RESUMEN
Proteasome inhibitors are widely used anticancer drugs. The three clinically approved agents are modified small peptides that preferentially target one of the proteasome's three active sites (ß5) at physiologic concentrations. In addition to these drugs, there is also an endogenous proteasome inhibitor, PI31/Fub1, that enters the proteasome's interior to simultaneously yet specifically inhibit all three active sites. Here, we have used PI31's evolutionarily optimized inhibitory mechanisms to develop a suite of potent and specific ß2 inhibitors. The lead compound strongly inhibited growth of multiple myeloma cells as a standalone agent, indicating the compound's cell permeability and establishing ß2 as a potential therapeutic target in multiple myeloma. The lead compound also showed strong synergy with the existing ß5 inhibitor bortezomib; such combination therapies might help with existing challenges of resistance and severe side effects. These results represent an effective method for rational structure-guided development of proteasome inhibitors.
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Antineoplásicos , Mieloma Múltiple , Humanos , Inhibidores de Proteasoma/farmacología , Inhibidores de Proteasoma/uso terapéutico , Antineoplásicos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Complejo de la Endopetidasa Proteasomal/química , Bortezomib/farmacología , Bortezomib/uso terapéuticoRESUMEN
The persistence and fall rate of snags (standing dead trees) generated during bark beetle outbreaks have consequences for the behavior, effects, and suppression of potential wildfires, hazard tree and timber salvage operations, wildlife habitat, and numerous ecosystem processes. However, post-beetle snagfall dynamics are poorly understood in most forest types. We tagged standing live and dead lodgepole pine (Pinus contorta), subalpine fir (Abies lasiocarpa), and Engelmann spruce (Picea engelmannii), including beetle-killed pine snags following the peak of a recent mountain pine bark beetle outbreak in watersheds at the Fraser Experimental Forest in northcentral Colorado and sampled snagfall 10 and 12 years later. Bark beetle attacks began in 2003, peaked by 2006, and killed 78% of overstory lodgepole pine in 133 plots distributed across a range of stand and site conditions. Of those snags, only 17% fell between 2007 and 2018. Most snags broke at ground level, due to butt rot, and were oriented downhill. In contrast, snags that tipped up or snapped off above the ground were oriented with the prevailing winds. Equal numbers of snags fell singly and in multiple-tree groups, and equal numbers remained elevated rather than in contact with the ground. Lodgepole pine snagfall was 1.6-times higher on steep slopes (>40%) where dead pine density was higher, compared to flatter sites. Based on our findings and previous research, we estimate that one-half the beetle-killed lodgepole pine in high-elevation forests such as those at Fraser may fall within 15-20 yr of beetle infestation, but that some pine snags are likely to persist for decades longer. Post-outbreak snagfall dynamics create a multiple-decade legacy of bark beetle outbreaks that will persist longer in high-elevation compared to lower-elevation forests.
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Escarabajos , Pinus , Animales , Colorado , Ecosistema , Bosques , Corteza de la PlantaRESUMEN
BACKGROUND AND PURPOSE: Data from both humans and animal models suggest that most recovery from motor impairment after stroke occurs in a sensitive period that lasts only weeks and is mediated, in part, by an increased responsiveness to training. Here, we used a mouse model of focal cortical stroke to test 2 hypotheses. First, we investigated whether responsiveness to training decreases over time after stroke. Second, we tested whether fluoxetine, which can influence synaptic plasticity and stroke recovery, can prolong the period over which large training-related gains can be elicited after stroke. METHODS: Mice were trained to perform a skilled prehension task to an asymptotic level of performance after which they underwent stroke induction in the caudal forelimb area. The mice were then retrained after a 1- or 7-day delay with and without fluoxetine. RESULTS: Recovery of prehension after a caudal forelimb area stroke was complete if training was initiated 1 day after stroke but incomplete if it was delayed by 7 days. In contrast, if fluoxetine was administered at 24 hours after stroke, then complete recovery of prehension was observed even with the 7-day training delay. Fluoxetine seemed to mediate its beneficial effect by reducing inhibitory interneuron expression in intact premotor cortex rather than through effects on infarct volume or cell death. CONCLUSIONS: There is a gradient of diminishing responsiveness to motor training over the first week after stroke. Fluoxetine can overcome this gradient and maintain maximal levels of responsiveness to training even 7 days after stroke.
