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1.
PLoS Biol ; 18(4): e3000656, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32271748

RESUMEN

Chemokines and their receptors are orchestrators of cell migration in humans. Because dysregulation of the receptor-chemokine system leads to inflammation and cancer, both chemokines and receptors are highly sought therapeutic targets. Yet one of the barriers for their therapeutic targeting is the limited understanding of the structural principles behind receptor-chemokine recognition and selectivity. The existing structures do not include CXC subfamily complexes and lack information about the receptor distal N-termini, despite the importance of the latter in signaling, regulation, and bias. Here, we report the discovery of the geometry of the complex between full-length CXCR4, a prototypical CXC receptor and driver of cancer metastasis, and its endogenous ligand CXCL12. By comprehensive disulfide cross-linking, we establish the existence and the structure of a novel interface between the CXCR4 distal N-terminus and CXCL12 ß1-strand, while also recapitulating earlier findings from nuclear magnetic resonance, modeling and crystallography of homologous receptors. A cross-linking-informed high-resolution model of the CXCR4-CXCL12 complex pinpoints the interaction determinants and reveals the occupancy of the receptor major subpocket by the CXCL12 proximal N terminus. This newly found positioning of the chemokine proximal N-terminus provides a structural explanation of CXC receptor-chemokine selectivity against other subfamilies. Our findings challenge the traditional two-site understanding of receptor-chemokine recognition, suggest the possibility of new affinity and signaling determinants, and fill a critical void on the structural map of an important class of therapeutic targets. These results will aid the rational design of selective chemokine-receptor targeting small molecules and biologics with novel pharmacology.


Asunto(s)
Quimiocina CXCL12/química , Quimiocina CXCL12/metabolismo , Receptores CXCR4/química , Receptores CXCR4/metabolismo , Animales , Sitios de Unión , Western Blotting , Quimiocina CXCL12/genética , Cisteína/química , Cisteína/genética , Disulfuros/química , Citometría de Flujo , Células HEK293 , Humanos , Insectos/citología , Modelos Moleculares , Mutación , Conformación Proteica , Dominios y Motivos de Interacción de Proteínas , Receptores CXCR4/genética , beta-Arrestinas/metabolismo
2.
Proc Natl Acad Sci U S A ; 111(50): E5363-72, 2014 Dec 16.
Artículo en Inglés | MEDLINE | ID: mdl-25468967

RESUMEN

Chemokines and their receptors regulate cell migration during development, immune system function, and in inflammatory diseases, making them important therapeutic targets. Nevertheless, the structural basis of receptor:chemokine interaction is poorly understood. Adding to the complexity of the problem is the persistently dimeric behavior of receptors observed in cell-based studies, which in combination with structural and mutagenesis data, suggest several possibilities for receptor:chemokine complex stoichiometry. In this study, a combination of computational, functional, and biophysical approaches was used to elucidate the stoichiometry and geometry of the interaction between the CXC-type chemokine receptor 4 (CXCR4) and its ligand CXCL12. First, relevance and feasibility of a 2:1 stoichiometry hypothesis was probed using functional complementation experiments with multiple pairs of complementary nonfunctional CXCR4 mutants. Next, the importance of dimers of WT CXCR4 was explored using the strategy of dimer dilution, where WT receptor dimerization is disrupted by increasing expression of nonfunctional CXCR4 mutants. The results of these experiments were supportive of a 1:1 stoichiometry, although the latter could not simultaneously reconcile existing structural and mutagenesis data. To resolve the contradiction, cysteine trapping experiments were used to derive residue proximity constraints that enabled construction of a validated 1:1 receptor:chemokine model, consistent with the paradigmatic two-site hypothesis of receptor activation. The observation of a 1:1 stoichiometry is in line with accumulating evidence supporting monomers as minimal functional units of G protein-coupled receptors, and suggests transmission of conformational changes across the dimer interface as the most probable mechanism of altered signaling by receptor heterodimers.


