155 expression and prolongs the survival of mice engrafted with leukemic cells. Our study demonstrates the potential of miR-155 as a novel therapeutic target in AML via pharmacologic interference with NF-κB-dependent regulatory mechanisms. We show the targeting of this oncogenic microRNA with MLN4924, a compound presently being evaluated in clinical trials in AML. As high miR-155 levels have been consistently associated with aggressive clinical phenotypes, our work opens new avenues for microRNA-targeting therapeutic approaches to leukemia and cancer patients.
Subject(s)
Cyclopentanes/pharmacology , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , MicroRNAs/genetics , Pyrimidines/pharmacology , Tandem Repeat Sequences/genetics , Ubiquitins/antagonists & inhibitors , fms-Like Tyrosine Kinase 3/genetics , Animals , Apoptosis/drug effects , Blotting, Western , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Chromatin Immunoprecipitation , Drug Resistance, Neoplasm , Female , Gene Expression Regulation, Leukemic/drug effects , Humans , Leukemia, Myeloid, Acute/pathology , Mice , Mice, Inbred NOD , Mice, SCID , Monocytes/drug effects , Monocytes/metabolism , Monocytes/pathology , NEDD8 Protein , NF-kappa B/genetics , NF-kappa B/metabolism , Promoter Regions, Genetic , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/drug effects , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Histone deacetylase (HDAC) inhibitors either alone or in combination with hypomethylating agents have limited clinical effect in acute myeloid leukemia (AML). Previously, we demonstrated that AML patients with higher miR (microRNA)-29b expression had better response to the hypomethylating agent decitabine. Therefore, an increase in miR-29b expression preceding decitabine treatment may provide a therapeutic advantage. We previously showed that miR-29b expression is suppressed by a repressor complex that includes HDACs. Thus, HDAC inhibition may increase miR-29b expression. We hypothesized that priming AML cells with the novel HDAC inhibitor (HDACI) AR-42 would result in increased response to decitabine treatment via upregulation of miR-29b. Here, we show that AR-42 is a potent HDACI in AML, increasing miR-29b levels and leading to downregulation of known miR-29b targets (that is, SP1, DNMT1, DNMT3A and DNMT3B). We then demonstrated that the sequential administration of AR-42 followed by decitabine resulted in a stronger anti-leukemic activity in vitro and in vivo than decitabine followed by AR-42 or either drug alone. These preclinical results with AR-42 priming before decitabine administration represent a promising, novel treatment approach and a paradigm shift with regard to the combination of epigenetic-targeting compounds in AML, where decitabine has been traditionally given before HDACIs.
Subject(s)
Azacitidine/analogs & derivatives , Epigenesis, Genetic , Histone Deacetylase Inhibitors/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , MicroRNAs/genetics , Phenylbutyrates/therapeutic use , Animals , Azacitidine/therapeutic use , Blotting, Western , Cell Line, Tumor , Decitabine , Histone Deacetylases/metabolism , Humans , Leukemia, Myeloid, Acute/enzymology , Leukemia, Myeloid, Acute/genetics , Mice , Mice, Inbred NOD , Mice, SCID , Up-Regulation/drug effectsABSTRACT
BACKGROUND AND PURPOSE: The passage of drugs across the blood-brain barrier (BBB) limits the efficacy of chemotherapy in brain tumours. For instance, the anticancer drug doxorubicin, which is effective against glioblastoma in vitro, has poor efficacy in vivo, because it is extruded by P-glycoprotein (Pgp/ABCB1), multidrug resistance-related proteins and breast cancer resistance protein (BCRP/ABCG2) in BBB cells. The aim of this study was to convert poorly permeant drugs like doxorubicin into drugs able to cross the BBB. EXPERIMENTAL APPROACH: Experiments were performed on primary human cerebral microvascular endothelial hCMEC/D3 cells, alone and co-cultured with human brain and epithelial tumour cells. KEY RESULTS: Statins reduced the efflux activity of Pgp/ABCB1 and BCRP/ABCG2 in hCMEC/D3 cells by increasing the synthesis of NO, which elicits the nitration of critical tyrosine residues on these transporters. Statins also increased the number of low-density lipoprotein (LDL) receptors exposed on the surface of BBB cells, as well as on tumour cells like human glioblastoma. We showed that the association of statins plus drug-loaded nanoparticles engineered as LDLs was effective as a vehicle for non-permeant drugs like doxorubicin to cross the BBB, allowing its delivery into primary and metastatic brain tumour cells and to achieve significant anti-tumour cytotoxicity. CONCLUSIONS AND IMPLICATIONS: We suggest that our 'Trojan horse' approach, based on the administration of statins plus a LDL receptor-targeted liposomal drug, might have potential applications in the pharmacological therapy of different brain diseases for which the BBB represents an obstacle.