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Conducta Animal/efectos de los fármacos , Fluoxetina/farmacología , Actividad Motora/efectos de los fármacos , Corteza Motora/efectos de los fármacos , Rehabilitación Neurológica , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Rehabilitación de Accidente Cerebrovascular , Animales , Modelos Animales de Enfermedad , Masculino , Ratones , Corteza Motora/patología , Corteza Motora/fisiopatología , Destreza Motora/efectos de los fármacos , Movimiento/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Recuperación de la Función/efectos de los fármacos , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/fisiopatología , Tiempo de TratamientoRESUMEN
BACKGROUND: Caloric restriction promotes neuroplasticity and recovery after neurological injury. In mice, we tested the hypothesis that caloric restriction can act post-stroke to enhance training-associated motor recovery. METHODS: Mice were trained to perform a skilled prehension task. We then induced a photothrombotic stroke in the caudal forelimb area, after which we retrained animals on the prehension task following an 8-day delay. Mice underwent either ad libitum feeding or alternate day fasting beginning 1-day after stroke and persisting for either 7 days or the entire post-stroke training period until sacrifice. RESULTS: Prior studies have shown that post-stroke recovery of prehension can occur if animals receive rehabilitative training during an early sensitive period but is incomplete if rehabilitative training is delayed. In contrast, we show complete recovery of prehension, despite a delay in rehabilitative training, when mice underwent alternate day fasting beginning 1-day post-stroke and persisting for either 7 days or the entire post-stroke training period until sacrifice. Recovery was independent of weight loss. Stroke volumes were similar across groups. CONCLUSIONS: Post-stroke caloric restriction led to recovery of motor function independent of a protective effect on stroke volume. Prehension recovery improved even after ad libitum feeding was reinstituted suggesting that the observed motor recovery was not merely a motivational response. These data add to the growing evidence that post-stroke caloric restriction can enhance recovery.
Asunto(s)
Rehabilitación de Accidente Cerebrovascular , Accidente Cerebrovascular , Humanos , Ratones , Animales , Miembro Anterior , Extremidad Superior , Recuperación de la Función/fisiología , Ayuno , Modelos Animales de EnfermedadRESUMEN
Delivering small interfering RNA (siRNA) to tumors is the major technical hurdle that prevents the advancement of siRNA-based cancer therapy. One of the difficulties associated with the development of clinically relevant delivery systems is the lack of reliable tools for monitoring siRNA delivery to tumors in vivo. We describe here a novel, positive-readout system where siRNA-mediated target knockdown elicits a rapid and robust increase of reporter activity. Using the positive-readout system, we created (1) ß-galactosidase-based tumor models that allow the detection of target knockdown in 1%-2% of tumor cells and can distinguish between tumor areas where effective target knockdown occurs versus tumor areas that are not accessible to delivery, and (2) luciferase-based tumor models that allow the quantitative assessment of a large number of delivery systems. Using these positive-readout models, we screened a number of literature-described siRNA delivery systems and identified lipid nanoparticles as a promising delivery platform for siRNA-based cancer therapy.
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Técnicas de Silenciamiento del Gen , Monitoreo Fisiológico/métodos , Neoplasias/terapia , ARN Interferente Pequeño/administración & dosificación , Animales , Secuencia de Bases , Línea Celular Tumoral , Femenino , Genes Reporteros , Vectores Genéticos , Liposomas , Ratones , Ratones SCID , Datos de Secuencia Molecular , Nanopartículas/administración & dosificación , ARN Interferente Pequeño/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto , beta-Galactosidasa/genéticaRESUMEN
Soil biotic and abiotic factors strongly influence nitrogen (N) availability and increases in nitrification rates associated with the application of manure. In this study, we examine the effects of edaphic properties and a dairy (Bos taurus) slurry amendment on N availability, nitrification rates and nitrifier communities. Soils of variable texture and clay mineralogy were collected from six USDA-ARS research sites and incubated for 28 d with and without dairy slurry applied at a rate of ~300 kg N ha(-1). Periodically, subsamples were removed for analyses of 2 M KCl extractable N and nitrification potential, as well as gene copy numbers of ammonia-oxidizing bacteria (AOB) and archaea (AOA). Spearman coefficients for nitrification potentials and AOB copy number were positively correlated with total soil C, total soil N, cation exchange capacity, and clay mineralogy in treatments with and without slurry application. Our data show that the quantity and type of clay minerals present in a soil affect nitrifier populations, nitrification rates, and the release of inorganic N. Nitrogen mineralization, nitrification potentials, and edaphic properties were positively correlated with AOB gene copy numbers. On average, AOA gene copy numbers were an order of magnitude lower than those of AOB across the six soils and did not increase with slurry application. Our research suggests that the two nitrifier communities overlap but have different optimum environmental conditions for growth and activity that are partly determined by the interaction of manure-derived ammonium with soil properties.
