RESUMEN
OBJECTIVE: To compare prostate artery embolisation (PAE) to the combination of tamsulosin and dutasteride therapy as a potential first-line therapy for obstructive benign prostatic hyperplasia (BPH) in treatment-naïve patients in the 'Prostate Embolisation AS first-line therapY compAred to meDication in treatment naïVe men with prostAte eNlargement, a randomised ControllEd trial' (P-EASY ADVANCE). PATIENTS AND METHODS: A total of 39 men with enlarged prostates, moderate-severe lower urinary tract symptoms (LUTS) and obstructed/equivocal urodynamic studies (UDS), and who had no prior treatment for BPH, were randomised to receive either combined medical therapy with tamsulosin and dutasteride (medication) or PAE. Follow-up UDS, International Prostate Symptom Score (IPSS), uroflowmetry and ultrasound were performed at short- to medium-term intervals following interventions and compared to baseline. RESULTS: The medication and PAE treatment groups had similar baseline characteristics, including prostate volumes (87.8 and 85.4 mL respectively), maximum urinary flow rate (Qmax; 6.5 and 6.6 mL/s, respectively), IPSS (19.5 and 21, respectively) and obstructed UDS (79% and 74%, respectively). Both interventions improved voiding and bladder outflow obstruction from baseline, with more patients unobstructed after PAE (63%) compared to medication (28%) (P = 0.03). PAE patients had significantly greater reductions in prostate size (P < 0.001), incomplete emptying (P = 0.002), total IPSS (P = 0.032), Qmax (P = 0.006) and quality of life (P = 0.001). Altered ejaculation, erectile dysfunction and nausea were more common in the medication group. CONCLUSION: Prostate artery embolisation was more effective than combined medical therapy at reducing urinary obstruction, decreasing prostate volume and improving LUTS in patients with BPH who had not previously been treated. This is the first randomised control study to compare PAE and combined medical therapy in exclusively treatment-naïve patients and raises the potential of PAE as an alternative early treatment option for BPH. Further randomised comparative trials are planned to further validate the role of PAE in mitigating obstructive BPH.
RESUMEN
OBJECTIVES: To assess the safety, short-term efficacy and early functional results of prostate artery embolisation (PAE), an emerging minimally invasive treatment for symptomatic benign prostate hyperplasia (BPH). PATIENTS AND METHODS: In all, 51 men with BPH (prostate size >40 mL) causing moderate-severe lower urinary tract symptoms, who had either failed or ceased medical therapy and had declined or were considered unsuitable for surgical intervention, were recruited to this study. All men underwent baseline clinical assessment, PAE, and 3-month follow-up. The primary endpoints of this study were safety and feasibility. Safety was measured by the incidence of post-PAE adverse events and feasibility was defined by technical success. Secondary endpoints were changes in the International Prostate Symptom Score (IPSS) and quality of life (QoL) score at 3 months after PAE. RESULTS: There were no serious adverse events and all procedures were technically successful. For non-catheterised patients, improvement in IPSS and QoL was reported in 95.1% of cases (P < 0.001). The mean reductions in IPSS and QoL were 18.8 points (80.7%) (P < 0.001) and 3.8 points (80.6%) (P < 0.001), respectively. Of the 30 non-indwelling-catheter-dependent men on medical therapy, 23 men were able to completely cease all medications, with all but one of the remaining men reporting significant improvements in IPSS and QoL score. CONCLUSION: PAE is a technically feasible and safe procedure, with excellent short-term efficacy. High rates of patient satisfaction were achieved in this study, along with significant reductions in prostate symptoms and improvements in QoL. PAE may be an alternative to long-term use of medical therapy for symptoms due to BPH.