Subject(s)
Blood-Brain Barrier/metabolism , Doxorubicin/administration & dosage , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Lovastatin/analogs & derivatives , Receptors, LDL/metabolism , Simvastatin/administration & dosage , ATP-Binding Cassette Transporters/metabolism , Cell Line , Cell Line, Tumor , Humans , Liposomes , Lovastatin/administration & dosage , NF-kappa B/metabolism , Nitric Oxide Synthase/metabolism , Nitrites/metabolism , rho-Associated Kinases/metabolism , rhoA GTP-Binding Protein/metabolismSubject(s)
Antimetabolites, Antineoplastic/therapeutic use , Azacitidine/analogs & derivatives , DNA (Cytosine-5-)-Methyltransferases/genetics , Leukemia, Myeloid, Acute/drug therapy , Mutation , Aged , Aged, 80 and over , Azacitidine/therapeutic use , DNA Methyltransferase 3A , Decitabine , Female , Humans , Leukemia, Myeloid, Acute/genetics , Male , Middle AgedABSTRACT
La seguridad del paciente es una preocupación mundial, en Colombia es liderada por el Sistema Obligatorio de Garantía de calidad en salud con el objetivo de prevenir la presencia de situaciones que afecten la seguridad del paciente durante la atención, reducir y de ser posible eliminar la ocurrencia de Eventos adversos para garantizar instituciones seguras y competitivas. Lo que se obtiene a través de los componentes obligatorios del sistema de garantía de la calidad, uno de ellos Auditoria para el Mejoramiento Continuo, cuyo objetivo es realizar seguimiento y control a todos los procesos, como una estrategia que garantice atenciones más seguras. Los informes de auditoría reflejan datos que son el resultado de la revisión y análisis integral de todas las atenciones realizadas, basan sus análisis en los atributos de calidad de la atención en salud, asume los lineamientos contractualmente definidos y acoge las normas vigentes frente a las atenciones en salud brindadas a las personas que las requieren. El Programa creado como una estrategia por el ministerio de la protección social involucra a todos los profesionales de salud y los compromete a asegurar la calidad del servicio en todos los ámbito; enfermería tiene a cargo la responsabilidad de brindar la atención directa, por lo tanto debe contribuir a la detección oportuna de atenciones inseguras y brindar cuidados oportunos, de calidad en lo posible libres de riesgo. Esta investigación se abordó como un estudio cuantitativo, retrospectivo de tipo descriptivo, para determinar la presencia de indicios de atención insegura, errores y eventos adversos que ocurrieron durante las atenciones realizadas en una IPS de II nivel de complejidad y que fueron presentados como atenciones no conformes en general en los informes de auditoría, para luego especificar cuáles de ellos son atribuidos específicamente a las acciones de enfermería. Los resultados obtenidos muestran un comportamiento similar a los estudios realizados por la Organización Mundial y permiten a los directivos de las instituciones, definir estrategias de mejoramiento continuo y establecer una estrategia permanente de evaluación y control, que permita a los profesionales de enfermería implementarla como herramienta que garantice la calidad del cuidado durante la atención.