Asunto(s)
Quimiocina CXCL12/química , Modelos Moleculares , Complejos Multiproteicos/química , Receptores CXCR4/química , Biofisica , Biología Computacional/métodos , Dimerización , Células HEK293 , Humanos , Inmunoprecipitación , Resonancia Magnética Nuclear Biomolecular , Conformación Proteica , Receptores CXCR4/genética
3.
J Assoc Inf Sci Technol ; 72(11): 1337-1353, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34692897

RESUMEN

This paper examines how shared affiliations within an institution (e.g., same primary appointment, same secondary appointment, same research center, same laboratory/facility) and physical proximity (e.g., walking distance between collaborator offices) shape knowledge creation through biomedical science collaboration in general, and interdisciplinary collaboration in particular. Using archival and publication data, we examine pairwise research collaborations among 1,138 faculty members over a 12-year period at a medical school in the United States. Modeling at the dyadic level, we find that faculty members with more shared institutional affiliations are positively associated with knowledge creation and knowledge impact, and that this association is moderated by the physical proximity of collaborators. We further find that the positive influence of disciplinary diversity (e.g., collaborators from different fields) on knowledge impact is stronger among pairs that share more affiliations and is significantly reduced as the physical distance among collaborators increases. These results support the idea that shared institutional affiliations and physical proximity can increase interpersonal contact, providing more opportunities to develop trust and mutual understanding, and thus alleviating some of the coordination issues that can arise with higher disciplinary diversity. We discuss the implications for future research on scientific collaborations, managerial practice regarding office space allocation, and strategic planning of initiatives aimed at promoting interdisciplinary collaboration.

4.
Sci Signal ; 13(640)2020 07 14.
Artículo en Inglés | MEDLINE | ID: mdl-32665413

RESUMEN

Because of their prominent roles in development, cancer, and HIV, the chemokine receptor CXCR4 and its ligand CXCL12 have been the subject of numerous structural and functional studies, but the determinants of ligand binding, selectivity, and signaling are still poorly understood. Here, building on our latest structural model, we used a systematic mutagenesis strategy to dissect the functional anatomy of the CXCR4-CXCL12 complex. Key charge swap mutagenesis experiments provided evidence for pairwise interactions between oppositely charged residues in the receptor and chemokine, confirming the accuracy of the predicted orientation of the chemokine relative to the receptor and providing insight into ligand selectivity. Progressive deletion of N-terminal residues revealed an unexpected contribution of the receptor N terminus to chemokine signaling. This finding challenges a longstanding "two-site" hypothesis about the essential features of the receptor-chemokine interaction in which the N terminus contributes only to binding affinity. Our results suggest that although the interaction of the chemokine N terminus with the receptor-binding pocket is the key driver of signaling, the signaling amplitude depends on the extent to which the receptor N terminus binds the chemokine. Together with systematic characterization of other epitopes, these data enable us to propose an experimentally consistent structural model for how CXCL12 binds CXCR4 and initiates signal transmission through the receptor transmembrane domain.


Asunto(s)
Quimiocina CXCL12/química , Modelos Moleculares , Complejos Multiproteicos/química , Receptores CXCR4/química , Animales , Células CHO , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Cricetulus , Células HEK293 , Humanos , Complejos Multiproteicos/genética , Complejos Multiproteicos/metabolismo , Mutagénesis Sitio-Dirigida , Estructura Cuaternaria de Proteína , Receptores CXCR4/genética , Receptores CXCR4/metabolismo
5.
Cell Rep ; 24(12): 3312-3323.e5, 2018 09 18.
Artículo en Inglés | MEDLINE | ID: mdl-30232011

RESUMEN

Ubiquitination is essential for protein degradation and signaling and pivotal to many physiological processes. Ubiquitination of a subset of G-protein-coupled receptors (GPCRs) by the E3 ligase NEDD4-2 is required for p38 activation, but how GPCRs activate NEDD4-2 to promote ubiquitin-mediated signaling is not known. Here, we report that the GPCR protease-activated receptor-1 (PAR1) stimulates c-Src-mediated tyrosine phosphorylation and activation of NEDD4-2 to promote p38 signaling and endothelial barrier disruption. Using mass spectrometry, we identified a unique phosphorylated tyrosine (Y)-485 within the 2,3-linker peptide between WW domain 2 and 3 of NEDD4-2 in agonist-stimulated cells. Mutation of NEDD4-2 Y485 impaired E3 ligase activity and failed to rescue PAR1-stimulated p38 activation and endothelial barrier permeability. The purinergic P2Y1 receptor also required c-Src and NEDD4-2 tyrosine phosphorylation for p38 activation. These studies reveal a novel role for c-Src in GPCR-induced NEDD4-2 activation, which is critical for driving ubiquitin-mediated p38 inflammatory signaling.


