RESUMEN
Cellulose nanomaterials (CNMs) are a class of materials that have recently garnered attention in fields as varied as structural materials, biomaterials, rheology modifiers, construction, paper enhancement, and others. As the principal structural reinforcement of biomass giving wood its mechanical properties, CNM is strong and stiff, but also nontoxic, biodegradable, and sustainable with a very large (Gton yr-1 ) source. Unfortunately, due to the relatively young nature of the field and inherent incompatibility of CNM with most man-made materials in use today, research has tended to be more basic-science oriented rather than commercially applicable, so there are few CNM-enabled products on the market today. Herein, efforts are presented for preparing and forming cellulose nanomaterial nanocomposites. The focus is on recent efforts attempting to mitigate common impediments to practical commercialization but is also placed in context with traditional efforts. The work is presented in terms of the progress made, and still to be made, on solving the most pressing challenges-getting properties that are competitive with currently used materials, removing organic solvent, solving the inherent incompatibility between CNM and polymers of interest, and incorporation into commonly used industrial processing techniques.
RESUMEN
Large insertions/deletions mutations are frequently found in genes associated with certain diseases such as hereditary cancers. These mutations are mostly overlooked by current classical screening techniques due to their certain limitations. This justifies the need to improve the existing techniques or design novel ones. A modified version of quantitative multiplex PCR short fluorescent fragment (QMPSF), termed universally primed QMPSF (upQMPSF), was developed. The modifications enhance multiplexing capacity, reduce cost, and improve the mutation detection spectrum. upQMPSF was used to screen germline mutations in 88 familial ovarian cancer patients negative for point mutations. upQMPSF successfully detected a 2.8 kb copy number gain spanning exon 15 of BRCA1 gene mediated by Alu-Alu homologous-based recombination. upQMPSF is a cost-efficient, versatile method, and demonstrated efficiency in detecting structural variations as a potential method for genetic testing in clinical and research laboratories.
Asunto(s)
Proteína BRCA1/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Exones , Dosificación de Gen , Reacción en Cadena de la Polimerasa Multiplex/métodos , Neoplasias Ováricas/genética , Femenino , Variación Genética , HumanosRESUMEN
BACKGROUND: 4-Hydroxy-tamoxifen (4OHT) triggers Cre-mediated K-Ras removal in [H-Ras-/-; N-Ras-/-; K-Ras lox/lox; RERT ert/ert] fibroblasts, generating growth-arrested "Rasless" MEFs which are able to recover their proliferative ability after ectopic expression of Ras oncoproteins or constitutively active BRAF or MEK1. RESULTS: Comparison of the transcriptional profiles of Rasless fibroblasts with those of MEFs lacking only H-Ras and N-Ras identified a series of differentially expressed mRNAs and microRNAs specifically linked to the disappearance of K-Ras from these cells. The rescue of cell cycle progression in Rasless cells by activated BRAF or MEK1 resulted in the reversal of most such transcriptional mRNA and microRNA alterations.Functional analysis of the differentially expressed mRNAs uncovered a significant enrichment in the components of pathways regulating cell division, DNA/RNA processing and response to DNA damage. Consistent with G1/S blockade, Rasless cells displayed repression of a series of cell cycle-related genes, including Cyclins, Cyclin-dependent kinases, Myc and E2F transcription targets, and upregulation of Cyclin-dependent kinase inhibitors. The profile of differentially expressed microRNAs included a specific set of oncomiR families and clusters (repressed miR-17 ~ 92, miR-106a ~ 363, miR-106b ~ 25, miR-212 ~ 132, miR-183 ~ 182, and upregulated miR-335) known for their ability to target a specific set of cellular regulators and checkpoint sensors (including Rb, E2F and Cdkns) able to modulate the interplay between the pro- and anti-proliferative or stress-response pathways that are reversibly altered in Rasless cells. CONCLUSIONS: Our data suggest that the reversible proliferation phenotype of Rasless cells is the pleiotropic result of interplay among distinct pro- and anti-proliferative, and stress-response pathways modulated by a regulatory circuitry constituted by a specific set of differentially expressed mRNAs and microRNAs and preferentially targeting two cross-talking signalling axes: Myc-Rb-E2F-dependent and Cdkns-p53-dependent pathways.