Patient safety is a global concern, in Colombia is led by the Mandatory System of Quality Assurance in Health with the goal of preventing the occurrence of situations that affect patient safety during care, reduce and possibly eliminate the occurrence Adverse Event to ensure safe and competitive institutions. What we get through the mandatory components of system quality assurance, one auditing for continuous improvement, which aims to track and control all processes, as a strategy to ensure safer care. Audit reports show data that is the result of the comprehensive review and analysis of all patients attended, based their analysis on the quality attributes of health care, assumed contractually defined guidelines and welcomes the current rules about the attentions extended to health than those required. The program was created by the ministry of social protection, and involves all health professionals and make them promise to ensuring the quality of service in all aspects ; nursing has in its shoulders the responsibility of providing direct care, therefore must contribute to the timely detection of unsafe care and provide timely care, with quality and free of any risk. The research was approached as a quantitative, descriptive, retrospective study, to determine the presence of signs of unsafe care, mistakes and adverse events that occurred during care attention in an IPS on level II of complexity that were presented as "nonconforming attentions" generally in the audit reports, and then specify which of them are specifically attributed to nursing actions. The results show a behavior similar to studies by the World Health Organization and allow managers of institutions, defining continuous improvement strategies and establish a permanent strategy evaluation and control, enabling nurses to implement it as a tool ensure the quality of care for attention.
Subject(s)
Humans , Male , Female , Delivery of Health Care , Patient Safety , Quality of Health Care , Drug-Related Side Effects and Adverse Reactions/prevention & control , Nursing CareABSTRACT
La seguridad del paciente es una preocupación mundial, en Colombia es liderada por el Sistema Obligatorio de Garantía de calidad en salud con el objetivo de prevenir la presencia de situaciones que afecten la seguridad del paciente durante la atención, reducir y de ser posible eliminar la ocurrencia de Eventos adversos para garantizar instituciones seguras y competitivas. Lo que se obtiene a través de los componentes obligatorios del sistema de garantía de la calidad, uno de ellos Auditoria para el Mejoramiento Continuo, cuyo objetivo es realizar seguimiento y control a todos los procesos, como una estrategia que garantice atenciones más seguras. Los informes de auditoría reflejan datos que son el resultado de la revisión y análisis integral de todas las atenciones realizadas, basan sus análisis en los atributos de calidad de la atención en salud, asume los lineamientos contractualmente definidos y acoge las normas vigentes frente a las atenciones en salud brindadas a las personas que las requieren. El Programa creado como una estrategia por el ministerio de la protección social involucra a todos los profesionales de salud y los compromete a asegurar la calidad del servicio en todos los ámbito; enfermería tiene a cargo la responsabilidad de brindar la atención directa, por lo tanto debe contribuir a la detección oportuna de atenciones inseguras y brindar cuidados oportunos, de calidad en lo posible libres de riesgo. Esta investigación se abordó como un estudio cuantitativo, retrospectivo de tipo descriptivo, para determinar la presencia de indicios de atención insegura, errores y eventos adversos que ocurrieron durante las atenciones realizadas en una IPS de II nivel de complejidad y que fueron presentados como atenciones no conformes en general en los informes de auditoría, para luego especificar cuáles de ellos son atribuidos específicamente a las acciones de enfermería. Los resultados obtenidos muestran un comportamiento similar a los estudios realizados por la Organización Mundial y permiten a los directivos de las instituciones, definir estrategias de mejoramiento continuo y establecer una estrategia permanente de evaluación y control, que permita a los profesionales de enfermería implementarla como herramienta que garantice la calidad del cuidado durante la atención.
Patient safety is a global concern, in Colombia is led by the Mandatory System of Quality Assurance in Health with the goal of preventing the occurrence of situations that affect patient safety during care, reduce and possibly eliminate the occurrence Adverse Event to ensure safe and competitive institutions. What we get through the mandatory components of system quality assurance, one auditing for continuous improvement, which aims to track and control all processes, as a strategy to ensure safer care. Audit reports show data that is the result of the comprehensive review and analysis of all patients attended, based their analysis on the quality attributes of health care, assumed contractually defined guidelines and welcomes the current rules about the attentions extended to health than those required. The program was created by the ministry of social protection, and involves all health professionals and make them promise to ensuring the quality of service in all aspects ; nursing has in its shoulders the responsibility of providing direct care, therefore must contribute to the timely detection of unsafe care and provide timely care, with quality and free of any risk. The research was approached as a quantitative, descriptive, retrospective study, to determine the presence of signs of unsafe care, mistakes and adverse events that occurred during care attention in an IPS on level II of complexity that were presented as "nonconforming attentions" generally in the audit reports, and then specify which of them are specifically attributed to nursing actions. The results show a behavior similar to studies by the World Health Organization and allow managers of institutions, defining continuous improvement strategies and establish a permanent strategy evaluation and control, enabling nurses to implement it as a tool ensure the quality of care for attention.