Asunto(s)
Ubiquitina-Proteína Ligasas Nedd4/química , Receptor PAR-1/metabolismo , Transducción de Señal , Permeabilidad Capilar , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Ubiquitina-Proteína Ligasas Nedd4/genética , Ubiquitina-Proteína Ligasas Nedd4/metabolismo , Dominios Proteicos , Receptores Purinérgicos P2Y1/metabolismo , Tirosina/genética , Tirosina/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Familia-src Quinasas/metabolismo
6.
Microsc Res Tech ; 70(4): 372-81, 2007 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-17262788

RESUMEN

We develop a method, which utilizes a combined atomic force microscope (AFM)/fluorescence microscope and small copy number polymerase chain reaction (PCR), to affinity-select individual aptamer species in a single cycle from a small pool of random-sequence oligonucleotides (oligos). In this method, a library of small beads, each of which is functionalized with fluorescent oligos of different sequences, is created. This library of oligo-functionalized beads is flowed over immobilized target molecules on a glass cover slip. High-affinity target-specific aptamers bind tightly to the target for prolonged periods and resist subsequent washes, resulting in a strong fluorescence signal on the substrate surface. This signal is observed from underneath the sample via fluorescence microscopy. The AFM tip, situated above the sample, is then directed to the coordinates of the fluorescence signal and is used to capture a three-dimensional high-resolution image of the surface-bound bead and to extract the bead (plus attached oligo). The extracted oligo is PCR-amplified, sequenced, and may then be subjected to further biochemical analysis. Here, we describe the underlying principles of this method, the required microscopy instrumentation, and the results of proof-of-principle experiments. In these experiments, we selected aptamers in eight trials from a binary pool containing a 1:1 mixture of thrombin aptamer oligo and a nonsense oligo. In each of the eight trials, the positive control aptamer was successfully detected, imaged, extracted, and characterized by PCR amplification and sequencing. In no case was the nonsense oligo selected, indicating good selectivity at this early stage of technology development.


Asunto(s)
Aptámeros de Nucleótidos/química , Microscopía de Fuerza Atómica/instrumentación , Microscopía Fluorescente/métodos , Secuencia de Bases , Microscopía de Fuerza Atómica/métodos , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa
7.
Annu Rev Biophys ; 46: 175-198, 2017 05 22.
Artículo en Inglés | MEDLINE | ID: mdl-28532213

RESUMEN

Chemokines and their cell surface G protein-coupled receptors are critical for cell migration, not only in many fundamental biological processes but also in inflammatory diseases and cancer. Recent X-ray structures of two chemokines complexed with full-length receptors provided unprecedented insight into the atomic details of chemokine recognition and receptor activation, and computational modeling informed by new experiments leverages these insights to gain understanding of many more receptor:chemokine pairs. In parallel, chemokine receptor structures with small molecules reveal the complicated and diverse structural foundations of small molecule antagonism and allostery, highlight the inherent physicochemical challenges of receptor:chemokine interfaces, and suggest novel epitopes that can be exploited to overcome these challenges. The structures and models promote unique understanding of chemokine receptor biology, including the interpretation of two decades of experimental studies, and will undoubtedly assist future drug discovery endeavors.