Asunto(s)
Fibroblastos/metabolismo , MicroARNs/metabolismo , ARN Mensajero/metabolismo , Proteínas ras/genética , Animales , Análisis por Conglomerados , Daño del ADN , Puntos de Control de la Fase G1 del Ciclo Celular , MAP Quinasa Quinasa 1/genética , MAP Quinasa Quinasa 1/metabolismo , Ratones , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Transcriptoma , Proteínas ras/metabolismoRESUMEN
The DNA polymerase-gamma (POLG) gene, which encodes the catalytic subunit of enzyme responsible for directing mitochondrial DNA replication in humans, contains a polyglutamine tract encoded by CAG repeats of varying length. The length of the CAG repeat has been associated with the risk of testicular cancer, and other genomic variants that impact mitochondrial function have been linked to breast cancer risk in African-American (AA) women. We evaluated the potential role of germline POLG-CAG repeat variants in breast cancer risk in a sample of AA women (100 cases and 100 age-matched controls) who participated in the Women's Circle of Health Study, an ongoing multi-institutional, case-control study of breast cancer. Genotyping was done by fragment analysis in a blinded manner. Results from this small study suggest the possibility of an increased risk of breast cancer in women with minor CAG repeat variants of POLG, but no statistically significant differences in CAG repeat length were observed between cases and controls (multivariate-adjusted odds ratio 1.74; 95% CI, 0.49-6.21). Our study suggests that POLG-CAG repeat length is a potential risk factor for breast cancer that needs to be explored in larger population-based studies.
Asunto(s)
Neoplasias de la Mama/genética , ADN Mitocondrial/genética , ADN Polimerasa Dirigida por ADN/genética , Repeticiones de Trinucleótidos/genética , Adulto , Negro o Afroamericano , Anciano , Estudios de Casos y Controles , ADN Polimerasa gamma , Femenino , Predisposición Genética a la Enfermedad/genética , Mutación de Línea Germinal/genética , Humanos , Persona de Mediana Edad , Factores de RiesgoRESUMEN
Retrotransposons constitute over 40% of the human genome and play important roles in the evolution of the genome. Since certain types of retrotransposons, particularly members of the Alu, L1, and SVA families, are still active, their recent and ongoing propagation generates a unique and important class of human genomic diversity/polymorphism (for the presence and absence of an insertion) with some elements known to cause genetic diseases. So far, over 2,300, 500, and 80 Alu, L1, and SVA insertions, respectively, have been reported to be polymorphic and many more are yet to be discovered. We present here the Database of Retrotransposon Insertion Polymorphisms (dbRIP; http://falcon.roswellpark.org:9090), a highly integrated and interactive database of human retrotransposon insertion polymorphisms (RIPs). dbRIP currently contains a nonredundant list of 1,625, 407, and 63 polymorphic Alu, L1, and SVA elements, respectively, or a total of 2,095 RIPs. In dbRIP, we deploy the utilities and annotated data of the genome browser developed at the University of California at Santa Cruz (UCSC) for user-friendly queries and integrative browsing of RIPs along with all other genome annotation information. Users can query the database by a variety of means and have access to the detailed information related to a RIP, including detailed insertion sequences and genotype data. dbRIP represents the first database providing comprehensive, integrative, and interactive compilation of RIP data, and it will be a useful resource for researchers working in the area of human genetics.