Subject(s)
Humans , Male , Female , Quality of Health Care , Health Strategies , Medical Errors , Patient Safety , Nursing CareABSTRACT
El análisis del rendimiento académico de los estudiantes que ingresan a una institución de educación superior, así como los factores que pueden estar influyendo en él, genera respuestas a los interrogantes que corrientemente se hacen las personas involucradas en los procesos educativos y permite proponer soluciones para mejorar el desempeño de los estudiantes universitarios. Sujetos y métodos. Se determinó la asociación entre el rendimiento académico de los estudiantes en el primer nivel de Bioquímica, con los factores de tipo académico y demográfico; se utilizaron dos métodos de análisis: el primero, numérico, de acuerdo con los promedios de las notas parciales y finales; el segundo, categorizado como éxito (≥ 3,0) o fracaso (< 3,0),de acuerdo con el promedio de la nota definitiva de la asignatura. Resultados. Se encontró una asociación positiva y estadísticamente significativa entre los resultados de las pruebas de estado generales y específicas (ciencias naturales y matemáticas), el estatus de becario institucional y el ingreso directo a la carrera sin realizar cursos preuniversitarios, con el rendimiento académico en Bioquímica. Factores como el colegio en el cual realizaron la educación secundaria y la ciudad de procedencia no afectaron significativamente el rendimiento en ninguno de los análisis aplicados. Conclusiones. El rendimiento académico en Bioquímica se ve afectado directamente por factores que involucran las competencias individuales de los estudiantes, pero no por factores demográficos (AU)
Introduction. The analysis of the students academic achievement in a higher education institution together with the different factors that affect the students performance generates answers to the questions that the people involved in the teach ingprocess commonly ask themselves. This analysis is therefore, an excellent way to find and propose solutions in order to improve the students performance. Subjects and methods. The association between the students academic performance and the academic and demographic factors was determined in the first level of Biochemistry. Two methodologies were used for this purpose. The first one, a numerical analysis based on the partial and final grades, and a second categorical method based on the final success (≥ 3.0) or failure (< 3.0) on the subject. Results. A positive and statistically significant correlation was found when the academic performance in Biochemistry, the general and specific results of the state test (natural sciences and mathematics), the institutional scholarship status and entering the Medicine program without pre-university courses was analyzed. Factors, such as coming from different schools and the city of origin, do not affect significantly the performance in any of the analyses. Conclusions. Academic performance in Biochemistry is directly affected by factors involving the individual students skills while the demographical factors are not involved (AU)
Subject(s)
Humans , Achievement , Biochemistry/education , Education, Medical/statistics & numerical data , Colombia , Students, Health Occupations/statistics & numerical dataABSTRACT
MicroRNAs (miRNAs) are short non-coding RNAs that have key functions in a wide array of critical cell processes, including haematopoiesis by regulating the expression of multiple genes. Aberrant miRNA expression has been described in acute myeloid leukaemia suggesting a role in leukaemogenesis. In this review we summarise the current knowledge.
Subject(s)
Leukemia, Myeloid, Acute/genetics , MicroRNAs/genetics , MicroRNAs/metabolism , Humans , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/therapy , PrognosisABSTRACT
MicroRNAs (miRNAs) are a family of 19-24 nucleotide noncoding RNAs (ncRNAs) with posttranscriptional regulatory functions. Increasing evidences from the literature show that miRNAs play a pivotal role in human tumorigenesis. Many studies have addressed the role of miRNAs in normal hematopoiesis, giving an interpretative key to the aberrancies of expression observed in human hematological malignancies. Moreover, the recent demonstration that other ncRNAs, the ultraconserved genes (UCGs) or transcribed ultraconserved regions (T-UCRs), are involved in human cancerogenesis, suggests that the wider family of ncRNAs (including both miRNAs and UCGs) could contribute to the development of the malignant phenotype. Here we review the main studies investigating the role of miRNAs and UCRs in both normal hemopoiesis and hematological malignancies, and identify the molecular, clinical and therapeutic implications of these recent findings.
