Crump Institute for Molecular Imaging

Westwood, CA, United States

Crump Institute for Molecular Imaging

Westwood, CA, United States
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Koya R.C.,Roswell Park Cancer Institute | Tsui C.,University of California at Los Angeles | Robert L.,University of California at Los Angeles | Wu L.,Institute for Molecular Medicine | And 8 more authors.
Cancer Research | Year: 2014

Colony stimulating factor 1 (CSF-1) recruits tumor-infiltrating myeloid cells (TIM) that suppress tumor immunity, including M2 macrophages and myeloid-derived suppressor cells (MDSC). The CSF-1 receptor (CSF-1R) is a tyrosine kinase that is targetable by small molecule inhibitors such as PLX3397. In this study, we used a syngeneic mouse model of BRAFV600E-driven melanoma to evaluate the ability of PLX3397 to improve the efficacy of adoptive cell therapy (ACT). In this model, we found that combined treatment produced superior antitumor responses compared with single treatments. In mice receiving the combined treatment, a dramatic reduction of TIMs and a skewing of MHCII low to MHCIIhi macrophages were observed. Furthermore, mice receiving the combined treatment exhibited an increase in tumor-infiltrating lymphocytes (TIL) and T cells, as revealed by real-time imaging in vivo. In support of these observations, TILs from these mice released higher levels of IFN-γ. In conclusion, CSF-1R blockade with PLX3397 improved the efficacy of ACT immunotherapy by inhibiting the intratumoral accumulation of immunosuppressive macrophages. © 2014 American Association for Cancer Research.


Koya R.C.,Crump Institute for Molecular Imaging | Koya R.C.,University of California at Los Angeles | Mok S.,Crump Institute for Molecular Imaging | Otte N.,Crump Institute for Molecular Imaging | And 11 more authors.
Cancer Research | Year: 2012

Combining immunotherapy with targeted therapy blocking oncogenic BRAF V600 may result in improved treatments for advanced melanoma. In this study, we developed a BRAFV600E-driven murine model of melanoma, SM1, which is syngeneic to fully immunocompetent mice. SM1 cells exposed to the BRAF inhibitor vemurafenib (PLX4032) showed partial in vitro and in vivo sensitivity resulting from the inhibition of MAPK pathway signaling. Combined treatment of vemurafenib plus adoptive cell transfer therapy with lymphocytes genetically modified with a T-cell receptor (TCR) recognizing chicken ovalbumin (OVA) expressed by SM1-OVA tumors or pmel-1 TCR transgenic lymphocytes recognizing gp100 endogenously expressed by SM1 resulted in superior antitumor responses compared with either therapy alone. T-cell analysis showed that vemurafenib did not significantly alter the expansion, distribution, or tumor accumulation of the adoptively transferred cells. However, vemurafenib paradoxically increased mitogen-activated protein kinase (MAPK) signaling, in vivo cytotoxic activity, and intratumoral cytokine secretion by adoptively transferred cells. Taken together, our findings, derived from 2 independent models combining BRAF-targeted therapy with immunotherapy, support the testing of this therapeutic combination in patients with BRAFV600 mutant metastatic melanoma. ©2012 AACR.