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Archaea/metabolismo , Bacterias/metabolismo , Ecosistema , Nitrificación , Contaminantes del Suelo/química , Suelo/química , Amoníaco/química , Amoníaco/metabolismo , Animales , Bovinos , Industria Lechera , Monitoreo del Ambiente , Estiércol , Nitrógeno/química , Oxidación-Reducción , Eliminación de Residuos Líquidos/métodosRESUMEN
The rheological properties of synovial fluid and hyaluronate (HA) solutions have been studied using a variety of viscometers and rheometers. These devices measure the viscosity of the fluid's resistance to shearing forces, which is useful when studying the lubrication and frictional properties of movable joints. Less commonly used is a squeeze-film fluid test, mechanistically similar to when two joint surfaces squeeze interposed fluid. In our study, we used squeeze-film tests to determine the rheological response of normal bovine synovial fluid and 10 mg/ml HA-based solutions, Hyalgan/Hyalovet, commercially available 500-700 kDa HA viscosupplements, and a 1000 kDa sodium hyaluronate (NaHy) solution. We found similar rheological responses (fluid thickness, viscosity, viscosity-pressure relationship) for all three fluids, though synovial fluid's minimum squeeze-film thickness was slightly thicker. Squeeze-film loading speed did not affect these results. Different HA concentrations and molecular weights also did not have a significant or consistent effect on the squeeze-film responses. An unexpected result for the HA-solutions was a linear increase in minimum fluid-film thickness with increasing initial fluid-film thickness. This result was attributed to faster gelling of thicker HA-solutions, which formed at a lower squeeze-film strain and higher squeeze-film strain rate compared to thinner layers. Also included is a review of the literature on viscosity measurements of synovial fluid and HA solutions.
Asunto(s)
Ácido Hialurónico/química , Osteoartritis/terapia , Líquido Sinovial/metabolismo , Viscosuplementos , Adolescente , Anciano , Animales , Cartílago Articular/fisiología , Bovinos , Diseño de Equipo , Femenino , Fricción , Glicosaminoglicanos , Humanos , Lubrificación , Masculino , Persona de Mediana Edad , Osteoartritis/fisiopatología , Presión , Reología , Estrés Mecánico , Viscosidad , Adulto JovenRESUMEN
BACKGROUND: Motor recovery after stroke in humans and in rodent models is time sensitive. Recovery in patients is a result of biological spontaneous recovery via endogenous repair mechanisms and is likely improved by enhancing the synaptic plasticity required for endogenous repair. Cerebrolysin is a polypeptide preparation known to enhance neuroplasticity and may improve recovery in patients. In mice, we tested the hypothesis that Cerebrolysin can act poststroke to enhance both spontaneous and training-associated motor recovery. METHODS: Mice were trained to perform a skilled prehension task. We then induced a photothrombotic stroke in the caudal forelimb area, after which we retrained animals on the prehension task in the presence or absence of Cerebrolysin after a 2-day or 8-day delay. Mice received daily intraperitoneal Cerebrolysin or saline injections starting poststroke day 1 or poststroke day 7. RESULTS: Prior studies showed that poststroke recovery of prehension can occur if animals receive rehabilitative training during an early sensitive period but is incomplete if rehabilitative training is delayed. In contrast, we show complete recovery of prehension, despite a delay in rehabilitative training, when mice receive daily Cerebrolysin administration starting on poststroke day 1 or on poststroke day 8. When Cerebrolysin is given on poststroke day 1, recovery occurred even in the absence of training. Stroke volumes were similar across groups. CONCLUSIONS: Poststroke Cerebrolysin administration leads to recovery of motor function independent of rehabilitative training without a protective effect on stroke volume. This is one of the first demonstrations of training-independent motor recovery in rodent stroke models.