Asunto(s)
Arterias , Embolización Terapéutica/efectos adversos , Próstata/irrigación sanguínea , Hiperplasia Prostática/terapia , Prostatismo/terapia , Anciano , Anciano de 80 o más Años , Embolización Terapéutica/métodos , Estudios de Factibilidad , Humanos , Masculino , Persona de Mediana Edad , Tamaño de los Órganos , Próstata/patología , Hiperplasia Prostática/complicaciones , Hiperplasia Prostática/tratamiento farmacológico , Hiperplasia Prostática/patología , Prostatismo/etiología , Calidad de Vida , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Filanesib (ARRY-520) is a highly selective inhibitor of kinesin spindle protein, which has demonstrated preclinical antimyeloma activity. METHODS: This open-label Phase 1/2 study determined the maximum tolerated dose of Filanesib administered on Days 1 and 2 of 14-Day Cycles in patients with multiple myeloma (MM) and included expansion cohorts with and without dexamethasone (40 mg/week). Patients in the dose-escalation (N = 31) and Phase 2 single-agent (N = 32) cohorts had received prior bortezomib as well as prior thalidomide and/or lenalidomide. Patients in the Phase 2 Filanesib plus dexamethasone cohort (N = 55) had received prior alkylator therapy and had disease refractory to lenalidomide, bortezomib, and dexamethasone. Prophylactic filgrastim was incorporated during dose escalation and was used throughout Phase 2. RESULTS: Patients in each cohort had received a median of ≥6 prior therapies. The most common dose-limiting toxicities were febrile neutropenia and mucosal inflammation. In Phase 2, Grade 3 and 4 cytopenias were reported in approximately 50% of patients. Nonhematologic toxicities were infrequent. Phase 2 response rates (partial responses or better) were 16% (single agent) and 15% (Filanesib plus dexamethasone). All responding patients had low baseline levels of α1-acid glycoprotein, a potential selective biomarker. CONCLUSIONS: Filanesib 1.50 mg/m2 /day administered with prophylactic filgrastim has a manageable safety profile and encouraging activity in heavily pretreated patients This study is registered at www.clinicaltrials.gov as NCT00821249. Cancer 2017;123:4617-4630. © 2017 American Cancer Society.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Mieloma Múltiple/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Terapia Recuperativa , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Dexametasona/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Mieloma Múltiple/patología , Recurrencia Local de Neoplasia/patología , Pronóstico , Tasa de Supervivencia , Tiadiazoles/administración & dosificaciónRESUMEN
BACKGROUND: Filanesib is a kinesin spindle protein inhibitor that has demonstrated encouraging activity in patients with recurrent/refractory multiple myeloma. Preclinical synergy with bortezomib was the rationale for the current phase 1 study. METHODS: The current study was a multicenter study with an initial dose-escalation phase to determine the maximum tolerated dose of 2 schedules of filanesib plus bortezomib with and without dexamethasone, followed by a dose-expansion phase. RESULTS: With the addition of prophylactic filgastrim, the maximum planned dose was attained: 1.3 mg/m2 /day of bortezomib plus 40 mg of dexamethasone on days 1, 8, and 15 of a 28-day cycle, with filanesib given intravenously either at a dose of 1.5 mg/m2 /day (schedule 1: days 1, 2, 15, and 16) or 3 mg/m2 /day (schedule 2: days 1 and 15). The most common adverse events (assessed for severity using version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events) were transient, noncumulative neutropenia and thrombocytopenia with grade 3/4 events reported in 44% (16% in cycle 1 with filgastrim) and 29% of patients, respectively. A low (≤11%) overall rate of nonhematological grade 3/4 toxicity was observed. With a median of 3 prior lines of therapy and 56% of patients with disease that was refractory to proteasome inhibitors, the overall response rate was 20% (55 patients), and was 29% in 14 patients with proteasome inhibitors-refractory disease receiving filanesib at a dose of ≥1.25 mg/m2 (duration of response, 5.2 to ≥21.2 months). CONCLUSIONS: The current phase 1 study established a dosing schedule for the combination of these agents that demonstrated a favorable safety profile with a low incidence of nonhematologic toxicity and manageable hematologic toxicity. The combination of filanesib, bortezomib, and dexamethasone appears to have durable activity in patients with recurrent/refractory multiple myeloma. Cancer 2016;122:3327-3335. © 2016 American Cancer Society.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Mieloma Múltiple/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Terapia Recuperativa , Adulto , Anciano , Bortezomib/administración & dosificación , Dexametasona/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Mieloma Múltiple/patología , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pronóstico , Tiadiazoles/administración & dosificaciónRESUMEN
Transcatheter hepatic arterial administration of irinotecan-loaded drug-eluting beads (DEBIRI) is used to treat liver-only or liver-dominant metastatic disease from colorectal cancer (CRC). Eligibility for DEBIRI should be established in each individual patient by a multidisciplinary team based on comprehensive clinical, imaging, and laboratory assessment. Standardization of DEBIRI technique and protocols would be expected to lead to improved efficacy and safety. The present article provides a set of technical recommendations for the use of DEBIRI in the treatment of hepatic CRC metastases.
