Homo sapiens
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PROVIDER: PRJNA141501 | ENA |
REPOSITORIES: ENA
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Project description:Development of a xenograft model for clinical oligo- and poly-metastatic progression
| PRJNA140747 | ENA
Project description:Background: Many strategies to define subtypes and treat cancer relies on a presumption of either localized or widespread (poly)metastatic disease. We proposed an intermediate state of metastasis termed oligometastasis(es) characterized by limited metastatic progression and amenable to treatment by localized methods e.g. surgery or radiotherapy. Methods: To understand the biological basis of oligometastatic and polymetastatic progression, we analyzed microRNA expression patterns from lung tumor samples of patients with less than five metastases at first metastasis presentation and treated with metastasis-directed surgery. Results: Patients were stratified into four subgroups of oligo- and poly-metastatic progression based on the rate of metastatic progression over follow-up period. We prioritized microRNAs between the extremes of oligo- vs. poly-metastatic progression and validated their capacity to distinguish these phenotypes and predict survival in an independent validation dataset. Conclusions: Our results provide further evidence for the biological underpinnings of oligometastasis(es) and potential microRNA candidates to predict progression trajectories of patients and optimize corresponding metastasis-directed treatment. We collected tumor samples from 63 patients that (i) had between one and five metastasis(es) at first metastatic presentation and no clinical or radiologic evidence of metastases in the pleural, peritoneal, pericardial or retroperitoneal cavities,(ii) at the time of lung surgery, had every site of known metastases treated with definitive intent, and (iii) had a minimum of 16 months of follow-up after surgery was required. Total RNA were derived from FFPE metastatic tissue samples. Patient samples were subsequently classified into 3 groups: those from patients with high, intermediate and low rates of progression.
2012-06-13 | E-GEOD-38698 | biostudies-arrayexpress
Project description:Background: Many strategies to define subtypes and treat cancer relies on a presumption of either localized or widespread (poly)metastatic disease. We proposed an intermediate state of metastasis termed oligometastasis(es) characterized by limited metastatic progression and amenable to treatment by localized methods e.g. surgery or radiotherapy. Methods: To understand the biological basis of oligometastatic and polymetastatic progression, we analyzed microRNA expression patterns from lung tumor samples of patients with less than five metastases at first metastasis presentation and treated with metastasis-directed surgery. Results: Patients were stratified into four subgroups of oligo- and poly-metastatic progression based on the rate of metastatic progression over follow-up period. We prioritized microRNAs between the extremes of oligo- vs. poly-metastatic progression and validated their capacity to distinguish these phenotypes and predict survival in an independent validation dataset. Conclusions: Our results provide further evidence for the biological underpinnings of oligometastasis(es) and potential microRNA candidates to predict progression trajectories of patients and optimize corresponding metastasis-directed treatment.
2012-06-13 | GSE38698 | GEO
Project description:We previously proposed a clinically meaningful intermediate metastatic state defined by a limited number of new metastases (≤5) after 3 months of follow-up, termed oligometastasis that has the curative potential by local cancer treatments as in contrast to the incurable widespread polymetastatic dissemination. While animal models of polymetastasis exist and this phenotype can be further enhanced upon serial in vivo passage, animal models of oligometastasis are not available. Here, we report the creation of an oligometastasis model of MDA-MB-435 human tumor in nude mice in which the oligometastatic phenotype exhibits stability during successive in vivo testing, and satisfies the criteria of ≤ 5 total body macroscopic metastases definition of the human cancer oligometastatic state. In parallel, we also developed an MDA-MB-435 polymetastatic model in which the polymetastatic dissemination pattern was either poly-foci at lung, or involved multiple anatomic sites including lung, heart, muscle, ovaries, kidney, brain and pleura. We have conducted microRNA expression profiling of cell lines derived from distinct lungs of oligo- and poly-metastatic animals. Animal model-derived microRNA expression features that discriminate oligometastatic cell lines from those of polymetastases accurately identify oligometastatic patients who failed to develop widespread metastases (P=0.005). These results demonstrate the clinical relevance of the oligo- and polymetastatic animal models we have developed and their potential in elucidating the molecular underpinnings of oligometastasis progression. We developed a stable human tumor (MDA-MB-435-GFP) xenograft model of oligometastatic and polymetastatic progression by conducting three consecutive rounds of experimental lung colonization assays. In the first round, we generated oligometastases-like lung derivative MDA-MB-435-L1-GFP (L1) or polymetastases-like MDA-MB-435-L1Mic-GFP (L1Mic) cell lines. We subsequently generated three oligometastatic L1 lung cell lines as well as four polymetastatic L1Mic lung cell lines from seven distinct animals of the second in vivo passage for further biological characterization and for microRNA expression analysis.
