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2.
Nat Commun ; 15(1): 275, 2024 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-38177131

RESUMEN

Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So far only a few ligases have been utilized for TPD. Interestingly, the workhorse ligase CRBN has been observed to be downregulated in settings of resistance to immunomodulatory inhibitory drugs (IMiDs). Here we show that the essential E3 ligase receptor DCAF1 can be harnessed for TPD utilizing a selective, non-covalent DCAF1 binder. We confirm that this binder can be functionalized into an efficient DCAF1-BRD9 PROTAC. Chemical and genetic rescue experiments validate specific degradation via the CRL4DCAF1 E3 ligase. Additionally, a dasatinib-based DCAF1 PROTAC successfully degrades cytosolic and membrane-bound tyrosine kinases. A potent and selective DCAF1-BTK-PROTAC (DBt-10) degrades BTK in cells with acquired resistance to CRBN-BTK-PROTACs while the DCAF1-BRD9 PROTAC (DBr-1) provides an alternative strategy to tackle intrinsic resistance to VHL-degrader, highlighting DCAF1-PROTACS as a promising strategy to overcome ligase mediated resistance in clinical settings.


Asunto(s)
Proteínas Portadoras , Quimera Dirigida a la Proteólisis , Ubiquitina-Proteína Ligasas , Proteínas Portadoras/metabolismo , Proteolisis , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo
3.
ACS Med Chem Lett ; 14(7): 949-954, 2023 Jul 13.
Artículo en Inglés | MEDLINE | ID: mdl-37465299

RESUMEN

In this study, we describe the rapid identification of potent binders for the WD40 repeat domain (WDR) of DCAF1. This was achieved by two rounds of iterative focused screening of a small set of compounds selected on the basis of internal WDR domain knowledge followed by hit expansion. Subsequent structure-based design led to nanomolar potency binders with a clear exit vector enabling DCAF1-based bifunctional degrader exploration.

4.
J Med Chem ; 64(8): 4677-4696, 2021 04 22.
Artículo en Inglés | MEDLINE | ID: mdl-33844524

RESUMEN

Starting from lead compound 4, the 1,4-oxazine headgroup was optimized to improve potency and brain penetration. Focusing at the 6-position of the 5-amino-1,4-oxazine, the insertion of a Me and a CF3 group delivered an excellent pharmacological profile with a pKa of 7.1 and a very low P-gp efflux ratio enabling high central nervous system (CNS) penetration and exposure. Various synthetic routes to access BACE1 inhibitors bearing a 5-amino-6-methyl-6-(trifluoromethyl)-1,4-oxazine headgroup were investigated. Subsequent optimization of the P3 fragment provided the highly potent N-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide 54 (NB-360), able to reduce significantly Aß levels in mice, rats, and dogs in acute and chronic treatment regimens.


Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/metabolismo , Inhibidores Enzimáticos/síntesis química , Ácidos Picolínicos/síntesis química , Tiazinas/síntesis química , Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Animales , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/metabolismo , Sitios de Unión , Encéfalo/metabolismo , Cristalografía por Rayos X , Perros , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/uso terapéutico , Semivida , Humanos , Ratones , Simulación de Dinámica Molecular , Oxazinas/química , Ácidos Picolínicos/farmacocinética , Ácidos Picolínicos/uso terapéutico , Ratas , Relación Estructura-Actividad , Tiazinas/farmacocinética , Tiazinas/uso terapéutico
5.
Nat Commun ; 12(1): 898, 2021 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-33563973

RESUMEN

Radiation sensitivity varies greatly between tissues. The transcription factor p53 mediates the response to radiation; however, the abundance of p53 protein does not correlate well with the extent of radiosensitivity across tissues. Given recent studies showing that the temporal dynamics of p53 influence the fate of cultured cells in response to irradiation, we set out to determine the dynamic behavior of p53 and its impact on radiation sensitivity in vivo. We find that radiosensitive tissues show prolonged p53 signaling after radiation, while more resistant tissues show transient p53 activation. Sustaining p53 using a small molecule (NMI801) that inhibits Mdm2, a negative regulator of p53, reduced viability in cell culture and suppressed tumor growth. Our work proposes a mechanism for the control of radiation sensitivity and suggests tools to alter the dynamics of p53 to enhance tumor clearance. Similar approaches can be used to enhance killing of cancer cells or reduce toxicity in normal tissues following genotoxic therapies.