Asunto(s)
Receptores de Quimiocina/antagonistas & inhibidores , Receptores de Quimiocina/química , Regulación Alostérica , Animales , Quimiocinas/química , Quimiocinas/metabolismo , Cristalografía por Rayos X , Descubrimiento de Drogas , Humanos , Modelos Moleculares
8.
Nat Commun ; 8: 14135, 2017 01 18.
Artículo en Inglés | MEDLINE | ID: mdl-28098154

RESUMEN

Chemokines drive cell migration through their interactions with seven-transmembrane (7TM) chemokine receptors on cell surfaces. The atypical chemokine receptor 3 (ACKR3) binds chemokines CXCL11 and CXCL12 and signals exclusively through ß-arrestin-mediated pathways, without activating canonical G-protein signalling. This receptor is upregulated in numerous cancers making it a potential drug target. Here we collected over 100 distinct structural probes from radiolytic footprinting, disulfide trapping, and mutagenesis to map the structures of ACKR3:CXCL12 and ACKR3:small-molecule complexes, including dynamic regions that proved unresolvable by X-ray crystallography in homologous receptors. The data are integrated with molecular modelling to produce complete and cohesive experimentally driven models that confirm and expand on the existing knowledge of the architecture of receptor:chemokine and receptor:small-molecule complexes. Additionally, we detected and characterized ligand-induced conformational changes in the transmembrane and intracellular regions of ACKR3 that elucidate fundamental structural elements of agonism in this atypical receptor.


Asunto(s)
Receptores CXCR/química , Quimiocina CXCL12/química , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Células HEK293 , Humanos , Ligandos , Modelos Moleculares , Unión Proteica , Receptores CXCR/genética , Receptores CXCR/metabolismo , Transducción de Señal
9.
Sci Signal ; 10(471)2017 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-28325822

RESUMEN

Chemokines orchestrate cell migration for development, immune surveillance, and disease by binding to cell surface heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs). The array of interactions between the nearly 50 chemokines and their 20 GPCR targets generates an extensive signaling network to which promiscuity and biased agonism add further complexity. The receptor CXCR4 recognizes both monomeric and dimeric forms of the chemokine CXCL12, which is a distinct example of ligand bias in the chemokine family. We demonstrated that a constitutively monomeric CXCL12 variant reproduced the G protein-dependent and ß-arrestin-dependent responses that are associated with normal CXCR4 signaling and lead to cell migration. In addition, monomeric CXCL12 made specific contacts with CXCR4 that are not present in the structure of the receptor in complex with a dimeric form of CXCL12, a biased agonist that stimulates only G protein-dependent signaling. We produced an experimentally validated model of an agonist-bound chemokine receptor that merged a nuclear magnetic resonance-based structure of monomeric CXCL12 bound to the amino terminus of CXCR4 with a crystal structure of the transmembrane domains of CXCR4. The large CXCL12:CXCR4 protein-protein interface revealed by this structure identified previously uncharacterized functional interactions that fall outside of the classical "two-site model" for chemokine-receptor recognition. Our model suggests a mechanistic hypothesis for how interactions on the extracellular face of the receptor may stimulate the conformational changes required for chemokine receptor-mediated signal transduction.


Asunto(s)
Quimiocina CXCL12/química , Multimerización de Proteína , Receptores CXCR4/química , Transducción de Señal , Secuencia de Aminoácidos , Línea Celular Tumoral , Movimiento Celular/genética , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Células HEK293 , Humanos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Mutación , Unión Proteica , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Arrestina beta 2/genética , Arrestina beta 2/metabolismo
10.
Psychiatr Serv ; 66(2): 115-7, 2015 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-25642608

RESUMEN

Similar to other states, Georgia is facing workforce challenges within its community mental health system. These issues may be exacerbated as implementation of the Affordable Care Act expands demand for behavioral health services. Georgia's Department of Behavioral Health and Developmental Disabilities commissioned a needs assessment to examine the shortage of prescribing providers (psychiatrists, advanced practice registered nurses, and physician assistants) in the state's public mental health system. A unique partnership of key stakeholders developed and conducted the mixed-methods needs assessment at six of Georgia's 27 community mental health centers serving more than 40,000 patients annually. The assessment documented challenges in recruiting and retaining psychiatrists and workforce shortages for all prescriber groups. The authors describe opportunities for optimizing the psychiatric workforce and training the next generation of community psychiatrists.