Asunto(s)
Camptotecina/análogos & derivados , Quimioembolización Terapéutica/normas , Neoplasias Colorrectales/terapia , Preparaciones de Acción Retardada/administración & dosificación , Stents Liberadores de Fármacos/normas , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/terapia , Camptotecina/administración & dosificación , Relación Dosis-Respuesta a Droga , Quimioterapia/normas , Humanos , Inyecciones Intraarteriales/normas , Internacionalidad , Irinotecán , Guías de Práctica Clínica como AsuntoRESUMEN
Developing therapies for the activated B-cell like (ABC) subtype of diffuse large B-cell lymphomas (DLBCL) remains an area of unmet medical need. A subset of ABC DLBCL tumors is driven by activating mutations in myeloid differentiation primary response protein 88 (MYD88), which lead to constitutive activation of interleukin-1 receptor associated kinase 4 (IRAK4) and cellular proliferation. IRAK4 signaling is driven by its catalytic and scaffolding functions, necessitating complete removal of this protein and its escape mechanisms for complete therapeutic suppression. Herein, we describe the identification and characterization of a dual-functioning molecule, KT-413 and show it efficiently degrades IRAK4 and the transcription factors Ikaros and Aiolos. KT-413 achieves concurrent degradation of these proteins by functioning as both a heterobifunctional degrader and a molecular glue. Based on the demonstrated activity and safety of KT-413 in preclinical studies, a phase 1 clinical trial in B-cell lymphomas, including MYD88 mutant ABC DLBCL, is currently underway.
Asunto(s)
Quinasas Asociadas a Receptores de Interleucina-1 , Linfoma de Células B Grandes Difuso , Mutación , Factor 88 de Diferenciación Mieloide , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Factor 88 de Diferenciación Mieloide/metabolismo , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Humanos , Animales , Línea Celular Tumoral , Descubrimiento de Drogas , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Ratones , Imidazoles/química , Imidazoles/farmacología , Imidazoles/metabolismo , Proteolisis/efectos de los fármacos , Relación Estructura-ActividadAsunto(s)
Encéfalo/diagnóstico por imagen , Cartílago/diagnóstico por imagen , Medios de Contraste/química , Rodilla/diagnóstico por imagen , Imagen por Resonancia Magnética , Adolescente , Adulto , Algoritmos , Mama/diagnóstico por imagen , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Imagenología Tridimensional , Persona de Mediana Edad , Reproducibilidad de los Resultados , Programas Informáticos , Líquido Sinovial/diagnóstico por imagen , Adulto JovenRESUMEN
PURPOSE: To compare automated segmentation of the quadratus lumborum (QL) based on statistical shape modeling (SSM) with conventional manual processing of magnetic resonance (MR) images for segmentation of this paraspinal muscle. MATERIALS AND METHODS: The automated SSM scheme for QL segmentation was developed using an MR database of 7 mm axial images of the lumbar region from 20 subjects (cricket fast bowlers and athletic controls). Specifically, a hierarchical 3D-SSM scheme for segmentation of the QL, and surrounding psoas major (PS) and erector spinae+multifidus (ES+MT) musculature, was implemented after image preprocessing (bias field correction, partial volume interpolation) followed by image registration procedures to develop average and probabilistic MR atlases for initializing and constraining the SSM segmentation of the QL. The automated and manual QL segmentations were compared using spatial overlap and average surface distance metrics. RESULTS: The spatial overlap between the automated SSM and manual segmentations had a median Dice similarity metric of 0.87 (mean = 0.86, SD = 0.08) and mean average surface distance of 1.26 mm (SD = 0.61) and 1.32 mm (SD = 0.60) for the right and left QL muscles, respectively. CONCLUSION: The current SSM scheme represents a promising approach for future automated morphometric analyses of the QL and other paraspinal muscles from MR images.
