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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 27 March 2018, Vol.115(13), pp.3392-3397
    Description: The main cell of origin of the Sonic hedgehog (SHH) subgroup of medulloblastoma (MB) is granule cell precursors (GCPs), a SHH-dependent transient amplifying population in the developing cerebellum. SHH-MBs can be further subdivided based on molecular and clinical parameters, as well as location because SHH-MBs occur preferentially in the lateral cerebellum (hemispheres). Our analysis of adult patient data suggests that tumors with Smoothened () mutations form more specifically in the hemispheres than those with Patched 1 () mutations. Using sporadic mouse models of SHH-MB with the two mutations commonly seen in adult MB, constitutive activation of () or loss-of-, we found that regardless of timing of induction or type of mutation, tumors developed primarily in the hemispheres, with -mutants indeed showing a stronger specificity. We further uncovered that GCPs in the hemispheres are more susceptible to high-level SHH signaling compared with GCPs in the medial cerebellum (vermis), as more or -mutant hemisphere cells remain undifferentiated and show increased tumorigenicity when transplanted. Finally, we identified location-specific GCP gene-expression profiles, and found that deletion of the genes most highly expressed in the hemispheres () or vermis (Engrailed1) showed opposing effects on GCP differentiation. Our studies thus provide insights into intrinsic differences within GCPs that impact on SHH-MB progression.
    Keywords: En1 ; Mri ; Nr2f2 ; Cerebellar Hemispheres ; Granule Cell Precursors ; Cerebellar Neoplasms -- Pathology ; Cerebellum -- Pathology ; Hedgehog Proteins -- Metabolism ; Medulloblastoma -- Pathology ; Patched-1 Receptor -- Metabolism ; Smoothened Receptor -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: 2013, Vol.7(5), p.e2197
    Description: The live-attenuated TC-83 strain is the only licensed veterinary vaccine available to protect equids against Venezuelan equine encephalitis virus (VEEV) and to protect humans indirectly by preventing equine amplification. However, TC-83 is reactogenic due to its reliance on only two attenuating point mutations and has infected mosquitoes following equine vaccination. To increase its stability and safety, a recombinant TC-83 was previously engineered by placing the expression of the viral structural proteins under the control of the Internal Ribosome Entry Site (IRES) of encephalomyocarditis virus (EMCV), which drives translation inefficiently in insect cells. However, this vaccine candidate was poorly immunogenic. Here we describe a second generation of the recombinant TC-83 in which the subgenomic promoter is maintained and only the capsid protein gene is translated from the IRES. This VEEV/IRES/C vaccine candidate did not infect mosquitoes, was stable in its attenuation phenotype after serial murine passages, and was more attenuated in newborn mice but still as protective as TC-83 against VEEV challenge. Thus, by using the IRES to modulate TC-83 capsid protein expression, we generated a vaccine candidate that combines efficient immunogenicity and efficacy with lower virulence and a reduced potential for spread in nature. ; Venezuelan equine encephalitis virus (VEEV) is transmitted by mosquitoes and widely distributed in Central and South America, causing regular outbreaks in horses and humans. Often misdiagnosed as dengue, VEEV infection in humans can lead to lifelong neurological sequelae and is fatal in up to 〉80% of equine cases, representing a significant socio-economic burden and constant public health threats for developing countries of Latin America. The only available vaccine, the live-attenuated TC-83 strain, is restricted to veterinary use due to its high reactogenicity in humans and risk for reversion to virulence, which could initiate an epidemic. By using an attenuation approach that allows the modulation of the virus capsid protein expression, we generated a new version of TC-83 that is more attenuated but still induces a protective immune response in mice. Additionally, this new vaccine cannot infect mosquitoes, which prevents the risk of spreading in nature. The attenuation approach we describe can be applied to a lot of other alphaviruses to develop vaccines against diseases regularly emerging and threatening developing countries.
    Keywords: Research Article ; Biology
    ISSN: 19352727
    E-ISSN: 1935-2735
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  • 3
    Language: English
    In: Virology, 2006, Vol.344(2), pp.315-327
    Description: Alphaviruses are regarded as attractive systems for expression of heterologous genes and development of recombinant vaccines. Venezuelan equine encephalitis virus (VEE)-based vectors are particularly promising because of their specificity to lymphoid tissues and strong resistance to interferon. To improve understanding of the VEE genome packaging and optimize application of this virus as a vector, we analyzed in more detail the mechanism of packaging of the VEE-specific RNAs. The presence of the RNAs in the VEE particles during serial passaging in tissue culture was found to depend not only on the presence of packaging signal(s), but also on the ability of these RNAs to express in nsP1, nsP2 and nsP3 in the form of a P123 precursor. Packaging of VEE genomes into infectious virions was also found to be more efficient compared to that of Sindbis virus, in spite of lower levels of RNA replication and structural protein production.
