Vesiclepedia is a community-annotated compendium of molecular data on extracellular vesicles.
Genetic and metabolic studies have been done on a large kindred in which several males are affected by a syndrome of borderline mental retardation and abnormal behavior. The types of behavior that occurred include impulsive aggression, arson, attempted rape, and exhibitionism. Analysis of 24-hour urine samples indicated markedly disturbed monoamine metabolism. This syndrome was associated with a complete and selective deficiency of enzymatic activity of monoamine oxidase A (MAOA). In each of five affected males, a point mutation was identified in the eighth exon of the MAOA structural gene, which changes a glutamine to a termination codon. Thus, isolated complete MAOA deficiency in this family is associated with a recognizable behavioral phenotype that includes disturbed regulation of impulsive aggression.
Glioblastomas shed large quantities of small, membrane-bound microvesicles (MVs) into the circulation. While these hold promise as potential biomarkers of therapeutic response, their identification and quantitation remain challenging. Here, we describe a highly sensitive and rapid analytical technique for profiling circulating MVs directly from blood samples of glioblastoma patients. MVs, introduced onto a dedicated microfluidic chip, are labeled with target-specific magnetic nanoparticles and detected by a miniaturized nuclear magnetic resonance system. Compared with current methods, this integrated system has a much higher detection sensitivity, and can differentiate glioblastoma multiforme (GBM) MVs from non-tumor host cell-derived MVs. We also show that circulating GBM MVs can serve as a surrogate for primary tumor mutations and a predictive metric of treatment-induced changes. This platform could provide both an earlier indicator of drug efficacy and a potential molecular stratifier for human clinical trials.
Herein, we describe a novel approach in the search for prostate cancer biomarkers, which relies on the transcriptome within tumour exosomes. As a proof-of-concept, we show the presence of two known prostate cancer biomarkers, PCA-3 and TMPRSS2:ERG the in exosomes isolated from urine of patients, showing the potential for diagnosis and monitoring cancer patients status.
Microvesicles (exosomes) shed from both normal and cancerous cells may serve as means of intercellular communication. These microvesicles carry proteins, lipids and nucleic acids derived from the host cell. Their isolation and analysis from blood samples have the potential to provide information about state and progression of malignancy and should prove of great clinical importance as biomarkers for a variety of disease states. However, current protocols for isolation of microvesicles from blood require high-speed centrifugation and filtration, which are cumbersome and time consuming. In order to take full advantage of the potential of microvesicles as biomarkers for clinical applications, faster and simpler methods of isolation will be needed. In this paper, we present an easy and rapid microfluidic immunoaffinity method to isolate microvesicles from small volumes of both serum from blood samples and conditioned medium from cells in culture. RNA of high quality can be extracted from these microvesicles providing a source of information about the genetic status of tumors to serve as biomarkers for diagnosis and prognosis of cancer.
Luciferases are widely used to monitor various biological processes. Here, we describe the naturally secreted Gaussia luciferase as a highly sensitive reporter for quantitative assessment of cells in vivo by measuring its levels in blood. The Gluc blood assay complements in vivo bioluminescence imaging which has the ability to localize the signal and provides a multifaceted assessment of cell viability, proliferation and location in experimental disease and therapy models.Luciferase-mediated bioluminescence imaging has served as a reporting tool for monitoring various biological processes in vitro and in vivo in different fields 3 , including immunology 4 oncology 5 , virology 6 , and neuroscience 7 . After systemic substrate injection, a charge coupled device (CCD) camera can be used to localize the luciferase photon signals in vivo. Recently, we have characterized a naturally secreted luciferase from the marine copepod Gaussia princeps (Gaussia luciferase, Gluc) and found it to be over 2000-fold more sensitive than firefly and Renilla reniformis luciferases and 20,000-fold more sensitive than the secreted alkaline phosphatase (SEAP) when expressed in mammalian cells 8,9 . Gluc expression levels can be easily quantified in cell-free, conditioned medium by adding its substrate coelenterazine and measuring emitted photons using a luminometer. Since Gluc is secreted from mammalian cells in culture 9 , we hypothesized that it might also be secreted into the blood of animals harboring cells expressing this reporter.In order to assess the potential of Gluc as a reporter to monitor biological processes by measuring its level in the blood of small animals, we transduced Gli36 human glioma cells with a lentivirus vector encoding Gluc (Gli36-Gluc) and implanted them in different numbers into the flanks of nude mice. We visualized the tumors 3 days post-implantation by in vivo bioluminescence imaging after intravenous (i.v.) injection of the Gluc substrate, coelenterazine (4 mg/kg body weight) and acquiring photon counts using a CCD camera (Fig. 1a). At the same time, we withdrew 5 μl blood samples from these mice and directly aliquoted them into tubes containing EDTA (1 μl 20 mM), after which we measured the Gluc activity by adding coelenterazine (100 μM) and acquiring photon counts using a luminometer (Supplementary Methods online). The Gluc activity in the blood was linear with respect to cell number in a NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript range covering over 5 orders of magnitude, and correlated well with values obtained using the CCD camera (Fig. 1b). Further, Gluc activity could also be detected in the urine, albeit to a lesser extent than in the blood, which indicates it is cleared by the kidneys (Fig. 1b). In addition, there was no detrimental effect of EDTA on Gluc activity measured in blood ( Supplementary Fig. 1a online), and no significant differences were detected between the Gluc activity measured in serum or whole blood samples, showing that hemoglobin, which can int...
We have examined data on six closely linked microsatellite loci on chromosome 9q34 from 59 Ashkenazi Jewish families with idiopathic torsion dystonia (ITD). Our data show that the vast majority (> 90%) of early-onset ITD cases in the Ashkenazi population are due to a single founder mutation, which we estimate first appeared approximately 350 years ago. We also show that carriers preferentially originate from the northern part of the historic Jewish Pale of settlement (Lithuania and Byelorussia). The recent origin of this dominant mutation and its current high frequency (between 1/6,000 and 1/2,000) suggest that the Ashkenazi population descends from a limited group of founders, and emphasize the importance of genetic drift in determining disease allele frequencies in this population.
Oncolytic viral therapy provides a promising approach to treat certain human malignancies. These vectors improve on replication-deficient vectors by increasing the viral load within tumors through preferential viral replication within tumor cells. However, the inability to efficiently propagate throughout the entire tumor and infect cells distant from the injection site has limited the capacity of oncolytic viruses to achieve consistent therapeutic responses. Here we show that the spread of the oncolytic herpes simplex virus (HSV) vector MGH2 within the human melanoma Mu89 is limited by the fibrillar collagen in the extracellular matrix. This limitation seems to be size specific as nanoparticles of equivalent size to the virus distribute within tumors to the same extent whereas smaller particles distribute more widely. Due to limited viral penetration, tumor cells in inaccessible regions continue to grow, remaining out of the range of viral infection, and tumor eradication cannot be achieved. Matrix modification with bacterial collagenase coinjection results in a significant improvement in the initial range of viral distribution within the tumor. This results in an extended range of infected tumor cells and improved virus propagation, ultimately leading to enhanced therapeutic outcome. Thus, fibrillar collagen can be a formidable barrier to viral distribution and matrixmodifying treatments can significantly enhance the therapeutic response. (Cancer Res 2006; 66(5): 2509-13)
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