Asunto(s)
Tolerancia a Radiación , Proteína p53 Supresora de Tumor/metabolismo , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Humanos , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias/radioterapia , Unión Proteica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Tolerancia a Radiación/efectos de los fármacos , Distribución Tisular/efectos de los fármacos , Carga Tumoral/efectos de los fármacos , Proteína p53 Supresora de Tumor/efectos de la radiación , Ensayos Antitumor por Modelo de Xenoinjerto
6.
ChemMedChem ; 14(14): 1305-1314, 2019 07 17.
Artículo en Inglés | MEDLINE | ID: mdl-31066983

RESUMEN

Hdm2 (human MDM2, human double minute 2 homologue) counteracts p53 function by direct binding to p53 and by ubiquitin-dependent p53 protein degradation. Activation of p53 by inhibitors of the p53-Hdm2 interaction is being pursued as a therapeutic strategy in p53 wild-type cancers. In addition, HdmX (human MDMX, human MDM4) was also identified as an important therapeutic target to efficiently reactivate p53, and it is likely that dual inhibition of Hdm2 and HdmX is beneficial. Herein we report four new X-ray structures for Hdm2 and five new X-ray structures for HdmX complexes, involving different classes of synthetic compounds (including the worldwide highest resolutions for Hdm2 and HdmX, at 1.13 and 1.20 Å, respectively). We also reveal the key additive 18-crown-ether, which we discovered to enable HdmX crystallization and show its stabilization of various Lys residues. In addition, we report the previously unpublished details of X-ray structure determinations for eight further Hdm2 complexes, including the clinical trial compounds NVP-CGM097 and NVP-HDM201. An analysis of all compound binding modes reveals new and deepened insight into the possible adaptations and structural states of Hdm2 (e.g., flip of F55, flip of Y67, reorientation of H96) and HdmX (e.g., flip of H55, dimer induction), enabling key binding interactions for different compound classes. To facilitate comparisons, we used the same numbering for Hdm2 (as in Q00987) and HdmX (as in O15151, but minus 1). Taken together, these structural insights should prove useful for the design and optimization of further selective and/or dual Hdm2/HdmX inhibitors.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Compuestos Heterocíclicos/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Sitios de Unión , Proteínas de Ciclo Celular/química , Cristalografía por Rayos X , Compuestos Heterocíclicos/química , Humanos , Unión Proteica , Proteínas Proto-Oncogénicas/química , Proteínas Proto-Oncogénicas c-mdm2/química
7.
Bioorg Med Chem Lett ; 28(20): 3404-3408, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30217415

RESUMEN

Small molecule inhibitors of the p53-MDM2 protein complex are under intense investigation in clinical trials as anti-cancer agents, including our first generation inhibitor NVP-CGM097. We recently described the rational design of a novel pyrazolopyrrolidinone core as a new lead structure and now we report on the synthesis and optimization of this to provide a highly potent lead compound. This new compound displayed excellent oral efficacy in our preclinical mechanistic in vivo model and marked a significant milestone towards the identification of our second generation clinical candidate NVP-HDM201.


Asunto(s)
Antineoplásicos/farmacología , Multimerización de Proteína/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Pirazoles/farmacología , Pirrolidinonas/farmacología , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Perros , Haplorrinos , Humanos , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacocinética , Pirrolidinonas/síntesis química , Pirrolidinonas/química , Pirrolidinonas/farmacocinética , Ratas Sprague-Dawley , Estereoisomerismo
8.
Cancer Res ; 78(21): 6257-6267, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30135191

RESUMEN

Activation of p53 by inhibitors of the p53-MDM2 interaction is being pursued as a therapeutic strategy in p53 wild-type cancers. Here, we report distinct mechanisms by which the novel, potent, and selective inhibitor of the p53-MDM2 interaction HDM201 elicits therapeutic efficacy when applied at various doses and schedules. Continuous exposure of HDM201 led to induction of p21 and delayed accumulation of apoptotic cells. By comparison, high-dose pulses of HDM201 were associated with marked induction of PUMA and a rapid onset of apoptosis. shRNA screens identified PUMA as a mediator of the p53 response specifically in the pulsed regimen. Consistent with this, the single high-dose HDM201 regimen resulted in rapid and marked induction of PUMA expression and apoptosis together with downregulation of Bcl-xL in vivo Knockdown of Bcl-xL was identified as the top sensitizer to HDM201 in vitro, and Bcl-xL was enriched in relapsing tumors from mice treated with intermittent high doses of HDM201. These findings define a regimen-dependent mechanism by which disruption of MDM2-p53 elicits therapeutic efficacy when given with infrequent dosing. In an ongoing HDM201 trial, the observed exposure-response relationship indicates that the molecular mechanism elicited by pulse dosing is likely reproducible in patients. These data support the clinical comparison of daily and intermittent regimens of p53-MDM2 inhibitors.Significance: Pulsed high doses versus sustained low doses of the p53-MDM2 inhibitor HDM201 elicit a proapoptotic response from wild-type p53 cancer cells, offering guidance to current clinical trials with this and other drugs that exploit the activity of p53. Cancer Res; 78(21); 6257-67. ©2018 AACR.