    Keywords: Alphavirus ; Vee ; RNA Replication ; Packaging ; Nonstructural Proteins ; Biology
    ISSN: 0042-6822
    E-ISSN: 1096-0341
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  • 4
    In: The Journal of Virology, 2007, Vol. 81(5), p.2472
    Description: Alphaviruses are widely distributed throughout the world. During the last few thousand years, the New World viruses, including Venezuelan equine encephalitis virus (VEEV) and eastern equine encephalitis virus (EEEV), evolved separately from those of the Old World, i.e., Sindbis virus (SINV) and Semliki Forest virus (SFV). Nevertheless, the results of our study indicate that both groups have developed the same characteristic: their replication efficiently interferes with cellular transcription and the cell response to virus replication. Transcriptional shutoff caused by at least two of the Old World alphaviruses, SINV and SFV, which belong to different serological complexes, depends on nsP2, but not on the capsid protein, functioning. Our data suggest that the New World alphaviruses VEEV and EEEV developed an alternative mechanism of transcription inhibition that is mainly determined by their capsid protein, but not by the nsP2. The ability of the VEEV capsid to inhibit cellular transcription appears to be controlled by the amino-terminal fragment of the protein, but not by its protease activity or by the positively charged RNA-binding domain. These data provide new insights into alphavirus evolution and present a plausible explanation for the particular recombination events that led to the formation of western equine encephalitis virus (WEEV) from SINV- and EEEV-like ancestors. The recombination allowed WEEV to acquire capsid protein functioning in transcription inhibition from EEEV-like virus. Identification of the new functions in the New World alphavirus-derived capsids opens an opportunity for developing new, safer alphavirus-based gene expression systems and designing new types of attenuated vaccine strains of VEEV and EEEV.
    Keywords: Gene Expression ; Capsids ; Recombination ; Replication ; Transcription ; Proteinase ; Vaccines ; Evolution ; Capsid Protein ; Western Equine Encephalitis Virus ; Venezuelan Equine Encephalitis Virus ; Eastern Equine Encephalitis Virus ; Sindbis Virus ; Alphavirus ; Semliki Forest Virus ; Genetics, Taxonomy & Structure ; DNA Metabolism & Structure;
    ISSN: 0022-538X
    ISSN: 0022538X
    E-ISSN: 10985514
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  • 5
    In: The Journal of Virology, 2005, Vol. 79(12), p.7597
    Description: Venezuelan equine encephalitis (VEE) and eastern equine encephalitis (EEE) viruses are important, naturally emerging zoonotic viruses. They are significant human and equine pathogens which still pose a serious public health threat. Both VEE and EEE cause chronic infection in mosquitoes and persistent or chronic infection in mosquito-derived cell lines. In contrast, vertebrate hosts infected with either virus develop an acute infection with high-titer viremia and encephalitis, followed by host death or virus clearance by the immune system. Accordingly, EEE and VEE infection in vertebrate cell lines is highly cytopathic. To further understand the pathogenesis of alphaviruses on molecular and cellular levels, we designed EEE- and VEE-based replicons and investigated their replication and their ability to generate cytopathic effect (CPE) and to interfere with other viral infections. VEE and EEE replicons appeared to be less cytopathic than Sindbis virus-based constructs that we designed in our previous research and readily established persistent replication in BHK-21 cells. VEE replicons required additional mutations in the 5' untranslated region and nsP2 or nsP3 genes to further reduce cytopathicity and to become capable of persisting in cells with no defects in alpha/beta interferon production or signaling. The results indicated that alphaviruses strongly differ in virus-host cell interactions, and the ability to cause CPE in tissue culture does not necessarily correlate with pathogenesis and strongly depends on the sequence of viral nonstructural proteins.