Asunto(s)
Aminoácidos/farmacología , Fármacos Neuroprotectores/farmacología , Recuperación de la Función/efectos de los fármacos , Rehabilitación de Accidente Cerebrovascular , Accidente Cerebrovascular/terapia , Aminoácidos/administración & dosificación , Animales , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Fármacos Neuroprotectores/administración & dosificación , Accidente Cerebrovascular/tratamiento farmacológico , Factores de TiempoRESUMEN
This Letter describes the lead discovery, optimization, and biological characterization of a series of substituted 4-amino-1H-pyrazolo[3,4-d]pyrimidines as potent inhibitors of IGF1R, EGFR, and ErbB2. The leading compound 11 showed an IGF1R IC(50) of 12 nM, an EGFR (L858R) IC(50) of 31 nM, and an ErbB2 IC(50) of 11 nM, potent activity in cellular functional and anti-proliferation assays, as well as activity in an in vivo pharmacodynamic assay.
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Adenina/análogos & derivados , Antineoplásicos/química , Antineoplásicos/farmacología , Receptores ErbB/antagonistas & inhibidores , Receptor ErbB-2/antagonistas & inhibidores , Receptor IGF Tipo 1/antagonistas & inhibidores , Adenina/química , Adenina/farmacocinética , Adenina/farmacología , Animales , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Receptores ErbB/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Neoplasias/tratamiento farmacológico , Ratas , Receptor ErbB-2/metabolismo , Receptor IGF Tipo 1/metabolismo , Relación Estructura-ActividadRESUMEN
The design and enzyme activities of a novel class of imidazo[2,1-b]thiazoles is presented.
Asunto(s)
Receptores ErbB/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Tiazoles/farmacología , Modelos Moleculares , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Tiazoles/químicaRESUMEN
BACKGROUND: The insulin-like growth factor (IGF) axis is an important signaling pathway in the growth and survival of many cell and tissue types. This pathway has also been implicated in many aspects of cancer progression from tumorigenesis to metastasis. The multiple roles of IGF signaling in cancer suggest that inhibition of the pathway might yield clinically effective therapeutics. METHODS: We describe A-928605, a novel pyrazolo [3,4-d]pyrimidine small molecule inhibitor of the receptor tyrosine kinases (IGF1R and IR) responsible for IGF signal transduction. This compound was first tested for its activity and selectivity via conventional in vitro kinome profiling and cellular IGF1R autophosphorylation. Additionally, cellular selectivity and efficacy of A-928605 were analyzed in an IGF1R oncogene-addicted cell line by proliferation, signaling and microarray studies. Finally, in vivo efficacy of A-928605 was assessed in the oncogene-addicted cell line and in a neuroblastoma model as a single agent as well as in combination with clinically approved therapeutics targeting EGFR in models of pancreatic and non-small cell lung cancers. RESULTS: A-928605 is a selective IGF1R inhibitor that is able to abrogate activation of the pathway both in vitro and in vivo. This novel compound dosed as a single agent is able to produce significant growth inhibition of neuroblastoma xenografts in vivo. A-928605 is also able to provide additive effects when used in combination with clinically approved agents directed against EGFR in non-small cell lung and human pancreatic tumor models. CONCLUSION: These results suggest that a selective IGF1R inhibitor such as A-928605 may provide a useful clinical therapeutic for IGF pathway affected tumors and warrants further investigation.
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Proliferación Celular/efectos de los fármacos , Neoplasias/fisiopatología , Proteínas Oncogénicas/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Pirimidinas/farmacología , Receptores de Somatomedina/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Transformación Celular Neoplásica/efectos de los fármacos , Femenino , Humanos , Ratones , Ratones Desnudos , Ratones SCID , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Proteínas Oncogénicas/metabolismo , Fosforilación/efectos de los fármacos , Receptores de Somatomedina/metabolismo , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Aniline 'headgroups' were synthesized and incorporated into an alkynyl thienopyrimidine series of EGFR and ErbB-2 inhibitors. Potent inhibition of enzyme activity and cellular proliferation was observed. In certain instances, protein binding was reduced and oral exposure was found to be somewhat improved relative to compounds containing the reference aniline.