Asunto(s)
Antineoplásicos/administración & dosificación , Imidazoles/administración & dosificación , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Pirimidinas/administración & dosificación , Pirroles/administración & dosificación , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Animales , Antineoplásicos/farmacología , Apoptosis , Área Bajo la Curva , Línea Celular Tumoral , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Imidazoles/farmacología , Estimación de Kaplan-Meier , Dosis Máxima Tolerada , Ratones , Trasplante de Neoplasias , Pirimidinas/farmacología , Pirroles/farmacología , ARN Interferente Pequeño/metabolismo , Factores de Tiempo , Proteína bcl-X/metabolismo
9.
Bioorg Med Chem Lett ; 28(12): 2195-2200, 2018 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-29764741

RESUMEN

New amino-1,4-oxazine derived BACE-1 inhibitors were explored and various synthetic routes developed. The binding mode of the inhibitors was elucidated by co-crystallization of 4 with BACE-1 and X-ray analysis. Subsequent optimization led to inhibitors with low double digit nanomolar activity in a biochemical and single digit nanomolar potency in a cellular assays. To assess the inhibitors for their permeation properties and potential to cross the blood-brain-barrier a MDR1-MDCK cell model was successfully applied. Compound 8a confirmed the in vitro results by dose-dependently reducing Aß levels in mice in an acute treatment regimen.


Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Oxazinas/farmacología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Perros , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Células de Riñón Canino Madin Darby/efectos de los fármacos , Ratones , Modelos Moleculares , Conformación Molecular , Oxazinas/síntesis química , Oxazinas/química , Relación Estructura-Actividad
10.
Chimia (Aarau) ; 71(10): 716-721, 2017 Oct 25.
Artículo en Inglés | MEDLINE | ID: mdl-29070416

RESUMEN

As a result of our persistent efforts to discover novel inhibitors of the p53-MDM2 protein-protein interaction useful for the treatment of cancer, the potent and selective MDM2 inhibitors NVP-CGM097 and NVP-HDM201 with excellent in vitro and in vivo profile were selected as clinical candidates and are currently in phase 1 clinical development. This short review article provides a summary of the program history, the applied pharmacophore model and the discovery story of these novel p53-MDM2 inhibitor investigational drugs.


Asunto(s)
Antineoplásicos/farmacología , Descubrimiento de Drogas , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Ensayos Clínicos Fase I como Asunto , Humanos , Proteínas Proto-Oncogénicas c-mdm2/química , Proteína p53 Supresora de Tumor/química
11.
ACS Med Chem Lett ; 8(3): 338-343, 2017 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-28337327

RESUMEN

Misdirected catalytic activity of histone methyltransferase Dot1L is believed to be causative for a subset of highly aggressive acute leukemias. Targeting the catalytic domain of Dot1L represents a potential therapeutic approach for these leukemias. In the context of a comprehensive Dot1L hit finding strategy, a knowledge-based virtual screen of the Dot1L SAM binding pocket led to the discovery of 2, a non-nucleoside fragment mimicking key interactions of SAM bound to Dot1L. Fragment linking of 2 and 3, an induced back pocket binder identified in earlier studies, followed by careful ligand optimization led to the identification of 7, a highly potent, selective and structurally novel Dot1L inhibitor.

13.
ACS Med Chem Lett ; 7(8): 735-40, 2016 Aug 11.
Artículo en Inglés | MEDLINE | ID: mdl-27563395

RESUMEN

Oncogenic MLL fusion proteins aberrantly recruit Dot1L, a histone methyltransferase, to ectopic loci, leading to local hypermethylation of H3K79 and misexpression of HoxA genes driving MLL-rearranged leukemias. Inhibition of the methyltransferase activity of Dot1L in this setting is predicted to reverse aberrant H3K79 methylation, leading to repression of leukemogenic genes and tumor growth inhibition. In the context of our Dot1L drug discovery program, high-throughput screening led to the identification of 2, a weak Dot1L inhibitor with an unprecedented, induced pocket binding mode. A medicinal chemistry campaign, strongly guided by structure-based consideration and ligand-based morphing, enabled the discovery of 12 and 13, potent, selective, and structurally completely novel Dot1L inhibitors.

