ONCOLOGIA MOLECULAR PDF
ONCOGENES PROTOTIPICOS= PROPIEDADES. Función. Oncogene. Propiedades. Tirosina-Quinasas Integrales de V-ERB B. EGFR-SIMIL. Membrana . ONCOLOGIA MOLECULAR. Maestría en Biología. Molecular Médica – molecular weights and presumably variable function. The abbreviation m-bcr. Request PDF on ResearchGate | On Jan 1, , Hermes J. Garbán and others published Bases moleculares del cáncer: oncología molecular.
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La hemato-oncología molecular y las nuevas estrategias terapéuticas específicas en leucemia. Article (PDF Available) in Gaceta medica de Mexico. MANUAL DE BASES TÉCNICAS DA ONCOLOGIA – SIA/SUS - SISTEMA DE molecular), em casos de câncer de mama; e outros que venham a se. BIBLIOGRAFÍA MASTER EN ONCOLOGÍA MOLECULAR. Módulo I: Clase: El TGF-beta: efectos en carcinogénesis. Isabel Fabregat. Viernes 11 de Marzo de.
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MicroRNAs: Characterization and Biogenesis
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Gene expression profile predictive of response to chemotherapy in metastatic colorectal cancer
Porto: Universidade Portucalense Infante D. Recent studies have demonstrated that the expression levels of miR and miR are significantly lower in colorectal tumors, thus suggesting that these miRNAs act as potential tumor suppressors Arndt et al.
Several classes of deregulated miRNAs have also been shown to be differentially expressed in breast cancer, compared with healthy breast tissue Volinia et al.
Moreover, the expression signatures of informative miRNA subsets have enabled better molecular classification than mRNA expression profiles in several types of human cancer Lu et al. Among the miRNAs differentially expressed in breast cancer, miRb, miR, miR, miR and miR have consistently presented the highest degree of deregulation.
Downregulation of miRb, miRb and miR and upregulation of miR and miR suggest that these miRNAs may play an important role as tumor-suppressors or oncogenes Blenkiron et al.
In particular, the miR miRNA is progressively downregulated when passing from healthy breast tissue to breast cancer with high cell proliferation rates. Similarly, but in the opposite direction, the expression of miR is progressively upregulated when comparing normal breast tissue with breast cancer at advanced stages.
Thus, the deregulation of these miRNAs may affect molecular events that are critical for tumor progression Yang et al.
Mechanisms and role of microRNA deregulation in cancer onset and progression
Some specific miRNAs have also been associated with tumor invasion and metastasis in breast cancer. For example, the level of miRb expression in primary breast carcinomas has been correlated with clinical progression of the disease Ma et al. Recently it was also observed that the expression of miR-7, miRa, miR and miRp was associated with aggressiveness in cases that were positive for estrogen-receptor tumors and negative for lymph node tumors Foekens et al.
In recent years, studies on miRNAs, especially on a large scale using microarrays, have provided a more comprehensive picture on the role of abnormal miRNA expression in neoplasia.
In line with this, novel molecular classifications of tumors based on their miRNA expression, have provided a wealth of new resources for predictive and prognostic biomarkers for clinical applications in cancer. Since the mode of action of miRNA is highly sequence-dependent, changing a single base in a miRNA sequence that alters binding specificities may affect multiple genes, thus impacting on one or several biological pathways.
Since a single miRNA can have multiple mRNA target sites, sequence polymorphisms in general have deeper and more extensive effects from a biological point of view than would sequence alterations to mRNA Sun et al. Duan and Pak identified a SNP within an essential region of miR that significantly changed the miRa sequence and abolished recognition of its target site.
Functional experiments in vivo confirmed that the presence of this polymorphism blocked the maturation of miRa. Another example of this process is a SNP in the precursor of miR-K5, that is encoded by the human herpes virus in association with Kaposi's sarcoma. This polymorphism correlated with abnormalities in the miRNA cleavage processing by the Drosha enzyme.
Moreover, it could be demonstrated that combinations of certain genotypes were strongly associated with predisposition towards bladder cancer, and that the presence of these specific miRNA genotypes could be used as a tool for predicting the risk of developing such tumors.
These examples illustrate that variations in the different biogenesis routes for miRNAs affect their own function and consequently the expression of the target messenger RNA. It was also shown that there is a relationship between the presence of polymorphism rs in the insulin receptor INSR and a higher risk of colorectal cancer due to modification of the binding affinity of the miRNAs and Landi et al. The presence of this polymorphism was associated with increased risk of lung cancer among smokers.