2011-05-21 | E-GEOD-29430 | biostudies-arrayexpress
Project description:Kynureninase is a member of a large family of catalytically diverse but structurally homologous pyridoxal 5'-phosphate (PLP) dependent enzymes known as the aspartate aminotransferase superfamily or alpha-family. The Homo sapiens and other eukaryotic constitutive kynureninases preferentially catalyze the hydrolytic cleavage of 3-hydroxy-l-kynurenine to produce 3-hydroxyanthranilate and l-alanine, while l-kynurenine is the substrate of many prokaryotic inducible kynureninases. The human enzyme was cloned with an N-terminal hexahistidine tag, expressed, and purified from a bacterial expression system using Ni metal ion affinity chromatography. Kinetic characterization of the recombinant enzyme reveals classic Michaelis-Menten behavior, with a Km of 28.3 +/- 1.9 microM and a specific activity of 1.75 micromol min-1 mg-1 for 3-hydroxy-dl-kynurenine. Crystals of recombinant kynureninase that diffracted to 2.0 A were obtained, and the atomic structure of the PLP-bound holoenzyme was determined by molecular replacement using the Pseudomonas fluorescens kynureninase structure (PDB entry 1qz9) as the phasing model. A structural superposition with the P. fluorescens kynureninase revealed that these two structures resemble the "open" and "closed" conformations of aspartate aminotransferase. The comparison illustrates the dynamic nature of these proteins' small domains and reveals a role for Arg-434 similar to its role in other AAT alpha-family members. Docking of 3-hydroxy-l-kynurenine into the human kynureninase active site suggests that Asn-333 and His-102 are involved in substrate binding and molecular discrimination between inducible and constitutive kynureninase substrates.
| S-EPMC2531291 | biostudies-literature
Project description:RNA extracted at 240min. Samples are rRNA depleted. Expression measurement of Homo sapiens genes.
2019-07-31 | GSE114179 | GEO
Project description:We previously proposed a clinically meaningful intermediate metastatic state defined by a limited number of new metastases (≤5) after 3 months of follow-up, termed oligometastasis that has the curative potential by local cancer treatments as in contrast to the incurable widespread polymetastatic dissemination. While animal models of polymetastasis exist and this phenotype can be further enhanced upon serial in vivo passage, animal models of oligometastasis are not available. Here, we report the creation of an oligometastasis model of MDA-MB-435 human tumor in nude mice in which the oligometastatic phenotype exhibits stability during successive in vivo testing, and satisfies the criteria of ≤ 5 total body macroscopic metastases definition of the human cancer oligometastatic state. In parallel, we also developed an MDA-MB-435 polymetastatic model in which the polymetastatic dissemination pattern was either poly-foci at lung, or involved multiple anatomic sites including lung, heart, muscle, ovaries, kidney, brain and pleura. We have conducted microRNA expression profiling of cell lines derived from distinct lungs of oligo- and poly-metastatic animals. Animal model-derived microRNA expression features that discriminate oligometastatic cell lines from those of polymetastases accurately identify oligometastatic patients who failed to develop widespread metastases (P=0.005). These results demonstrate the clinical relevance of the oligo- and polymetastatic animal models we have developed and their potential in elucidating the molecular underpinnings of oligometastasis progression.