14.
Bioorg Med Chem Lett ; 26(19): 4837-4841, 2016 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-27542305

RESUMEN

The p53-MDM2 interaction is an anticancer drug target under investigation in the clinic. Our compound NVP-CGM097 is one of the small molecule inhibitors of this protein-protein interaction currently evaluated in cancer patients. As part of our effort to identify new classes of p53-MDM2 inhibitors that could lead to additional clinical candidates, we report here the design of highly potent inhibitors having a pyrazolopyrrolidinone core structure. The conception of these new inhibitors originated in a consideration on the MDM2 bound conformation of the dihydroisoquinolinone class of inhibitors to which NVP-CGM097 belongs. This work forms the foundation of the discovery of HDM201, a second generation p53-MDM2 inhibitor that recently entered phase I clinical trial.


Asunto(s)
Descubrimiento de Drogas , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Cristalografía por Rayos X , Transferencia Resonante de Energía de Fluorescencia , Conformación Molecular , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo
15.
Bioorg Med Chem Lett ; 25(17): 3621-5, 2015 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-26141769

RESUMEN

Blocking the interaction between the p53 tumor suppressor and its regulatory protein MDM2 is a promising therapeutic concept under current investigation in oncology drug research. We report here the discovery of the first representatives of a new class of small molecule inhibitors of this protein-protein interaction: the dihydroisoquinolinones. Starting from an initial hit identified by virtual screening, a derivatization program has resulted in compound 11, a low nanomolar inhibitor of the p53-MDM2 interaction showing significant cellular activity. Initially based on a binding mode hypothesis, this effort was then guided by a X-ray co-crystal structure of MDM2 in complex with one of the synthesized analogs. The X-ray structure revealed an unprecedented binding mode for p53-MDM2 inhibitors.


Asunto(s)
Isoquinolinas/química , Isoquinolinas/farmacología , Mapas de Interacción de Proteínas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Cristalografía por Rayos X , Humanos , Simulación del Acoplamiento Molecular , Unión Proteica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Relación Estructura-Actividad , Proteína p53 Supresora de Tumor/antagonistas & inhibidores
16.
J Med Chem ; 58(16): 6348-58, 2015 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-26181851

RESUMEN

As a result of our efforts to discover novel p53:MDM2 protein-protein interaction inhibitors useful for treating cancer, the potent and selective MDM2 inhibitor NVP-CGM097 (1) with an excellent in vivo profile was selected as a clinical candidate and is currently in phase 1 clinical development. This article provides an overview of the discovery of this new clinical p53:MDM2 inhibitor. The following aspects are addressed: mechanism of action, scientific rationale, binding mode, medicinal chemistry, pharmacokinetic and pharmacodynamic properties, and in vivo pharmacology/toxicology in preclinical species.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Isoquinolinas/síntesis química , Isoquinolinas/farmacología , Piperazinas/síntesis química , Piperazinas/farmacología , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/genética , Animales , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Ensayos Clínicos Fase I como Asunto , Descubrimiento de Drogas , Humanos , Isoquinolinas/farmacocinética , Piperazinas/farmacocinética , Ratas , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
17.
Elife ; 42015 May 12.
Artículo en Inglés | MEDLINE | ID: mdl-25965177

RESUMEN

Biomarkers for patient selection are essential for the successful and rapid development of emerging targeted anti-cancer therapeutics. In this study, we report the discovery of a novel patient selection strategy for the p53-HDM2 inhibitor NVP-CGM097, currently under evaluation in clinical trials. By intersecting high-throughput cell line sensitivity data with genomic data, we have identified a gene expression signature consisting of 13 up-regulated genes that predicts for sensitivity to NVP-CGM097 in both cell lines and in patient-derived tumor xenograft models. Interestingly, these 13 genes are known p53 downstream target genes, suggesting that the identified gene signature reflects the presence of at least a partially activated p53 pathway in NVP-CGM097-sensitive tumors. Together, our findings provide evidence for the use of this newly identified predictive gene signature to refine the selection of patients with wild-type p53 tumors and increase the likelihood of response to treatment with p53-HDM2 inhibitors, such as NVP-CGM097.