Asunto(s)
Imagen por Resonancia Magnética/métodos , Músculo Esquelético/patología , Adolescente , Adulto , Algoritmos , Atletas , Automatización , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Masculino , Modelos Estadísticos , Reconocimiento de Normas Patrones Automatizadas/métodos , Probabilidad , Reproducibilidad de los ResultadosRESUMEN
Inhibition of mutant IDH1 is being evaluated clinically as a treatment option for oncology. Here we describe the structure-based design and optimization of quinoline lead compounds to identify FT-2102, a potent, orally bioavailable, brain penetrant, and selective mIDH1 inhibitor. FT-2102 has excellent ADME/PK properties and reduces 2-hydroxyglutarate levels in an mIDH1 xenograft tumor model. This compound has been selected as a candidate for clinical development in hematologic malignancies, solid tumors, and gliomas with mIDH1.
Asunto(s)
Antineoplásicos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Piridinas/uso terapéutico , Quinolinas/uso terapéutico , Quinolonas/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Línea Celular Tumoral , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Femenino , Humanos , Isocitrato Deshidrogenasa/metabolismo , Ratones Endogámicos BALB C , Estructura Molecular , Unión Proteica , Piridinas/síntesis química , Piridinas/metabolismo , Quinolinas/síntesis química , Quinolinas/metabolismo , Quinolonas/síntesis química , Quinolonas/metabolismo , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Aging skeletal muscle is characterized not only by a reduction in size (sarcopenia) and strength but also by an increase in fatty infiltration (myosteatosis). An effective countermeasure to sarcopenia is resistance exercise; however, its effect on fatty infiltration is less clear. OBJECTIVE: To examine in resistance-trained older persons whether muscle attenuation, a noninvasive measure of muscle density reflecting intramuscular lipid content, is altered with training status. METHODS: Thirteen healthy community-dwelling men and women aged 65-83 years (body mass index 27.0+/-1.2, mean+/-SE) had computed-tomography scans of the mid-thigh performed following 24 weeks of training, 24 weeks of detraining, and 12 weeks of retraining. Training and retraining were undertaken twice weekly for several upper- and lower-body muscle groups. Skeletal muscle attenuation in Hounsfield units (HU) as well as mid-thigh muscle volume was obtained for the quadriceps and hamstrings. Muscle strength was assessed by 1-repetition maximum and physical function by a battery of tests. RESULTS: The average change in muscle strength following training, detraining and retraining was 48.8+/-2.9%, -17.6+/-1.3%, and 19.8+/-2.0%, respectively. Strength changes were accompanied by significant alterations in muscle density (p<0.001), with the quadriceps HU decreasing by 7.7+/-1.0% following detraining and increasing by 5.4+/-0.5% with retraining. For the hamstrings HU measure, detraining and retraining resulted in an 11.9+/-1.4% loss and a 5.5+/-1.8% gain, respectively. There was no significant change in muscle volume. CONCLUSION: Cessation of resistance exercise in trained older persons increases the fatty infiltration of muscle, while resumption of exercise decreases it. Monitoring changes in both muscle size and fat infiltration may enable a more comprehensive assessment of exercise in combating age-related muscular changes.