News Article | November 15, 2016
Site: www.prweb.com

Preclinical imaging enables the measurement and assessment of biological processes in vivo utilizing methodologies such as bioluminescence, fluorescence and positron emission tomography (PET) to assay cells, tissues, and living organisms. PerkinElmer’s suite of optical and PET research scanners set the industry standard for sensitivity, quantitative accuracy, and data reproducibility. Such instruments helped to enable premier research institutions, like UCLA, the opportunity to advance preclinical and translational science while fostering collaboration among imaging laboratories both internally and externally. In this institutional highlight webinar series, participants will hear UCLA researchers share insight on how a successful imaging program at UCLA has been instrumental in generating novel models of disease and conducting cutting edge research. Employing several imaging modalities, these studies demonstrate a successful model for noninvasive, in vivo examination of spine implant infection where both bacterial burden and host inflammation can be monitored longitudinally in real-time without requiring animal sacrifice. The two UCLA researchers presenting during this webinar are Dr. Nick Bernthal, of the UCLA Global Orthopaedic Initiative, and Dr. Jason Lee, Director from the Department of Molecular and Medical Pharmacology (DMMP) at the David Geffen School of Medicine at UCLA. Bernthal is currently the chief at the Division of Musculoskeletal Oncology and director of the UCLA Global Orthopaedic Initiative. He graduated magna cum laude and phi beta kappa from Princeton University and received alpha omega alpha honors from Cornell University Medical School. He did his residency at UCLA in orthopaedic surgery and did fellowships in orthopaedic research and musculoskeletal oncology at UCLA and the Huntsman Cancer Institute, respectively. Lee is the director of the Preclinical Imaging Technology Center at the Crump Institute for Molecular Imaging in the Department of Molecular and Medical Pharmacology (DMMP), at the David Geffen School of Medicine at UCLA. He received his doctorate in DMMP under Dr. Caius Radu and his postdoctoral training in molecular imaging at Memorial Sloan Kettering Cancer Center under Dr. Vladimir Ponomarev. His work focuses on the development and integration of in vivo imaging assays to quantitatively assess the functional dynamics of health and disease, and to study associated therapeutic interventions in preclinical models. This webinar, hosted by LabRoots at no cost to users, will be presented December 1, 2016 at 8:00 a.m. PT, 11:00 a.m. ET; the presentation will be followed by a live Q&A. To get the full details of this webinar and to register, click here. About LabRoots LabRoots is the leading scientific social networking website and producer of educational virtual events and webinars. Contributing to the advancement of science through content sharing capabilities, LabRoots is a powerful advocate in amplifying global networks and communities. Founded in 2008, LabRoots emphasizes digital innovation in scientific collaboration and learning, and is a primary source for current scientific news, webinars, virtual conferences, and more. LabRoots has grown into the world’s largest series of virtual events within the Life Sciences and Clinical Diagnostics community.


Fitz-Gibbon S.,Crump Institute for Molecular Imaging | Tomida S.,Crump Institute for Molecular Imaging | Chiu B.-H.,Crump Institute for Molecular Imaging | Nguyen L.,Crump Institute for Molecular Imaging | And 15 more authors.
Journal of Investigative Dermatology | Year: 2013

The human skin microbiome has important roles in skin health and disease. However, bacterial population structure and diversity at the strain level is poorly understood. We compared the skin microbiome at the strain level and genome level of Propionibacterium acnes, a dominant skin commensal, between 49 acne patients and 52 healthy individuals by sampling the pilosebaceous units on their noses. Metagenomic analysis demonstrated that although the relative abundances of P. acnes were similar, the strain population structures were significantly different in the two cohorts. Certain strains were highly associated with acne, and other strains were enriched in healthy skin. By sequencing 66 previously unreported P. acnes strains and comparing 71 P. acnes genomes, we identified potential genetic determinants of various P. acnes strains in association with acne or health. Our analysis suggests that acquired DNA sequences and bacterial immune elements may have roles in determining virulence properties of P. acnes strains, and some could be future targets for therapeutic interventions. This study demonstrates a previously unreported paradigm of commensal strain populations that could explain the pathogenesis of human diseases. It underscores the importance of strain-level analysis of the human microbiome to define the role of commensals in health and disease. © 2013 The Society for Investigative Dermatology.


Knowles S.M.,Crump Institute for Molecular Imaging | Tavare R.,Crump Institute for Molecular Imaging | Zettlitz K.A.,Crump Institute for Molecular Imaging | Rochefort M.M.,University of California at Los Angeles | And 6 more authors.
Clinical Cancer Research | Year: 2014

Purpose: Prostate stem cell antigen (PSCA) is highly expressed in local prostate cancers and prostate cancer bone metastases and its expression correlates with androgen receptor activation and a poor prognosis. In this study, we investigate the potential clinical applications of immunoPET with the anti- PSCA A11 minibody, an antibody fragment optimized for use as an imaging agent. We compare A11 minibody immunoPET to 18F-Fluoride PET bone scans for detecting prostate cancer bone tumors and evaluate the ability of the A11 minibody to image tumor response to androgen deprivation.Experimental Design: Osteoblastic, PSCA-expressing, LAPC-9 intratibial xenografts were imaged with serial 124I-anti-PSCA A11 minibody immunoPET and 18F-Fluoride bone scans. Mice bearing LAPC-9 subcutaneous xenografts were treated with either vehicle or MDV-3100 and imaged with A11 minibody immunoPET/CT scans pre- and posttreatment. Ex vivo flow cytometry measured the change in PSCA expression in response to androgen deprivation.Results: A11 minibody demonstrated improved sensitivity and specificity over 18F-Fluoride bone scans for detecting LAPC-9 intratibial xenografts at all time points. LAPC-9 subcutaneous xenografts showed downregulation ofPSCA when treated with MDV-3100 which A11 minibody immunoPET was able to detect in vivo.Conclusions: A11 minibody immunoPET has the potential to improve the sensitivity and specificity of clinical prostate cancer metastasis detection over bone scans, which are the current clinical standard-of- care. A11 minibody immunoPET additionally has the potential to image the activity of the androgen signaling axis in vivo which may help evaluate the clinical response to androgen deprivation and the development of castration resistance. © 2014 American Association for Cancer Research.