Subject(s)
Hematologic Neoplasms/metabolism , MicroRNAs/physiology , RNA, Untranslated/physiology , Hematopoiesis/physiology , HumansABSTRACT
Immunosuppression and chronic graft-versus-host disease (GVHD) are major risk factors for the development of invasive pulmonary aspergillosis in bone marrow transplant patients. Although nocardial infections are well described in hematopoietic stem cell transplantation (HSCT) recipients, little information is available about the incidence of nocardiosis in patients with chronic GVHD after HSCT. Coexistence of invasive pulmonary aspergillosis and nocardiosis following non-myeloablative HSCT has not been reported previously. With the increasing use of pentostatin in the treatment of chronic GVHD in future and other nucleoside analogues as preparative regimens in patients undergoing reduced-intensity conditioning transplantation, the possibility of co-infection with rare organisms should be kept in mind while assessing at-risk patients.
Subject(s)
Aspergillosis/complications , Graft vs Host Disease/complications , Hematopoietic Stem Cell Transplantation/adverse effects , Lung Diseases, Fungal/complications , Nocardia Infections/complications , Transplantation, Homologous/adverse effects , Aspergillosis/microbiology , Aspergillus fumigatus/isolation & purification , Female , Humans , Lung Diseases, Fungal/microbiology , Middle Aged , Nocardia/isolation & purification , Nocardia Infections/microbiologyABSTRACT
MicroRNAs (miRNAs) are small non-coding RNAs of 19-25 nucleotides that are involved in the regulation of critical cell processes such as apoptosis, cell proliferation and differentiation. However, little is known about the role of miRNAs in granulopoiesis. Here, we report the expression of miRNAs in acute promyelocytic leukemia patients and cell lines during all-trans-retinoic acid (ATRA) treatment by using a miRNA microarrays platform and quantitative real time-polymerase chain reaction (qRT-PCR). We found upregulation of miR-15a, miR-15b, miR-16-1, let-7a-3, let-7c, let-7d, miR-223, miR-342 and miR-107, whereas miR-181b was downregulated. Among the upregulated miRNAs, miR-107 is predicted to target NFI-A, a gene that has been involved in a regulatory loop involving miR-223 and C/EBPa during granulocytic differentiation. Indeed, we have confirmed that miR-107 targets NF1-A. To get insights about ATRA regulation of miRNAs, we searched for ATRA-modulated transcription factors binding sites in the upstream genomic region of the let-7a-3/let-7b cluster and identified several putative nuclear factor-kappa B (NF-kappaB) consensus elements. The use of reporter gene assays, chromatin immunoprecipitation and site-directed mutagenesis revealed that one proximal NF-kappaB binding site is essential for the transactivation of the let-7a-3/let-7b cluster. Finally, we show that ATRA downregulation of RAS and Bcl2 correlate with the activation of known miRNA regulators of those proteins, let-7a and miR-15a/miR-16-1, respectively.
Subject(s)
Cell Differentiation/drug effects , Gene Expression/drug effects , Leukemia, Promyelocytic, Acute/pathology , MicroRNAs/genetics , Tretinoin/pharmacology , Base Sequence , Blotting, Northern , Blotting, Western , DNA Primers , Humans , Luciferases/genetics , RNA, Small Interfering , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
El Blanqueamiento Dental Interno es un procedimiento que busca mejorar la estética del paciente al aclarar el esmalte de dientes que presenten una cantidad considerable de pigmentos debidos a diversas causas tanto intrínsecas como extrínsecas. La reabsorción cervical externa es una de las desventajas del procedimiento utilizado para hacer más claro el esmalte dental y su mayor factor desencadenante son las acciones química y física de los materiales utilizados durante el procedimiento. Este estudio piloto y experimental tuvo como objetivo observar una posible vía de comunicación entre la cámara pulpar y la raíz dental y se realizó midiendo la microfiltración del agente blanqueador ocurrida a través de dos materiales selladores del tratamiento de conductos. Se realizó un procedimiento endodóntico convencional y estandarizado a 16 premolares uniradiculares, los cuales fueron divididos en 3 grupos experimentales; Grupo I: 4 dientes control (2 sellados con resina fluida y 2 con un ionómero de vidrio) Grupo II: 6 dientes sellados inmediatamente después de la endodoncia (3 sellados con resina fluida y 3 con un ionómero de vidrio), Grupo III: 6 dientes sellados una semana después de la endodoncia (3 sellados con resina fluida y 3 con un ionómero de vidrio). A los Grupos II y III se les realizó un procedimiento de blanqueamiento interno con Perborato de Sodio y Peróxido de Hidrógeno al 30, al cabo del mismo, todos los dientes fueron teñidos con Azul de Metileno, inmersos en resina epóxica, cortados longitudinalmente con un micrótomo para, finalmente, analizar la mitad más conveniente en un microscopio estereoscópico. Se encontró que a través de todos los dientes hubo microfiltración del agente blanqueador hacia la raíz, excepto en un diente que fue sellado con ionómero pero ocho días después de terminada la endodoncia.