    Keywords: Encephalitis Virus, Eastern Equine -- Physiology ; Encephalitis Virus, Venezuelan Equine -- Physiology ; Replicon -- Physiology ; Virus Replication -- Physiology;
    ISSN: 0022-538X
    ISSN: 0022538X
    E-ISSN: 10985514
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  • 6
    Language: English
    In: Molecular Imaging and Biology, 2017, Vol.19(2), pp.203-214
    Description: To access, purchase, authenticate, or subscribe to the full-text of this article, please visit this link: http://dx.doi.org/10.1007/s11307-016-1006-1 Byline: Giselle A. Suero-Abreu (1,2,3), Orlando Aristizabal (1), Benjamin B. Bartelle (1,4), Eugenia Volkova (1), Joe J. Rodriguez (1), Daniel H. Turnbull (1,2,3,5) Keywords: Ts-Biotag; Tie2 expression; B16 Melanoma; Ultrasound; MRI; Near infrared Abstract: Purpose In this study, we evaluated a genetic approach for in vivo multimodal molecular imaging of vasculature in a mouse model of melanoma. Procedures We used a novel transgenic mouse, Ts-Biotag, that genetically biotinylates vascular endothelial cells. After inoculating these mice with B16 melanoma cells, we selectively targeted endothelial cells with (strept)avidinated contrast agents to achieve multimodal contrast enhancement of Tie2-expressing blood vessels during tumor progression. Results This genetic targeting system provided selective labeling of tumor vasculature and showed in vivo binding of avidinated probes with high specificity and sensitivity using microscopy, near infrared, ultrasound, and magnetic resonance imaging. We further demonstrated the feasibility of conducting longitudinal three-dimensional (3D) targeted imaging studies to dynamically assess changes in vascular Tie2 from early to advanced tumor stages. Conclusions Our results validated the Ts-Biotag mouse as a multimodal targeted imaging system with the potential to provide spatio-temporal information about dynamic changes in vasculature during tumor progression. Author Affiliation: (1) Skirball Institute of Biomolecular Medicine, New York University School of Medicine (NYUSoM), 540 First Ave, New York, NY, 10016, USA (2) Biomedical Imaging Graduate Program, NYUSoM, New York, NY, USA (3) Department of Radiology, NYUSoM, New York, NY, USA (4) Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA (5) Department of Pathology, NYUSoM, New York, NY, USA Article History: Registration Date: 07/09/2016 Online Date: 27/09/2016 Article note: Electronic supplementary material The online version of this article (doi: 10.1007/s11307-016-1006-1) contains supplementary material, which is available to authorized users.
    Keywords: - ; Tie2 expression ; B16 Melanoma ; Ultrasound ; MRI ; Near infrared
    ISSN: 1536-1632
    E-ISSN: 1860-2002
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  • 7
    Language: English
    In: Virology, 2008, Vol.377(1), pp.160-169
    Description: The development of infectious cDNA for different alphaviruses opened an opportunity to explore their attenuation by extensively modifying the viral genomes, an approach that might minimize or exclude the reversion to the wild-type, pathogenic phenotype. Moreover, the genomes of such alphaviruses can be engineered to contain RNA elements that would be functional only in cells of vertebrate, but not insect, origin. In the present study, we developed a recombinant VEEV that is more attenuated than TC-83 and capable of replicating only in vertebrate cells. This phenotype was achieved by rendering the translation of the viral structural proteins, and ultimately viral replication, dependent on the internal ribosome entry site of encephalomyocarditis virus (EMCV IRES). This recombinant virus was viable, but required additional, adaptive mutations in nsP2 that strongly increased its replication rates. In spite of efficient replication in cultured vertebrate cells, the genetically modified VEEV demonstrated a highly attenuated phenotype in newborn mice, and yet induced protective immunity against VEEV infection.
    Keywords: Alphavirus ; Replication ; Mosquito Cells ; Emcv Ires ; Veev ; Biology
    ISSN: 0042-6822
    E-ISSN: 1096-0341
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  • 8
    Language: English
    In: Neoplasia, December 2014, Vol.16(12), pp.993-1006
    Description: Mouse models have increased our understanding of the pathogenesis of medulloblastoma (MB), the most common malignant pediatric brain tumor that often forms in the cerebellum. A major goal of ongoing research is to better understand the early stages of tumorigenesis and to establish the genetic and environmental changes that underlie MB initiation and growth. However, studies of MB progression in mouse models are difficult due to the heterogeneity of tumor onset times and growth patterns and the lack of clinical symptoms at early stages. Magnetic resonance imaging (MRI) is critical for noninvasive, longitudinal, three-dimensional (3D) brain tumor imaging in the clinic but is limited in resolution and sensitivity for imaging early MBs in mice. In this study, high-resolution (100 μm in 2 hours) and high-throughput (150 μm in 15 minutes) manganese-enhanced MRI (MEMRI) protocols were optimized for early detection and monitoring of MBs in a ( ) conditional knockout (CKO) model. The high tissue contrast obtained with MEMRI revealed detailed cerebellar morphology and enabled detection of MBs over a wide range of stages including pretumoral lesions as early as 2 to 3 weeks postnatal with volumes close to 0.1 mm . Furthermore, longitudinal MEMRI allowed noninvasive monitoring of tumors and demonstrated that lesions within and between individuals have different tumorigenic potentials. 3D volumetric studies allowed quantitative analysis of MB tumor morphology and growth rates in individual CKO mice. These results show that MEMRI provides a powerful method for early detection and longitudinal imaging of MB progression in the mouse brain.
