The Beckman Research Institute is a research facility located at the City of Hope National Medical Center in Duarte, CA, United States. It is dedicated to studying normal and abnormal biological processes which may be related to cancer. The institute was dedicated in 1952, and endowed by the Arnold and Mabel Beckman Foundation in 1983 when it was given its current name. It was the first of five Beckman institutes in the United States. It also hosts the Irell & Manella Graduate School of Biological science whose founding dean was Arthur Riggs. The BRI's current director is Richard Jove, Ph.D. Wikipedia.
Burnett J.C.,Beckman Research Institute |
Rossi J.J.,Beckman Research Institute
Chemistry and Biology | Year: 2012
Recent advances of biological drugs have broadened the scope of therapeutic targets for a variety of human diseases. This holds true for dozens of RNA-based therapeutics currently under clinical investigation for diseases ranging from genetic disorders to HIV infection to various cancers. These emerging drugs, which include therapeutic ribozymes, aptamers, and small interfering RNAs (siRNAs), demonstrate the unprecedented versatility of RNA. However, RNA is inherently unstable, potentially immunogenic, and typically requires a delivery vehicle for efficient transport to the targeted cells. These issues have hindered the clinical progress of some RNA-based drugs and have contributed to mixed results in clinical testing. Nevertheless, promising results from recent clinical trials suggest that these barriers may be overcome with improved synthetic delivery carriers and chemical modifications of the RNA therapeutics. This review focuses on the clinical results of siRNA, RNA aptamer, and ribozyme therapeutics and the prospects for future successes. © 2012 Elsevier Ltd All rights reserved.
Kato M.,Beckman Research Institute |
Natarajan R.,Beckman Research Institute
Nature Reviews Nephrology | Year: 2014
Diabetic nephropathy (DN), a severe microvascular complication frequently associated with both type 1 and type 2 diabetes mellitus, is a leading cause of renal failure. The condition can also lead to accelerated cardiovascular disease and macrovascular complications. Currently available therapies have not been fully efficacious in the treatment of DN, suggesting that further understanding of the molecular mechanisms underlying the pathogenesis of DN is necessary for the improved management of this disease. Although key signal transduction and gene regulation mechanisms have been identified, especially those related to the effects of hyperglycaemia, transforming growth factor Î 21 and angiotensin II, progress in functional genomics, high-throughput sequencing technology, epigenetics and systems biology approaches have greatly expanded our knowledge and uncovered new molecular mechanisms and factors involved in DN. These mechanisms include DNA methylation, chromatin histone modifications, novel transcripts and functional noncoding RNAs, such as microRNAs and long noncoding RNAs. In this Review, we discuss the significance of these emerging mechanisms, how they mediate the actions of growth factors to augment the expression of extracellular matrix and inflammatory genes associated with DN and their potential usefulness as diagnostic biomarkers or novel therapeutic targets for DN. © 2014 Macmillan Publishers Limited.
Boldin M.P.,Beckman Research Institute |
Baltimore D.,California Institute of Technology
Immunological Reviews | Year: 2012
Since its discovery 25years ago, nuclear factor-κB (NF-κB) has emerged as a transcription factor that controls diverse biological functions, ranging from inflammation to learning and memory. Activation of NF-κB initiates an elaborate genetic program. Some of the NF-κB-driven genes do not encode proteins but rather are precursors to microRNAs. These microRNAs play important roles in the regulation of the inflammatory process, some being inhibitory and others activating. Here, we discuss both the regulation of their expression and the function of some of these non-coding RNA genes. We also include a personal discussion of how NF-κB was first discovered. © 2012 John Wiley & Sons A/S.
Rossi J.J.,Beckman Research Institute
EMBO Journal | Year: 2011
Micro RNAs (miRNAs) are 21-23 nucleotide long RNAs that associate with the Argonaute family of proteins and direct interactions of these and RNA-induced silencing complex (RISC) components to the 30-UTRs of mRNAs that harbour partially complementary sequences. The paradigm for miRNA function has been that they inhibit gene expression by translational inhibition and subsequent mRNA degradation. However, a series of recent studies have revealed that subsets of miRNAs are also localized in the nucleus, suggesting that they perform different functions in this cellular compartment. In this issue of The EMBO Journal, Hansen et al (2011) describe that nuclear localized miRNAs target non-coding RNAs (ncRNAs) revealing an intriguing and novel mechanism for gene regulation. © 2011 European Molecular Biology Organization | All Rights Reserved.
Yu H.,Beckman Research Institute |
Lee H.,Beckman Research Institute |
Herrmann A.,Beckman Research Institute |
Buettner R.,Beckman Research Institute |
Jove R.,Vaccine and Gene Therapy Institute of Florida
Nature Reviews Cancer | Year: 2014
The Janus kinases (JAKs) and signal transducer and activator of transcription (STAT) proteins, particularly STAT3, are among the most promising new targets for cancer therapy. In addition to interleukin-6 (IL-6) and its family members, multiple pathways, including G-protein-coupled receptors (GPCRs), Toll-like receptors (TLRs) and microRNAs were recently identified to regulate JAK-STAT signalling in cancer. Well known for its role in tumour cell proliferation, survival, invasion and immunosuppression, JAK-STAT3 signalling also promotes cancer through inflammation, obesity, stem cells and the pre-metastatic niche. In addition to its established role as a transcription factor in cancer, STAT3 regulates mitochondrion functions, as well as gene expression through epigenetic mechanisms. Newly identified regulators and functions of JAK-STAT3 in tumours are important targets for potential therapeutic strategies in the treatment of cancer. © 2014 Macmillan Publishers Limited. All rights reserved.