Asunto(s)
Envejecimiento/patología , Envejecimiento/fisiología , Fuerza Muscular , Músculo Esquelético/anatomía & histología , Músculo Esquelético/fisiología , Entrenamiento de Fuerza , Tejido Adiposo/anatomía & histología , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Metabolismo de los Lípidos , Masculino , Músculo Esquelético/diagnóstico por imagen , Tomografía Computarizada por Rayos XRESUMEN
We present accurate QCD predictions for the transverse momentum ( p ⥠) spectrum of electroweak gauge bosons at the LHC for 13 TeV collisions, based on a consistent combination of a NNLO calculation at large p ⥠and N 3 LL resummation in the small p ⥠limit. The inclusion of higher order corrections leads to substantial changes in the shape of the differential distributions, and the residual perturbative uncertainties are reduced to the few percent level across the whole transverse momentum spectrum. We examine the ratio of p ⥠distributions in charged- and neutral-current Drell-Yan production, and study different prescriptions for the estimate of perturbative uncertainties that rely on different degrees of correlation between these processes. We observe an excellent stability of the ratios with respect to the perturbative order, indicating a strong correlation between the corresponding QCD corrections.
RESUMEN
Mutations at the arginine residue (R132) in isocitrate dehydrogenase 1 (IDH1) are frequently identified in various human cancers. Inhibition of mutant IDH1 (mIDH1) with small molecules has been clinically validated as a promising therapeutic treatment for acute myeloid leukemia and multiple solid tumors. Herein, we report the discovery and optimization of a series of quinolinones to provide potent and orally bioavailable mIDH1 inhibitors with selectivity over wild-type IDH1. The X-ray structure of an early lead 24 in complex with mIDH1-R132H shows that the inhibitor unexpectedly binds to an allosteric site. Efforts to improve the in vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) properties of 24 yielded a preclinical candidate 63. The detailed preclinical ADME and pharmacology studies of 63 support further development of quinolinone-based mIDH1 inhibitors as therapeutic agents in human trials.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Quinolonas/química , Quinolonas/farmacología , Sitio Alostérico/efectos de los fármacos , Animales , Disponibilidad Biológica , Línea Celular Tumoral , Cristalografía por Rayos X , Perros , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacocinética , Femenino , Humanos , Isocitrato Deshidrogenasa/química , Isocitrato Deshidrogenasa/genética , Células de Riñón Canino Madin Darby , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Mutación Puntual , Quinolonas/farmacocinéticaRESUMEN
The identification of a selective CDK2, 7, 9 inhibitor 4 with improved permeability is described. Compound 4 exhibits comparable CDK selectivity profile to SNS-032, but shows improved permeability and higher bioavailability in mice.
Asunto(s)
Oxazoles/química , Oxazoles/farmacocinética , Tiazoles/química , Tiazoles/farmacocinética , Animales , Disponibilidad Biológica , Ratones , PermeabilidadRESUMEN
Modifications of the isonipecotic acid fragment of SNS-032 results in analogs which are more permeable and lower effluxed than SNS-032. The enantiomerically pure synthesis and the in vivo profile of analog 20 is described.