Asunto(s)
Servicios Comunitarios de Salud Mental/normas , Evaluación de Necesidades/normas , Asociación entre el Sector Público-Privado/normas , Servicios Comunitarios de Salud Mental/estadística & datos numéricos , Georgia , Humanos , Evaluación de Necesidades/estadística & datos numéricos , Asociación entre el Sector Público-Privado/estadística & datos numéricos , Recursos Humanos
11.
PLoS One ; 9(1): e81454, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24489642

RESUMEN

Chemokines control cell migration in many contexts including development, homeostasis, immune surveillance and inflammation. They are also involved in a wide range of pathological conditions ranging from inflammatory diseases and cancer, to HIV. Chemokines function by interacting with two types of receptors: G protein-coupled receptors on the responding cells, which transduce signaling pathways associated with cell migration and activation, and glycosaminoglycans on cell surfaces and the extracellular matrix which organize and present some chemokines on immobilized surface gradients. To probe these interactions, imaging methods and fluorescence-based assays are becoming increasingly desired. Herein, a method for site-specific fluorescence labeling of recombinant chemokines is described. It capitalizes on previously reported 11-12 amino acid tags and phosphopantetheinyl transferase enzymes to install a fluorophore of choice onto a specific serine within the tag through a coenzyme A-fluorophore conjugate. The generality of the method is suggested by our success in labeling several chemokines (CXCL12, CCL2, CCL21 and mutants thereof) and visualizing them bound to chemokine receptors and glycosaminoglycans. CXCL12 and CCL2 showed the expected co-localization on the surface of cells with their respective receptors CXCR4 and CCR2 at 4 °C, and co-internalization with their receptors at 37 °C. By contrast, CCL21 showed the presence of large discrete puncta that were dependent on the presence of both CCR7 and glycosaminoglycans as co-receptors. These data demonstrate the utility of this labeling approach for the detection of chemokine interactions with GAGs and receptors, which can vary in a chemokine-specific manner as shown here. For some applications, the small size of the fluorescent adduct may prove advantageous compared to other methods (e.g. antibody labeling, GFP fusion) by minimally perturbing native interactions. Other advantages of the method are the ease of bacterial expression, the versatility of labeling with any maleimide-fluorophore conjugate of interest, and the covalent nature of the fluorescent adduct.


Asunto(s)
Quimiocinas/química , Quimiocinas/metabolismo , Proteínas Recombinantes/metabolismo , Línea Celular , Quimiocina CCL2/química , Quimiocina CCL2/metabolismo , Quimiocina CCL21/química , Quimiocina CCL21/metabolismo , Quimiocina CXCL12/química , Quimiocina CXCL12/metabolismo , Humanos , Receptores CCR2/química , Receptores CCR2/metabolismo , Receptores CCR7/química , Receptores CCR7/metabolismo , Receptores CXCR4/química , Receptores CXCR4/metabolismo , Proteínas Recombinantes/química
12.
Prog Mol Biol Transl Sci ; 115: 375-420, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23415099

RESUMEN

Oligomerization of chemokine receptors has been reported to influence many aspects of receptor function through allosteric communication between receptor protomers. Allosteric interactions within chemokine receptor hetero-oligomers have been shown to cause negative cooperativity in the binding of chemokines and to inhibit receptor activation in the case of some receptor pairs. Other receptor pairs can cause enhanced signaling and even activate entirely new, hetero-oligomer-specific signaling complexes and responses downstream of receptor activation. Many mechanisms contribute to these effects including direct allosteric coupling between the receptors, G protein-mediated allostery, G protein stealing, ligand sequestration, and recruitment of new intracellular proteins by exposing unique binding interfaces on the oligomerized receptors. These effects present both challenges as well as exciting opportunities for drug discovery. One of the most difficult challenges will involve determining if and when hetero-oligomers versus homomeric receptors are involved in specific disease states.


Asunto(s)
Multimerización de Proteína , Receptores de Quimiocina/química , Receptores de Quimiocina/metabolismo , Regulación Alostérica , Animales , Humanos , Ligandos , Modelos Moleculares , Unión Proteica
13.
Methods Mol Biol ; 1013: 93-127, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23625495