In a case-control study on lung cancer, the presence of this allele was associated with an increased risk of lung cancer relative risk of 2.
Functional studies demonstrated that the presence of this polymorphism diminished the binding affinity of let-7 to its target site in KRAS, and consequently, increased expression of KRAS. Nonetheless, Christensen et al reported that in head and neck cancer, this same polymorphism LCS6-KRAS was not associated with any general increase in cancer risk, but significantly so with reduced survival Christensen et al.
This risk was shown to be higher for premenopausal women with a positive family history of cancer Tchatchou et al. The mode of action was inferred to be due to a lower binding affinity of miR in the presence of the T allele, and concomitant reduced repression of the ESR1 gene.
Since loss of binding of miR, led to overexpression of both the ESR1 mRNA and its receptor protein, the breast cancer cancer risk is expected to be increased. Taken together the regulation and role of miRNAs and the large number of target sites in functionally important genes and associated pathways provides new insights into cancer risk. It is clear that both a single miR-SNP or a specific combination of miRNA gene variants may act together on their target mRNA sites to constitute a new previously unappreciated mechanism for predisposition to cancer.
Recent studies have indicated that miRNA expression can be regulated by different epigenetic mechanisms, including changes in DNA methylation in promoter regions and histone modification Scott et al. When expression of such a miRNA is affected, any methylation of this area will simultaneously alter the expression of any target mRNA and proteins modulated by the epigenetically modified miRNA Scott et al.
Recent studies involving epigenetic factors and changes to miRNA expression have mostly been restricted to assays on tumor cells. One of the first studies to be published involved miR, which acts to repress the tumor-specific expression of the proto-oncogene BCL After treating tumor cells with chromatin modifying agents, miR showed activity in different types of human cancer cell lines, inferring that its inactivation in these cells could involve chromatin-induced epigenetic alterations Saito et al.
Suppression of hsa-miR, hsa-miR and hsa-miR in colorectal cancer is, at least partly, mediated by epigenetic mechanisms such as DNA hypermethylation and histone deacetylation, as demonstrated in a recent study by Bandres et al This study also emphasized that frequent hypermethylation of these miRNA loci in colorectal cancer was correlated with clinicopathological abnormalities.
Expression of hsa-miR was associated with positive lymph node biopsies in patients with advanced stages of colorectal cancer.
DNA methylation was considered to be the most likely mechanism for diminishing or inhibiting the expression of these specific miRNAs. Considering that these miRNAs are not usually expressed in normal mucosal tissue, this epigenetic alteration would diminish the tracking of disease evolution Bandres et al. In breast cancer cell cultures, the homozygous variant of the miRNA hsa-miRa-2 rs, CT was shown to be significantly associated with diminished risk of breast cancer, and hypermethylation of a CpG island located base pairs above the precursor region of miRa-2 led to a reduction in the risk of breast cancer Hoffman et al.
Based on a series of molecular analyses, these authors suggested that miRa-2 might have oncogenic potential in breast cell tumorigenesis, and that functional genetic variations in this miRNA could serve as biomarkers for susceptibility to breast cancer.
Lodygin et al. It was shown that Independent of the approach, success in applying these techniques is essentially limited by the availability of fresh or frozen clinical tissue samples, which are considered to be the most reliable sources of integral RNA Zhang et al.
Nevertheless, miRNAs turned out to be less affected by fixation in formalin and embedding in paraffin than mRNAs because of their slower degradation, smaller size and lack of a poly-A tail. Samples preserved in paraffin are also useful in evaluating the action of a miRNA on a target gene and determining whether it may result in a change in the expression of the corresponding protein. Changes in the expression of proteins regulating the biogenesis of miRNA can also be evaluated at the cellular level.
Using immunohistochemistry and tissue microarrays, LIN28 and LIN28B were found to be overexpressed in colon, breast, lung and cervical cancers. Increased expression was associated with physiological repression of let-7 levels and tumor progression, implying a tumor-suppressing role for this miRNA Viswanathan et al.
In addition, the role of miRNA in tumor tissue samples can be evaluated by means of in situ hybridization ISH tests to measure expression levels of specific miRNAs in target cells. Recently, a highly sensitive technique was described for detecting single miRNA molecules in individual cells Lu and Tsourkas, In a study on gliomas, and especially multiform glioblastomas, the miRNAs regulated by Dicer, miR and miR were identified using ISH, while the endonuclease and the intercellular adhesion molecule ICAM-1 were evaluated by means of immunohistochemistry.
These miRNAs were shown to be expressed by the tumors and negatively regulated ICAM-1, given that the expression of these molecules presented inverse associations in the tissue samples Ueda et al. In expression microarrays, there was no difference in Dicer expression between normal prostatic tissue and organ-confined prostate cancer.