Asunto(s)
Bases de Datos Genéticas , Genoma Humano , Mutagénesis Insercional/genética , Polimorfismo Genético/genética , Retroelementos/genética , HumanosRESUMEN
Digitoxin is used in the treatment of cardiac congestion and some types of cardiac arrhythmias. The mechanism of action of this cardiac glycoside suggested that it might antagonize the anticancer activity of topoisomerase II poisons. The present report shows that digitoxin, at concentrations commonly found in the plasma of cardiac patients, significantly reduced etoposide and idarubicin-induced topoisomerase II cleavable complexes in K562 leukemia cells. This may lead to a reduction in the anticancer effect of these two topoisomerase II poisons when they are used in the clinic concurrently with digitoxin.
Asunto(s)
Antineoplásicos/farmacología , Digitoxina/farmacología , Etopósido/antagonistas & inhibidores , Idarrubicina/antagonistas & inhibidores , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Topoisomerasa II , Amsacrina/farmacología , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Etopósido/farmacología , Humanos , Idarrubicina/farmacología , Células K562 , Mitoxantrona/farmacología , Relación Estructura-ActividadRESUMEN
Alu elements are the most active and predominant type of short interspersed elements (SINEs) in the human genome. Recently inserted polymorphic (for presence/absence) Alu elements contribute to genome diversity among different human populations, and they are useful genetic markers for population genetic studies. The objective of this study is to identify polymorphic Alu insertions through an in silico comparative genomics approach and to analyze their distribution pattern throughout the human genome. By computationally comparing the public and Celera sequence assemblies of the human genome, we identified a total of 800 polymorphic Alu elements. We used polymerase chain reaction-based assays to screen a randomly selected set of 16 of these 800 Alu insertion polymorphisms using a human diversity panel to demonstrate the efficiency of our approach. Based on sequence analysis of the 800 Alu polymorphisms, we report three new Alu subfamilies, Ya3, Ya4b, and Yb11, with Yb11 being the smallest known Alu subfamily. Analysis of retrotransposition activity revealed Yb11, Ya8, Ya5, Yb9, and Yb8 as the most active Alu subfamilies and the maintenance of a very low level of retrotransposition activity or recent gene conversion events involving S subfamilies. The 800 polymorphic Alu insertions are characterized by the presence of target site duplications (TSDs) and longer than average polyA-tail length. Their pre-integration sites largely follow an extended "NT-AARA" motif. Among chromosomes, the density of Alu insertion polymorphisms is positively correlated with the Alu-site availability and is inversely correlated with the densities of older Alu elements and genes.
Asunto(s)
Elementos Alu/genética , Biología Computacional/métodos , Genoma , Genómica/métodos , Polimorfismo Genético , Secuencia de Aminoácidos , Animales , Cromosomas Humanos Par 6 , Genética de Población , Genoma Humano , Humanos , Datos de Secuencia Molecular , Mutagénesis Insercional , Homología de Secuencia de AminoácidoRESUMEN
The cardiac glycosides digitoxin (1) and digoxin (3) have been used in cardiac diseases for many years. During this time several reports have suggested the possible use of digitalis in medical oncology. Several analogues of digitoxin (1) were evaluated for growth inhibition activity in three human cancer cell lines; this study showed that digitoxin (1) was the most active compound and revealed some structural features that may play a role in the growth inhibition activity of these drugs. The IC50 values for 1 (3-33 nM) were within or below the concentration range seen in the plasma of patients with cardiac disease receiving this glycoside (20-33 nM). A renal adenocarcinoma cancer cell line (TK-10) was hypersensitive to this drug, and digitoxin toxicity on these cells was mediated by apoptosis. In vitro experiments showed that 1 at 30 nM induced levels of DNA-topoisomerase II cleavable complexes similar to etoposide, a topoisomerase II poison widely used in cancer chemotherapy. Using the individual cell assay TARDIS, cells exposed to 1 for 30 min showed low but statistically significant levels of DNA-topoisomerase II cleavable complexes; however these complexes disappeared after 24 h exposure.