Kato M.,Beckman Research Institute
Kidney International | Year: 2013
MicroRNAs (miRNAs) are emerging molecules in the pathogenesis of human diseases. Identification of miRNAs related to renal fibrosis provides clues to find new signaling pathways to fill the gaps between signaling molecules. Li et al. report another new pathway mediated by miR-433 that is induced by transforming growth factor-β1 in mouse models of renal fibrosis. The signaling also makes a positive-feedback circuit loop, which could be translated into new therapeutic targets.© 2013 International Society of Nephrology.
Zaia J.A.,Beckman Research Institute
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2013
With the advent of effective antiretroviral therapy, the treatment of patients with HIV-related malignancies, especially lymphoma, has greatly improved, yielding results comparable to those seen in patients with lymphoma unrelated to HIV. The platform of transplantation of hematopoietic stem cells has facilitated studies of genetically modified stem cells engineered to express antiretroviral genes to resist infection by the HIV virus, testing the concept that engraftment of these cells will lead to HIV resistance and elimination of the reservoir of virus in the body. Results in patients with HIV and lymphoma have now led to studies that will test these principles in HIV patients without concomitant malignancy. In addition, in a patient with HIV and acute myeloid leukemia, the success of an allogeneic transplantation from an unrelated donor carrying a mutation in the CCR5 genes has demonstrated that, in principle, such an approach could also lead to cure of patients with HIV. Case studies in HIV patients with leukemia undergoing allogeneic transplantation also suggest that there may be a therapeutic effect on the HIV reservoir that could alter the natural history of HIV in the allogeneic setting.
Roth M.,Beckman Research Institute |
Chen W.Y.,Beckman Research Institute
Oncogene | Year: 2014
The sirtuins (SIRT 1-7) comprise a family of NAD+ -dependent protein-modifying enzymes with activities in lysine deacetylation, adenosinediphospho(ADP)-ribosylation, and/or deacylation. These enzymes are involved in the cell's stress response systems and in regulating gene expression, DNA damage repair, metabolism and survival. Sirtuins have complex roles in both promoting and/or suppressing tumorigenesis. This review presents recent research progress concerning sirtuins and cancer. On one hand, functional loss of sirtuin genes, particularly SIRT1, involved in maintaining genome integrity and DNA repair will promote tumorigenesis because of genomic instability upon their loss. On the other hand, cancer cells tend to require sirtuins for these same processes to allow them to survive, proliferate, repair the otherwise catastrophic genomic events and evolve. The bifurcated roles of SIRT1, and perhaps several other sirtuins, in cancer may be in part a result of the nature of the genes that are involved in the cell's genome maintenance systems. The in-depth understanding of sirtuin functions may have significant implication in designing precise modulation of selective sirtuin members to aid cancer prevention or treatment under defined conditions. © 2014 Macmillan Publishers Limited.
Deng X.,Beckman Research Institute
BMC Bioinformatics | Year: 2011
Background: The popularity of massively parallel exome and transcriptome sequencing projects demands new data mining tools with a comprehensive set of features to support a wide range of analysis tasks.Results: SeqGene, a new data mining tool, supports mutation detection and annotation, dbSNP and 1000 Genome data integration, RNA-Seq expression quantification, mutation and coverage visualization, allele specific expression (ASE), differentially expressed genes (DEGs) identification, copy number variation (CNV) analysis, and gene expression quantitative trait loci (eQTLs) detection. We also developed novel methods for testing the association between SNP and expression and identifying genotype-controlled DEGs. We showed that the results generated from SeqGene compares favourably to other existing methods in our case studies.Conclusion: SeqGene is designed as a general-purpose software package. It supports both paired-end reads and single reads generated on most sequencing platforms; it runs on all major types of computers; it supports arbitrary genome assemblies for arbitrary organisms; and it scales well to support both large and small scale sequencing projects. The software homepage is http://seqgene.sourceforge.net. © 2011 Deng; licensee BioMed Central Ltd.
Pan H.,Beckman Research Institute |
Shively J.E.,Beckman Research Institute
Immunity | Year: 2010
Although carcinoembryonic antigen-related cell adhesion moclecule-1 (CEACAM1) is an activation marker for neutrophils and delays neutrophil apoptosis, the role of CEACAM1 in granulopoiesis and neutrophil-dependent host immune responses has not been investigated. CEACAM1 expression correlated with granulocytic differentiation, and Ceacam1-/- mice developed neutrophilia because of loss of the Src-homology-phosphatase-1 (SHP-1)-dependent inhibition of granulocyte colony-stimulating factor receptor (G-CSFR) signal transducer and activator of transcription (Stat3) pathway provided by CEACAM1. Moreover, Ceacam1-/- mice were hypersensitive to Listeria Monocytogenes (LM) infection with an accelerated mortality. Reintroduction of CEACAM1 into Ceacam1-/- bone marrow restored normal granulopoiesis and host sensitivity to LM infection, while mutation of its immunoreceptor tyrosine-based inhibitory motifs (ITIMs) abrogated this restoration. shRNA-mediated reduction of Stat3 amounts rescued normal granulopoiesis, attenuating host sensitivity to LM infection in Ceacam1-/- mice. Thus, CEACAM1 acted as a coinhibitory receptor for G-CSFR regulating granulopoiesis and host innate immune response to bacterial infections. © 2010 Elsevier Inc.