RESUMEN

Along with other resonance energy transfer techniques, bioluminescence resonance energy transfer (BRET) has emerged as an important method for demonstrating protein-protein interactions in cells. In the field of G-protein-coupled receptors, including chemokine receptors, BRET has been widely used to investigate homo- and heterodimerization, a feature of their interactions that is emerging as integral to function and regulation. While demonstrating the existence of dimers for a given receptor proved to be fairly straightforward, quantitative comparisons of different receptors or mutants are nontrivial because of inevitable variations in the expression of receptor constructs. The uncontrollable parameters of the cellular expression machinery make amounts of transfected DNA extremely poor predictors for the expression levels of BRET donor and acceptor receptor constructs, even in relative terms. In this chapter, we show that properly accounting for receptor expression levels is critical for quantitative interpretation of BRET data. We also provide a comprehensive account of expected responses in all types of BRET experiments and propose a framework for uniform and accurate quantitative treatment of these responses. The framework allows analysis of both homodimer and heterodimer BRET data. The important caveats and obstacles for quantitative treatment are outlined, and the utility of the approach is illustrated by its application to the homodimerization of wild-type (WT) and mutant forms of the chemokine receptor CXCR4.


Asunto(s)
Transferencia de Energía por Resonancia de Bioluminiscencia , Receptores Acoplados a Proteínas G/metabolismo , Animales , Células Cultivadas , Humanos , Modelos Moleculares , Mutación , Conformación Proteica , Multimerización de Proteína , Receptores CXCR4/química , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética , Proteínas Recombinantes de Fusión/metabolismo , Transfección
14.
ACS Chem Biol ; 8(9): 1955-63, 2013 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-23802178

RESUMEN

Tyrosine sulfation is a post-translational modification that enhances protein-protein interactions and may identify druggable sites in the extracellular space. The G protein-coupled receptor CXCR4 is a prototypical example with three potential sulfation sites at positions 7, 12, and 21. Each receptor sulfotyrosine participates in specific contacts with its chemokine ligand in the structure of a soluble, dimeric CXCL12:CXCR4(1-38) complex, but their relative importance for CXCR4 binding and activation by the monomeric chemokine remains undefined. NMR titrations with short sulfopeptides showed that the tyrosine motifs of CXCR4 varied widely in their contributions to CXCL12 binding affinity and site specificity. Whereas the Tyr21 sulfopeptide bound the same site as in previously solved structures, the Tyr7 and Tyr12 sulfopeptides interacted nonspecifically. Surprisingly, the unsulfated Tyr7 peptide occupied a hydrophobic site on the CXCL12 monomer that is inaccessible in the CXCL12 dimer. Functional analysis of CXCR4 mutants validated the relative importance of individual CXCR4 sulfotyrosine modifications (Tyr21 > Tyr12 > Tyr7) for CXCL12 binding and receptor activation. Biophysical measurements also revealed a cooperative relationship between sulfopeptide binding at the Tyr21 site and CXCL12 dimerization, the first example of allosteric behavior in a chemokine. Future ligands that occupy the sTyr21 recognition site may act as both competitive inhibitors of receptor binding and allosteric modulators of chemokine function. Together, our data suggests that sulfation does not ubiquitously enhance complex affinity and that distinct patterns of tyrosine sulfation could encode oligomer selectivity, implying another layer of regulation for chemokine signaling.


Asunto(s)
Quimiocina CXCL12/metabolismo , Péptidos/metabolismo , Receptores CXCR4/metabolismo , Secuencia de Aminoácidos , Animales , Células CHO , Quimiocina CXCL12/química , Cricetulus , Humanos , Modelos Moleculares , Péptidos/química , Unión Proteica , Multimerización de Proteína , Receptores CXCR4/química , Tirosina/química , Tirosina/metabolismo
15.
Appl Radiat Isot ; 68(10): 1928-32, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20554211

RESUMEN

We present a novel technique to produce narrow-band X-rays by preparing (161)Ho from the bombardment of dysprosium foil by 11.6 MeV protons. The activated foil produces predominantly 45-55 keV X-rays, which are suitable for activating iodinated radio-sensitizing agents (e.g. IUdR) for oncological therapy. We demonstrate that clinically useful quantities of the nuclide are easily produced with a medical cyclotron which is far from the current state of the art.


Asunto(s)
Holmio , Radioisótopos , Radioterapia/métodos , Rayos X , Oncología Médica/métodos , Métodos , Neoplasias/radioterapia , Protones , Radiación
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