    Keywords: Medicine
    ISSN: 1476-5586
    ISSN: 15228002
    E-ISSN: 1476-5586
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  • 9
    Language: English
    In: Journal of the American College of Cardiology, 07 February 2012, Vol.59(6), pp.616-26
    Description: This study sought to evaluate the in vivo magnetic resonance imaging (MRI) efficacy of manganese [Mn(II)] molecular imaging probes targeted to oxidation-specific epitopes (OSE). OSE are critical in the initiation, progression, and destabilization of atherosclerotic plaques. Gadolinium [Gd(III)]-based MRI agents can be associated with systemic toxicity. Mn is an endogenous, biocompatible, paramagnetic metal ion that has poor MR efficacy when chelated, but strong efficacy when released within cells. Multimodal Mn micelles were generated to contain rhodamine for confocal microscopy and conjugated with either the murine monoclonal IgG antibody MDA2 targeted to malondialdehyde (MDA)-lysine epitopes or the human single-chain Fv antibody fragment IK17 targeted to MDA-like epitopes ("targeted micelles"). Micelle formulations were characterized in vitro and in vivo, and their MR efficacy (9.4-T) evaluated in apolipoprotein-deficient (apoE(-/-)) and low-density lipoprotein receptor negative (LDLR(-/-)) mice (0.05 mmol Mn/kg dose) (total of 120 mice for all experiments). In vivo competitive inhibition studies were performed to evaluate target specificity. Untargeted, MDA2-Gd, and IK17-Gd micelles (0.075 mmol Gd/kg) were included as controls. In vitro studies demonstrated that targeted Mn micelles accumulate in macrophages when pre-exposed to MDA-LDL with ∼10× increase in longitudinal relativity. Following intravenous injection, strong MR signal enhancement was observed 48 to 72 h after administration of targeted Mn micelles, with colocalization within intraplaque macrophages. Co-injection of free MDA2 with the MDA2-Mn micelles resulted in full suppression of MR signal in the arterial wall, confirming target specificity. Similar MR efficacy was noted in apoE(-/-) and LDLR(-/-) mice with aortic atherosclerosis. No significant differences in MR efficacy were noted between targeted Mn and Gd micelles. This study demonstrates that biocompatible multimodal Mn-based molecular imaging probes detect OSE within atherosclerotic plaques and may facilitate clinical translation of noninvasive imaging of human atherosclerosis.
    Keywords: Biocompatible Materials ; Manganese ; Lipoproteins -- Chemistry ; Magnetic Resonance Spectroscopy -- Methods ; Plaque, Atherosclerotic -- Metabolism
    ISSN: 07351097
    E-ISSN: 1558-3597
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  • 10
    Language: English
    In: Advanced Drug Delivery Reviews
    Description: In recent years, as the mechanisms of vasculogenesis and angiogenesis have been uncovered, the functions of various pro-angiogenic growth factors (GFs) and cytokines have been identified. Therefore, therapeutic angiogenesis, by delivery of GFs, has been sought as a treatment for many vascular diseases. However, direct injection of these protein drugs has proven to have limited clinical success due to their short half-lives and systemic off-target effects. To overcome this, hydrogel carriers have been developed to conjugate single or multiple GFs with controllable, sustained, and localized delivery. However, these attempts have failed to account for the temporal complexity of natural angiogenic pathways, resulting in limited therapeutic effects. Recently, the emerging ideas of optimal sequential delivery of multiple GFs have been suggested to better mimic the biological processes and to enhance therapeutic angiogenesis. Incorporating sequential release into drug delivery platforms will likely promote the formation of neovasculature and generate vast therapeutic potential.
    Keywords: Sequential Release ; Angiogenesis ; Hydrogel Carriers ; Growth Factors ; Biology ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0169-409X
    E-ISSN: 1872-8294
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