Kang D.,Crump Institute for Molecular Imaging | Shi B.,Crump Institute for Molecular Imaging | Erfe M.C.,University of California at Los Angeles | Craft N.,University of California at Los Angeles | And 2 more authors.
Science Translational Medicine | Year: 2015

Various diseases have been linked to the human microbiota, but the underlying molecular mechanisms of the microbiota in disease pathogenesis are often poorly understood. Using acne as a disease model, we aimed to understand the molecular response of the skin microbiota to host metabolite signaling in disease pathogenesis. Metatranscriptomic analysis revealed that the transcriptional profiles of the skin microbiota separated acne patients from healthy individuals. The vitamin B12 biosynthesis pathway in the skin bacterium Propionibacterium acnes was significantly down-regulated in acne patients. We hypothesized that host vitamin B12 modulates the activities of the skin microbiota and contributes to acne pathogenesis. To test this hypothesis, we analyzed the skin microbiota in healthy subjects supplemented with vitamin B12. We found that the supplementation repressed the expression of vitamin B12 biosynthesis genes in P. acnes and altered the transcriptome of the skin microbiota. One of the 10 subjects studied developed acne 1 week after vitamin B12 supplementation. To further understand the molecular mechanism, we revealed that vitamin B12 supplementation in P. acnes cultures promoted the production of porphyrins, which have been shown to induce inflammation in acne. Our findings suggest a new bacterial pathogenesis pathway in acne and provide one molecular explanation for the long-standing clinical observation that vitamin B12 supplementation leads to acne development in a subset of individuals. Our study discovered that vitamin B12, an essential nutrient in humans, modulates the transcriptional activities of skin bacteria, and provided evidence that metabolite-mediated interactions between the host and the skin microbiota play essential roles in disease development.


Tavare R.,Crump Institute for Molecular Imaging | Wu W.H.,Crump Institute for Molecular Imaging | Zettlitz K.A.,Crump Institute for Molecular Imaging | Salazar F.B.,Crump Institute for Molecular Imaging | And 3 more authors.
Protein Engineering, Design and Selection | Year: 2014

Activated leukocyte cell adhesion molecule (ALCAM) is an immunoglobulin superfamily cell adhesion molecule that is aberrantly expressed in a wide variety of human tumors, including melanoma, prostate cancer, breast cancer, colorectal carcinoma, bladder cancer and pancreatic adenocarcinoma. This wide spectrum of human malignancies makes ALCAM a prospective pan-cancer immunoPET target to aid in detection and diagnosis in multiple malignancies. In this study, we assess site-specific versus non-site-specific conjugation strategies for 64Cu-DOTA (1,4,7,10-tetraazacyclo-dodecane-1,4,7,10-tetraacetic acid) immunoPET imaging of a fully human ALCAM cys-diabody (cDb) with a reduced linker length that retains its bivalent binding ability. ALCAM constructs with linker lengths of eight, five and three amino acids were produced to make true non-covalent site-specifically modified cDbs. Characterization by gel electrophoresis, size exclusion chromatography, flow cytometry and mass spectrometry of the various constructs was performed. To demonstrate the increased utility of targeting multiple malignancies expressing ALCAM, we compare the targeting of the site-specific versus non-site-specific conjugated cDbs to the human colorectal cancer xenograft LS174T. Interestingly, the conjugation strategy not only affects tumor targeting but also hepatic and renal uptake/clearance. © The Author 2014. Published by Oxford University Press. All rights reserved.