Asunto(s)
Compuestos de Anilina/síntesis química , Receptores ErbB/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Pirimidinas/síntesis química , Receptor ErbB-2/antagonistas & inhibidores , Administración Oral , Compuestos de Anilina/administración & dosificación , Compuestos de Anilina/farmacología , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos/métodos , Receptores ErbB/metabolismo , Inhibidores de Crecimiento/administración & dosificación , Inhibidores de Crecimiento/síntesis química , Inhibidores de Crecimiento/farmacología , Humanos , Ratones , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/administración & dosificación , Pirimidinas/farmacología , Receptor ErbB-2/metabolismoRESUMEN
Emerging clinical and pre-clinical data indicate that both insulin-like growth factor receptor (IGF-IR) and members of the epidermal growth factor (EGF) family of receptor tyrosine kinases (RTKs) exhibit significant cross-talk in human cancers. Therefore, a small molecule that successfully inhibits the signaling of both classes of oncogenic kinases might provide an attractive agent for chemotherapeutic use. Herein, we disclose the structure activity relationships that led to the synthesis and biological characterization of 14, a novel small molecule inhibitor of both IGF-IR and members of the epidermal growth factor family of RTKs.
Asunto(s)
Antineoplásicos/síntesis química , Química Farmacéutica/métodos , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Receptores de Somatomedina/antagonistas & inhibidores , Receptores de Somatomedina/metabolismo , Antineoplásicos/farmacología , Línea Celular Tumoral , Dimerización , Diseño de Fármacos , Humanos , Pulmón/metabolismo , Modelos Químicos , Neoplasias/metabolismo , Fosforilación , Pirimidinas/química , Proteínas Tirosina Quinasas Receptoras/química , Transducción de SeñalRESUMEN
A novel class of pyrrolidinyl-acetyleneic thieno[3,2-d]pyrimidines has been identified which potently inhibit the EGFR and ErbB-2 receptor tyrosine kinases. Synthetic modifications of the pyrrolidine carbamate moiety result in a range of effects on enzyme and cellular potency. In addition, the impact of the absolute stereochemical configuration on cellular potency and oral mouse pharmacokinetics is described.
Asunto(s)
Antineoplásicos/química , Receptores ErbB/antagonistas & inhibidores , Pirimidinas/farmacología , Pirrolidinas/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Administración Oral , Animales , Ratones , Farmacocinética , Pirimidinas/síntesis química , Pirrolidinas/síntesis química , Relación Estructura-ActividadRESUMEN
This study tested four theoretical models of leadership with data from the ethnographic record. The first was a game-theoretical model of leadership in collective actions, in which followers prefer and reward a leader who monitors and sanctions free-riders as group size increases. The second was the dominance model, in which dominant leaders threaten followers with physical or social harm. The third, the prestige model, suggests leaders with valued skills and expertise are chosen by followers who strive to emulate them. The fourth proposes that in small-scale, kin-based societies, men with high neural capital are best able to achieve and maintain positions of social influence (e.g., as headmen) and thereby often become polygynous and have more offspring than other men, which positively selects for greater neural capital. Using multiple search strategies we identified more than 1000 texts relevant to leadership in the Probability Sample of 60 cultures from the Human Relations Area Files (HRAF). We operationalized the model with variables and then coded all retrieved text records on the presence or absence of evidence for each of these 24 variables. We found mixed support for the collective action model, broad support for components of the prestige leadership style and the importance of neural capital and polygyny among leaders, but more limited support for the dominance leadership style. We found little evidence, however, of emulation of, or prestige-biased learning toward, leaders. We found that improving collective actions, having expertise, providing counsel, and being respected, having high neural capital, and being polygynous are common properties of leaders, which warrants a synthesis of the collective action, prestige, and neural capital and reproductive skew models. We sketch one such synthesis involving high-quality decision-making and other computational services.