Internal dental whitening is a procedure to improve patient´s aestethetic through removal of crown surface stains. External cervical resorption is one of the main disadventages and consequence of dental withening. This pilot study looked for a possible communication between the pulpar camera and the root surface by measuring microfiltration of the bleaching agent among two endodontic sealing materials.16 single rooted premolars were studied using standard and conventional endodontic treatment. There was tree experimental groups. Group 1 was a 4 teeth sealed 2 with glass ionomer and the rest (2 teeth) with fluid resin. Group 2 contained 6 teeth sealed inmediately after endodontic treatment, 3 with fluid resin and the rest with galls ionomer. Group 3 was composed by 6 teeth sealed one week after endodontic treatment sealed 3 with fluid resin ans another 3 with glass ionomer. Teeth groups 2 and 3 were exposed to internal bleaching with sodium perborate and 30 hydrogen peroxide all teeth specimens were stained with methylene blue and after embebed under epoxic resin and cotted with microtome and analised under the stereoscophic microscope. The conclusion, all teeth showed dye percolation of the bleachy agent towards the root, with one tooth exception sealend with glass ionomer belong to the group in wich the procedure was performed one week after endodontic treatment.
Subject(s)
Microstraining , Tooth Bleaching , Tooth, Nonvital , Endodontics , Hydrogen PeroxideABSTRACT
Objetivo: Comparar fuerzas de resistencia a la compresión, flexión y tensión de dos resinas microhíbridas disponibles en el mercado. Metodología: Se realizó un estudio cuasi experimental in vitro para evaluar las propiedades físico-mecánicas de las resinas Miris®, (Coltene) y EsthetX®, (Dentsply). Fundamentadas en las normas ISO internacionales se elaboraron probetas de aluminio para utilizarlas en la confección de un molde maestro con tres compartimentos destinados a la obtención de las muestras de cada una de las resinas. Por medio de una máquina universal de ensayos a cada muestra se le realizaron pruebas específicas de resistencia y los datos obtenidos se compararon con los de la otra resina. La información recolectada fue analizada con estadística no paramétrica (test de Mann-whitney, P≤0.05). Resultados: Bajo las pruebas de resistencia a la flexión los resultados fueron mas altos para la resina Miris® que para la Esthet-X® (P=0.0286). El módulo elástico (Young) fue mayor para Miris® (P= 0.0286) Bajo las pruebas de resistencia a la compresión los resultados fueron mas altos para la resina Esthet-X® que para la Miris® (P=0.0159) En la prueba de resistencia a la tracción no se obtuvieron valores confiables. Conclusiones: El módulo de Flexión más alto se relacionó con el menor porcentaje de deformación, obtenido para la resina Miris®. En contraste sus valores de resistencia a la compresión fueron menores a Esthet-X®. Miris® fue más rígida que Esthet-X®, pero Esthet-X® resistió mejor cargas compresivas. Ambas resinas mostraron resultados aceptables para ser usadas en el sector posterior, pero se recomienda limitar su uso en restauraciones conservadoras en premolares y molares.
Objective: To compare flexural and compressive strength of two microhibrid composite resins. Methods: A quasi-experimental in vitro study was performed to evaluate physical-mechanical properties of Miris®, (Coltene) and EsthetX®, (Dentsply) Results: Flexural resistance strength test showed higher values for Miris® than for Esthet-X® (P=0.0286). The elastic modulus (Young) test presented higher results for Miris® (P= 0.0286). Compressive resistance strength results were higher for Esthet-X® than for Miris ® (P=0.0159). When the tensional strength test was applied to the microhibrid resins, no reliable data were obtained. Conclusions: Higher Flexural modulus was correlated to lower deformation values, as showed by Miris®. In contrast, its compressive values were lower than Esthet-X®. Miris® was more rigid than Esthet-X®, but Esthet-X® resisted higher compressive load. Both systems showed acceptable physical-mechanical values to be considered for posterior restorations. Limited use of these resins to conservative preparations in bicuspids and molars should be considered.