Tomida S.,Crump Institute for Molecular Imaging | Nguyen L.,Crump Institute for Molecular Imaging | Chiu B.-H.,Crump Institute for Molecular Imaging | Liu J.,Crump Institute for Molecular Imaging | And 4 more authors.
mBio | Year: 2013

Propionibacterium acnes constitutes a major part of the skin microbiome and contributes to human health. However, it has also been implicated as a pathogenic factor in several diseases, including acne, one of the most common skin diseases. Its pathogenic role, however, remains elusive. To better understand the genetic landscape and diversity of the organism and its role in human health and disease, we performed a comparative genome analysis of 82 P. acnes strains, 69 of which were sequenced by our group. This collection covers all known P. acnes lineages, including types IA, IB, II, and III. Our analysis demonstrated that although the P. acnes pan-genome is open, it is relatively small and expands slowly. The core regions, shared by all the sequenced genomes, accounted for 88% of the average genome. Comparative genome analysis showed that within each lineage, the strains isolated from the same individuals were more closely related than the ones isolated from different individuals, suggesting that clonal expansions occurred within each individual microbiome. We also identified the genetic elements specific to each lineage. Differences in harboring these elements may explain the phenotypic and functional differences of P. acnes in functioning as a commensal in healthy skin and as a pathogen in diseases. Our findings of the differences among P. acnes strains at the genome level underscore the importance of identifying the human microbiome variations at the strain level in understanding its association with diseases and provide insight into novel and personalized therapeutic approaches for P. acnes-related diseases. IMPORTANCE Propionibacterium acnes is a major human skin bacterium. It plays an important role in maintaining skin health. However, it has also been hypothesized to be a pathogenic factor in several diseases, including acne, a common skin disease affecting 85% of teenagers. To understand whether different strains have different virulent properties and thus play different roles in health and diseases, we compared the genomes of 82 P. acnes strains, most of which were isolated from acne or healthy skin. We identified lineage-specific genetic elements that may explain the phenotypic and functional differences of P. acnes as a commensal in health and as a pathogen in diseases. By analyzing a large number of sequenced strains, we provided an improved understanding of the genetic landscape and diversity of the organism at the strain level and at the molecular level that can be further applied in the development of new and personalized therapies. © 2013 Tomida et al.


Barnard E.,Crump Institute for Molecular Imaging | Li H.,U.S. Department of Energy
Journal of Physiology | Year: 2016

The skin is the largest organ in the human body and provides the first line of defence against environmental attack and pathogen invasion. It harbor multiple commensal microbial communities at different body sites, which play important roles in sensing the environment, protecting against colonization and infection of pathogens, and guiding the host immune system in response to foreign invasions. The skin microbiome is largely variable between individuals and body sites, with several core commensal members commonly shared among individuals at the healthy state. These microbial commensals are essential to skin health and can potentially lead to disease when their abundances and activities change due to alterations in the environment or in the host. While recent advances in sequencing technologies have enabled a large number of studies to characterize the taxonomic composition of the skin microbiome at various body sites and under different physiological conditions, we have limited understanding of the microbiome composition and dynamics at the strain level, which is highly important to many microbe-related diseases. Functional studies of the skin microbial communities and the interactions among community members and with the host are currently scant, warranting future investigations. In this review, we summarize the recent findings on the skin microbiome, highlighting the roles of the major commensals, including bacteria, fungi and bacteriophages, in modulating skin functions in health and disease. Functional studies of the skin microbiota at the metatranscriptomic and proteomic levels are also included to illustrate the interactions between the microbiota and the host skin. Journal compilation © 2016 The Physiological Society.


Liu K.,Crump Institute for Molecular Imaging | Chen Y.-C.,Crump Institute for Molecular Imaging | Tseng H.-R.,Crump Institute for Molecular Imaging | Shen C.K.-F.,Crump Institute for Molecular Imaging | Van Dam R.M.,Crump Institute for Molecular Imaging
Microfluidics and Nanofluidics | Year: 2010

Using liquid slugs as microreactors and microvessels enable precise control over the conditions of their contents on short-time scales for a wide variety of applications. Particularly for screening applications, there is a need for control of slug parameters such as size and composition. We describe a new microfluidic approach for creating slugs in air, each comprising a size and composition that can be selected individually for each slug. Twocomponent slugs are formed by first metering the desired volume of each reagent, merging the two volumes into an end-to-end slug, and propelling the slug to induce mixing. Volume control is achieved by a novel mechanism: two closed chambers on the chip are initially filled with air, and a valve in each is briefly opened to admit one of the reagents. The pressure of each reagent can be individually selected and determines the amount of air compression, and thus the amount of liquid that is admitted into each chamber. We describe the theory of operation, characterize the slug generation chip, and demonstrate the creation of slugs of different compositions. The use of microvalves in this approach enables robust operation with different liquids, and also enables one to work with extremely small samples, even down to a few slug volumes. The latter is important for applications involving precious reagents such as optimizing the reaction conditions for radiolabeling biological molecules as tracers for positron emission tomography.

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