Beckman Research Institute

Duarte, CA, United States

Beckman Research Institute

Duarte, CA, United States

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.

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Vaidehi N.,Beckman Research Institute | Grisshammer R.,U.S. National Institutes of Health | Tate C.G.,Medical Research Council MRC
Trends in Pharmacological Sciences | Year: 2016

Structures of over 30 different G-protein-coupled receptors (GPCRs) have advanced our understanding of cell signaling and have provided a foundation for structure-guided drug design. This exciting progress has required the development of three complementary methods to facilitate GPCR crystallization, one of which is the thermostabilization of receptors by systematic mutagenesis. However, the reason why a particular mutation, or combination of mutations, stabilizes the receptor is not always evident from a static crystal structure. Molecular dynamics (MD) simulations have been used to identify and estimate the energetic factors that affect thermostability through comparing the dynamics of the thermostabilized receptors with structure-based models of the wild-type receptor. The data indicate that receptors are stabilized through a combination of factors, including an increase in receptor rigidity, a decrease in collective motion, reduced stress at specific residues, and the presence of ordered water molecules. Predicting thermostabilizing mutations computationally represents a major challenge for the field. © 2015 Elsevier Ltd. All rights reserved.


Vaidehi N.,Beckman Research Institute
Drug Discovery Today | Year: 2010

G-protein coupled receptors (GPCRs) are seven helical transmembrane proteins with functional diversity and form the largest superfamily of drug targets. The functional diversity of these receptors stems from the conformational flexibility of the receptor, the nature of the ligand activating the receptor, and the intracellular protein that the receptor couples to. A molecular level understanding of the influence of each of these factors will greatly aid the design of functional selective drugs. In this review, the current state of our understanding of the conformational flexibility and dynamics of class A GPCRs derived from a confluence of biophysical and computational techniques is elucidated. © 2010 Elsevier Ltd.


Sun G.,Beckman Research Institute | Rossi J.J.,Beckman Research Institute
Trends in Pharmacological Sciences | Year: 2011

Treatment and cure of HIV-1 infection remain one of the greatest therapeutic challenges owing to its persistent infection, which often leads to AIDS. Although it has been 28 years since the discovery of the virus, the development of an effective vaccine is still years away. Relatively newly discovered miRNAs are a family of small noncoding RNAs that can regulate gene expression primarily by binding to the 3′ untranslated region of targeted transcripts. An understanding of how HIV-1 infection affects the host miRNA pathway could generate new insights into the basic mechanisms underlying HIV-1-mediated pathologies and T-lymphocyte depletion. Here, we review literature on the biogenesis of HIV-1-encoded miRNAs, cellular miRNAs that can directly target HIV-1 or essential cellular factors required for HIV-1 replication. We also discuss the feasibility of using miRNAs for HIV-1 therapy. © 2011 Elsevier Ltd. All rights reserved.


Zhou J.,Beckman Research Institute | Rossi J.,Beckman Research Institute
Nature Reviews Drug Discovery | Year: 2017

Nucleic acid aptamers, often termed 'chemical antibodies', are functionally comparable to traditional antibodies, but offer several advantages, including their relatively small physical size, flexible structure, quick chemical production, versatile chemical modification, high stability and lack of immunogenicity. In addition, many aptamers are internalized upon binding to cellular receptors, making them useful targeted delivery agents for small interfering RNAs (siRNAs), microRNAs and conventional drugs. However, several crucial factors have delayed the clinical translation of therapeutic aptamers, such as their inherent physicochemical characteristics and lack of safety data. This Review discusses these challenges, highlighting recent clinical developments and technological advances that have revived the impetus for this promising class of therapeutics.


Bobbin M.L.,Massachusetts General Hospital | Rossi J.J.,Beckman Research Institute
Annual Review of Pharmacology and Toxicology | Year: 2016

A resurgence in clinical trials using RNA interference (RNAi) occurred in 2012. Although there were initial difficulties in achieving efficacious results with RNAi without toxic side effects, advances in delivery and improved chemistry made this resurgence possible. More than 20 RNAi-based therapeutics are currently in clinical trials, and several of these are Phase III trials. Continued positive results from these trials have helped bolster further attempts to develop clinically relevant RNAi therapies. With a wide variety of disease targets to choose from, the first RNAi therapeutic to be clinically approved is not far off. This review covers recently established and completed clinical trials. Copyright © 2016 by Annual Reviews. All rights reserved.


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.


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.


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.


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.


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.

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