Subject(s)
Elastic Modulus , Clinical Trial , Resins , Dental Restoration, Permanent/methodsABSTRACT
The results presented in this work are related to the design of a guideline to develop specific properties at the surface of an activated carbon (AC). For this, two model aromatic compounds have been synthesized and their electrolytic behavior in aqueous solutions was studied by a potentiometric method. The textural characteristics of the activated carbon were determined by porosimetry methods. The nature of oxygen-carrying functions and the acid-base behavior of the AC surface were characterized by TPD and potentiometric titration methods, respectively. The adsorption and desorption equilibria of the aromatic compounds on activated carbon were measured in aqueous solutions, and the hysteresis between adsorption and desorption, which reveals irreversible adsorption, was discussed on the basis of the frontier orbital theory. HOMO and LUMO orbitals of the adsorbent and adsorbates were calculated, and irreversible adsorption was attributed to the small energy difference between HOMO and LUMO of the aromatic adsorbates and the adsorbent. Adsorption equilibria of K2CrO4 in aqueous solution on the AC alone and on the AC-aromatic ligand adsorbents, respectively, prove the efficient development of specific chemical functions at the carbon surface provided by the adsorbed aromatic compounds.
ABSTRACT
Various prognostic factors and the International Prognosis Scoring System (IPSS) were assessed in our community hospital-based retrospective study of 55 cases of myelodysplastic syndromes (MDS). All cases were reviewed for clinical, hematologic, histopathologic, and cytogenetic data. The median follow-up was 1.61 years. Twenty patients (36%) were classified as refractory anemia (RA); seven (13%) as refractory anemia with ringed sideroblasts (RARS); 13 (24%) as chronic myelomonocytic leukemia (CMML); 11 (20%) as refractory anemia with excess blasts (RAEB); and four (7%) as refractory anemia with excess blasts in transformation (RAEB-t). Twenty-seven (49%) died during the follow-up period, seven with acute myelogenous leukemia (AML). The median survival was 2.8 years. The variables that showed association with survival by univariate analysis included the absolute neutrophil count, French-American-British (FAB) subtype, percentage of blasts, number of cytopenias, abnormal localization of immature precursors, and IPSS score. When entered into a regression model, IPSS showed a trend towards an association with survival (P 0.09). We conclude that the IPSS can prognostically stratify MDS patients. However, no independent prognostic factor was confirmed in our analysis. Further studies are needed to assess the utility of IPSS.
Subject(s)
Myelodysplastic Syndromes/mortality , Aged , Aged, 80 and over , Chi-Square Distribution , Female , Hospitals, Community , Humans , Male , Middle Aged , Myelodysplastic Syndromes/classification , Ohio/epidemiology , Prognosis , Proportional Hazards Models , Regression Analysis , Retrospective Studies , Risk , Survival AnalysisABSTRACT
The title anion, (C(7)H(8)N(5)O(4))(-), L(-), forms hydrated metal complexes with a range of metal ions M(+) and M(2+). Lithium and manganese(II) form finite molecular aggregates [Li(L)(H(2)O)(3)] (1) and [Mn(L)(2)(H(2)O)(4)].6H(2)O (4) in which the molecular aggregates are linked into three-dimensional frameworks by extensive hydrogen bonding. The sodium and potassium derivatives, [Na(2)(L)(2)(H(2)O)(3)] (2) and [K(L)(H(2)O)] (3) both form organic-inorganic hybrid sheets in which metal-oxygen ribbons are linked by strips containing only organic ligands: these sheets are linked by hydrogen bonds into three-dimensional frameworks. In (2) the metal-oxygen ribbon is built from pairs of edge-shared trigonal bipyramids linked by water molecules, while in (3) it consists of a continuous chain of vertex-sharing octahedra. The nitroso group in the anion acts as an eta(1) ligand towards Na(+) and as an eta(2) ligand towards K(+). In all cases the anion L(-) shows the same unusual pattern of interatomic distances as the neutral parent LH.