Asunto(s)
Biomarcadores/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Isoquinolinas/farmacología , Neoplasias/tratamiento farmacológico , Selección de Paciente , Piperazinas/farmacología , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/genética , Línea Celular Tumoral , Transferencia Resonante de Energía de Fluorescencia , Perfilación de la Expresión Génica , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo
18.
Opt Express ; 21(9): 10942-53, 2013 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-23669950

RESUMEN

An efficient and tunable 176-550 nm source based on the emission of resonant dispersive radiation from ultrafast solitons at 800 nm is demonstrated in a gas-filled hollow-core photonic crystal fiber (PCF). By careful optimization and appropriate choice of gas, informed by detailed numerical simulations, we show that bright, high quality, localized bands of UV light (relative widths of a few percent) can be generated at all wavelengths across this range. Pulse energies of more than 75 nJ in the deep-UV, with relative bandwidths of ~3%, are generated from pump pulses of a few µJ. Excellent agreement is obtained between numerical and experimental results. The effects of positive and negative axial pressure gradients are also experimentally studied, and the coherence of the deep-UV dispersive wave radiation numerically investigated.


Asunto(s)
Gases/química , Iluminación/instrumentación , Refractometría/instrumentación , Diseño de Equipo , Análisis de Falla de Equipo , Rayos Ultravioleta , Vacio
19.
Kidney Int ; 81(12): 1212-25, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22398409

RESUMEN

Eph receptor tyrosine kinases and their ligands (ephrins) have a pivotal role in the homeostasis of many adult organs and are widely expressed in the kidney. Glomerular diseases beginning with mesangiolysis can recover, with podocytes having a critical role in this healing process. We studied here the role of Eph signaling in glomerular disease recovery following mesangiolytic Thy1.1 nephritis in rats. EphB4 and ephrinBs were expressed in healthy glomerular podocytes and were upregulated during Thy1.1 nephritis, with EphB4 strongly phosphorylated around day 9. Treatment with NPV-BHG712, an inhibitor of EphB4 phosphorylation, did not cause glomerular changes in control animals. Nephritic animals treated with vehicle did not have morphological evidence of podocyte injury or loss; however, application of this inhibitor to nephritic rats induced glomerular microaneurysms, podocyte damage, and loss. Prolonged NPV-BHG712 treatment resulted in increased albuminuria and dysregulated mesangial recovery. Additionally, NPV-BHG712 inhibited capillary repair by intussusceptive angiogenesis (an alternative to sprouting angiogenesis), indicating a previously unrecognized role of podocytes in regulating intussusceptive vessel splitting. Thus, our results identify EphB4 signaling as a pathway allowing podocytes to survive transient capillary collapse during glomerular disease.


Asunto(s)
Glomerulonefritis/metabolismo , Glomérulos Renales/metabolismo , Podocitos/metabolismo , Receptor EphB4/metabolismo , Transducción de Señal , Cicatrización de Heridas , Albuminuria/inmunología , Albuminuria/metabolismo , Albuminuria/patología , Animales , Anticuerpos Monoclonales , Apoptosis , Capilares/inmunología , Capilares/metabolismo , Capilares/patología , Línea Celular , Modelos Animales de Enfermedad , Glomerulonefritis/inmunología , Glomerulonefritis/patología , Glomérulos Renales/irrigación sanguínea , Glomérulos Renales/efectos de los fármacos , Glomérulos Renales/inmunología , Glomérulos Renales/patología , Masculino , Ratones , Neovascularización Fisiológica , Fosforilación , Podocitos/efectos de los fármacos , Podocitos/inmunología , Podocitos/patología , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Antígenos Thy-1/inmunología , Factores de Tiempo , Factor de Crecimiento Transformador beta1/metabolismo , Cicatrización de Heridas/efectos de los fármacos
20.
Phys Rev Lett ; 107(20): 203902, 2011 Nov 11.
Artículo en Inglés | MEDLINE | ID: mdl-22181733

RESUMEN

We show theoretically that the photoionization process in a hollow-core photonic crystal fiber filled with a Raman-inactive noble gas leads to a constant acceleration of solitons in the time domain with a continuous shift to higher frequencies, limited only by ionization loss. This phenomenon is opposite to the well-known Raman self-frequency redshift of solitons in solid-core glass fibers. We also predict the existence of unconventional long-range nonlocal soliton interactions leading to spectral and temporal soliton clustering. Furthermore, if the core is filled with a Raman-active molecular gas, spectral transformations between redshifted, blueshifted, and stabilized solitons can take place in the same fiber.

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