Asunto(s)
Liderazgo , Modelos Psicológicos , Capital Social , Cultura , Toma de Decisiones , HumanosRESUMEN
We describe a method to introduce naïve mice to a novel prehension (reach-to-grasp) task. Mice are housed singly in cages with a frontal slot that permits the mouse to reach out of its cage and retrieve food pellets. Minimal food restriction is employed to encourage the mice to perform the food retrieval from the slot. As the mice begin to associate coming to the slot for food, the pellets are manually pulled away to stimulate extension and pronation of their paw to grasp and retrieve the pellet through the frontal slot. When the mice begin to reach for the pellets as they arrive at the slot, the behavioral assay can be performed by measuring the rate at which they successfully grasp and retrieve the desired pellet. They are then introduced to an auto-trainer that automates both the process of providing food pellets for the mouse to grasp, and the recording of successful and failed reaching and grasping attempts. This allows for the collection of reaching data for multiple mice with minimal effort, to be used in experimental analysis as appropriate.
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Fuerza de la Mano , Desempeño Psicomotor , Animales , Conducta Animal , Alimentos , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
A novel class of substituted pyrrolidinyl-acetylenic thieno[3,2-d]pyrimidines has been identified that are potent and selective inhibitors of both EGFR/ErbB-2 receptor tyrosine kinases. The inhibitors are found to display a range of enzyme and cellular potency and also to display a varying level of covalent modification of the kinase targets. Selected molecules, including compound 15h, were found to be potent in enzymatic and cellular assays while also demonstrating exposure in the mouse from an oral dose.
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Receptores ErbB/antagonistas & inhibidores , Pirimidinas/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Animales , Línea Celular , Ratones , Unión Proteica , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
Blacks experience disproportionately elevated rates of tobacco-related morbidity and mortality. Blacks experience delayed smoking initiation relative to other racial/ethnic groups, highlighting the importance of examining smoking correlates occurring in late adolescence/early adulthood. The current study reports data collected as part of an ongoing collaborative effort to assess alcohol and drug use on the campuses of historically black colleges and universities (HBCUs). Two-thousand, two-hundred, seventy-seven African-American subjects, aged 20.3 +/- 3.9 (range 18-53), completed the CORE Alcohol and Drug survey and a brief demographic questionnaire. Results indicated that 90% of all subjects overestimated the rate of smoking among their peers. Overestimating was associated with a > 80% increase in the risk of smoking. These data highlight the need to correct misinformation regarding smoking norms among students at some HBCUs.
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Negro o Afroamericano/estadística & datos numéricos , Disparidades en el Estado de Salud , Grupo Paritario , Fumar/epidemiología , Percepción Social , Tabaquismo/epidemiología , Adolescente , Adulto , Actitud Frente a la Salud , Estudios Transversales , Femenino , Conductas Relacionadas con la Salud , Conocimientos, Actitudes y Práctica en Salud , Encuestas Epidemiológicas , Humanos , Masculino , Persona de Mediana Edad , Proyectos de Investigación , Factores de Riesgo , Asunción de Riesgos , Estudiantes/estadística & datos numéricos , Estados Unidos/epidemiología , UniversidadesRESUMEN
Members of the BET family of bromodomain containing proteins have been identified as potential targets for blocking proliferation in a variety of cancer cell lines. A two-dimensional NMR fragment screen for binders to the bromodomains of BRD4 identified a phenylpyridazinone fragment with a weak binding affinity (1, Ki = 160 µM). SAR investigation of fragment 1, aided by X-ray structure-based design, enabled the synthesis of potent pyridone and macrocyclic pyridone inhibitors exhibiting single digit nanomolar potency in both biochemical and cell based assays. Advanced analogs in these series exhibited high oral exposures in rodent PK studies and demonstrated significant tumor growth inhibition efficacy in mouse flank xenograft models.
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Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/farmacología , Piridonas/química , Piridonas/farmacología , Animales , Cristalografía por Rayos X , Descubrimiento de Drogas , Compuestos Macrocíclicos/farmacocinética , Estructura Molecular , Piridonas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
Many addiction treatment patients suffer from health and psychosocial problems in addition to substance misuse at the time of their treatment entry. Outpatient treatment programs have attempted to address these problems by providing or facilitating access to comprehensive health and social services. Nevertheless, previous research have suggested high levels of unmet needs for these services in the addiction treatment population. Using data from a large study on community-based outpatient addiction treatment, this article provides additional information on levels of unmet service needs and the relationship between need and receipt of services during treatment. Our results suggest extremely high levels of unmet needs for a wide variety of health and psychosocial services. Specifically, the data suggest that unmet service needs may be far more prevalent than previous estimates and that addiction treatment populations in rural areas may be particularly disadvantaged.