However, immunohistochemical analysis demonstrated that in normal tissues, Dicer immunoreactivity was detected only in basal cells, proliferative neoplastic cells, and in invasive cancer. The redistribution of Dicer among the cell types seemed to be biologically significant with cancer progression and metastasis, and the level of this endonuclease continued to increase in the abnormal cells Chiosea et al.
The miR is one of the most-studied miRNAs in cancer cases and it is highly expressed in breast cancer. In addition, the expression of miR target genes such as PTEN, PDCD4 and TM1 was evaluated in the same tumor samples from the cohort at cellular level, and the cell transformation suppressor TM1 was confirmed as a target of miR in breast tumors, presenting reduced tissue immunoreactivity with progressive lesions, i.
Despite the fast advances in comprehending the biogenesis and action mechanism of miRNAs, many questions regarding their function and influence on central signaling pathways and cell cycle control remain.
The complex stochastic nature of gene expression in mammalian cells has wide-ranging impact on phenotypic diversity. It is therefore likely that evaluating mean miRNA expression levels in mixtures of cell populations may result in loss of crucial information for linking miRNA expression to cellular functions.
Thus, the physiological role of miRNA in single cells should be more informative in distinguishing the impact of miRNA on signaling networks and cellular pathways relevant to disease Lu and Tsourkas, This strategy has been used to detect site-specific target genes in cells, in relation to stem cell therapies and studies on transgenic animals.
Through this highly specific new approach a promising strategy has emerged, combining gene therapy with miRNA templates viruses carrying the target sequence , in an attempt to fully or partially inhibit the expression of these miRNAs. As described earlier, miRNAs can exert their effects either by acting as tumor suppressors or through favoring cancer development oncomirs.
When hyperexpression of miRNAs contributes towards oncogenesis, the rational strategy is to reduce their expression.
In this regard, inhibition of specific endogenous miRNAs has been used through administration of antisense synthetic oligonucleotides, which are complementary to endogenous mature miRNAs. These modifications have been incorporated through knowledge gained from interference RNA techniques RNAi , and were essential for offering resistance to enzymatic degradation, thereby improving OMA stability when exposed to the large quantities of nucleases present in blood and the cell environment.
Another important structural change incorporated into these oligonucleotides, with a view to improving their pharmacokinetic properties such as plasma half-life and increasing the uptake of the molecule by cells, was the introduction of a cholesterol molecule in the 3' terminal region of the nucleic acid Bijsterbosch et al. Applications of oligonucleotides that specifically inhibit oncomirs, such as mir, have been demonstrated in cultures on glioblastoma cells and breast cancer cells, thereby promoting increased caspase activation and mediating apoptosis in these cells Chan et al.
Furthermore, suppression of mir gave rise to significant reductions in invasions and lung metastases in cultures on MDA-MB breast cancer cells Zhu et al. The efficacy and significance of several OMAs have been examined and validated in several pioneering studies using a model that eliminates miR, which is hyperexpressed in rat livers after administration of specifically developed OMAs Krutzfeldt et al.
These authors were the first to demonstrate nontoxic long-duration silencing generated through intravenous injection of 'antagomirs' 2'-OMe that were complementary to miR, in mice. Notwithstanding, one of the major obstacles to applying 'antagomirs' in clinical screening is achieving effective release of RNAi in the target tissue Soifer et al.
Other alternatives, such as the use of cationic liposomes and cholesterol, conjugation with RNA-packaging phages and RNA aptamers that bind to receptors have been developed to release small RNAs in target cells Soutschek et al.When expression of such a miRNA is affected, any methylation of this area will simultaneously alter the expression of any target mRNA and proteins modulated by the epigenetically modified miRNA Scott et al. Bcl-2 appears to exert its antiapoptotic histopathology laboratories Serv.
It has been estimated that more than miRNAs exist in the human genome. Nat Methods Frameshift mutations in a single-repeat sequence within the coding region G 8 of the pro-apoptotic Bax gene have been related to microsatellite instability MSI and progression of some carcinomas and lymphomas. Table 1. In , the first miRNA, named lin-4 lineage-deficient-4 , was discovered in Caenorhabditis elegans , and was found to be associated with regulation of larval development.
MiRa and miR cluster functions in human leukemia. For this purpose we studied frameshift mutations of a microsatellite G 8 in the third exon of the Bax gene in a series of ductal breast carcinomas, at T1 and T2—3 stages, 45 of which had lymph node metastasis.
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