2011-06-14 | GSE29890 | GEO
Project description:We previously proposed a clinically meaningful intermediate metastatic state defined by a limited number of new metastases (≤5) after 3 months of follow-up, termed oligometastasis that has the curative potential by local cancer treatments as in contrast to the incurable widespread polymetastatic dissemination. While animal models of polymetastasis exist and this phenotype can be further enhanced upon serial in vivo passage, animal models of oligometastasis are not available. Here, we report the creation of an oligometastasis model of MDA-MB-435 human tumor in nude mice in which the oligometastatic phenotype exhibits stability during successive in vivo testing, and satisfies the criteria of ≤ 5 total body macroscopic metastases definition of the human cancer oligometastatic state. In parallel, we also developed an MDA-MB-435 polymetastatic model in which the polymetastatic dissemination pattern was either poly-foci at lung, or involved multiple anatomic sites including lung, heart, muscle, ovaries, kidney, brain and pleura. We have conducted microRNA expression profiling of cell lines derived from distinct lungs of oligo- and poly-metastatic animals. Animal model-derived microRNA expression features that discriminate oligometastatic cell lines from those of polymetastases accurately identify oligometastatic patients who failed to develop widespread metastases (P=0.005). These results demonstrate the clinical relevance of the oligo- and polymetastatic animal models we have developed and their potential in elucidating the molecular underpinnings of oligometastasis progression.
2011-05-21 | GSE29430 | GEO
Project description:As the evolution of miRNA genes has been found to be one of the important factors in formation of the modern type of man, we performed a comparative analysis of the evolution of miRNA genes in two archaic hominines, Homo sapiens neanderthalensis and Homo sapiens denisova, and elucidated the expression of their target mRNAs in bain.A comparative analysis of the genomes of primates, including species in the genus Homo, identified a group of miRNA genes having fixed substitutions with important implications for the evolution of Homo sapiens neanderthalensis and Homo sapiens denisova. The mRNAs targeted by miRNAs with mutations specific for Homo sapiens denisova exhibited enhanced expression during postnatal brain development in modern humans. By contrast, the expression of mRNAs targeted by miRNAs bearing variations specific for Homo sapiens neanderthalensis was shown to be enhanced in prenatal brain development.Our results highlight the importance of changes in miRNA gene sequences in the course of Homo sapiens denisova and Homo sapiens neanderthalensis evolution. The genetic alterations of miRNAs regulating the spatiotemporal expression of multiple genes in the prenatal and postnatal brain may contribute to the progressive evolution of brain function, which is consistent with the observations of fine technical and typological properties of tools and decorative items reported from archaeological Denisovan sites. The data also suggest that differential spatial-temporal regulation of gene products promoted by the subspecies-specific mutations in the miRNA genes might have occurred in the brains of Homo sapiens denisova and Homo sapiens neanderthalensis, potentially contributing to the cultural differences between these two archaic hominines.
| S-EPMC4686780 | biostudies-literature
Project description:PurposeWe investigated the evidence of recent positive selection in the human phototransduction system at single nucleotide polymorphism (SNP) and gene level.MethodsSNP genotyping data from the International HapMap Project for European, Eastern Asian, and African populations was used to discover differences in haplotype length and allele frequency between these populations. Numeric selection metrics were computed for each SNP and aggregated into gene-level metrics to measure evidence of recent positive selection. The level of recent positive selection in phototransduction genes was evaluated and compared to a set of genes shown previously to be under recent selection, and a set of highly conserved genes as positive and negative controls, respectively.ResultsSix of 20 phototransduction genes evaluated had gene-level selection metrics above the 90th percentile: RGS9, GNB1, RHO, PDE6G, GNAT1, and SLC24A1. The selection signal across these genes was found to be of similar magnitude to the positive control genes and much greater than the negative control genes.ConclusionsThere is evidence for selective pressure in the genes involved in retinal phototransduction, and traces of this selective pressure can be demonstrated using SNP-level and gene-level metrics of allelic variation. We hypothesize that the selective pressure on these genes was related to their role in low light vision and retinal adaptation to ambient light changes. Uncovering the underlying genetics of evolutionary adaptations in phototransduction not only allows greater understanding of vision and visual diseases, but also the development of patient-specific diagnostic and intervention strategies.
| S-EPMC3743458 | biostudies-literature