Asunto(s)
Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Ácidos Isonipecóticos/química , Oxazoles/síntesis química , Tiazoles/síntesis química , Animales , Técnicas Químicas Combinatorias , Ácidos Isonipecóticos/farmacología , Ratones , Estructura Molecular , Oxazoles/química , Oxazoles/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacologíaRESUMEN
PURPOSE: This prospective magnetic resonance (MR) imaging study investigated the development of symptomatic pars lesions in the lumbar spine of adolescent cricket fast bowlers. METHODS: Annual MR examinations of the lumbar spine in male fast bowlers (N = 51) and swimmers (N = 20) without a prestudy history of symptomatic back injury were conducted to identify stress-induced pars injuries over 4 and 2 yr periods, respectively. RESULTS: Symptomatic L4 and L5 pars lesions developed in 11 of 51 and 1 of 51 of the bowlers, respectively. Preexisting L5 lesions were observed in both bowlers (10 of 51) and swimmers (4 of 20). No significant difference existed between the proportion of bowlers and swimmers with preexisting L5 lesions (P = 1.00, Fisher's exact test). In contrast, bowlers had a significantly greater proportion of L4 pars lesions compared with swimmers, with 22% of the bowlers developing L4 injuries during the study, whereas there were no L4 lesions in the swimmers (P = 0.027, Fisher's exact test). The symptomatic L4 lesions in the bowlers developed between 15 and 17 yr of age, and all were unilateral lesions lateralized to the nonbowling-arm side. The MR characteristics of the L4 pars lesions were consistent with a stress fracture through the cortical bone. Of the acquired L4 lesions in the bowlers, 4 of 11 and 7 of 11 developed in individuals with and without preexisting L5 defects, respectively. No significant association existed between the acquired L4 pars lesions and preexisting L5 defects in the bowlers (P = 0.216, Fisher's exact test). CONCLUSION: Fast bowling was directly associated with the development of symptomatic pars lesions of the lumbar spine, particularly unilateral L4 stress lesions, in a significant proportion of the adolescent bowlers examined in this prospective MR study.
Asunto(s)
Traumatismos en Atletas , Fracturas por Estrés/fisiopatología , Vértebras Lumbares/fisiopatología , Espondilólisis , Adolescente , Fracturas por Estrés/diagnóstico , Humanos , Imagen por Resonancia Magnética , Masculino , Estudios Prospectivos , Queensland/epidemiología , Espondilólisis/diagnóstico , Espondilólisis/epidemiologíaRESUMEN
PURPOSE: This prospective study examined the association between quadratus lumborum (QL) asymmetry and the development of symptomatic pars interarticularis lesions in the lumbar spine of adolescent cricket fast bowlers. METHODS: Annual magnetic resonance imaging was used to measure QL volume asymmetry and for identifying pars lesions of the lumbar vertebrae in fast bowlers (N=51) and a control group of swimmers (N=18). Manual segmentation of axial images spanning the lumbar spine was performed to calculate percent QL asymmetry relative to the bowling- or throwing- (swimmers) arm side. Asymmetry above 100% indicated a larger QL volume on the bowling- (throwing) arm side. RESULTS: The mean QL asymmetry in bowlers of 110.5% (SD=12.1%) was significantly different from the 96.6% (SD=5.0%) asymmetry in swimmers (t=6.75, PAsunto(s)
Fracturas por Estrés/epidemiología
, Vértebras Lumbares/lesiones
, Músculo Esquelético/fisiología
, Adolescente
, Traumatismos en Atletas
, Fracturas por Estrés/diagnóstico
, Fracturas por Estrés/etiología
, Humanos
, Vértebras Lumbares/fisiopatología
, Imagen por Resonancia Magnética
, Masculino
, Estudios Prospectivos
, Queensland/epidemiología
RESUMEN
Pluripotent cells of embryonic origin proliferate at unusually rapid rates and have a characteristic cell cycle structure with truncated gap phases. To define the molecular basis for this we have characterized the cell cycle control of murine embryonic stem cells and early primitive ectoderm-like cells. These cells display precocious Cdk2, cyclin A and cyclin E kinase activities that are conspicuously cell cycle independent. Suppression of Cdk2 activity significantly decreased cycling times of pluripotent cells, indicating it to be rate-limiting for rapid cell division, although this had no impact on cell cycle structure and the establishment of extended gap phases. Cdc2-cyclin B was the only Cdk activity that was identified to be cell cycle regulated in pluripotent cells. Cell cycle regulation of cyclin B levels and Y(15) regulation of Cdc2 contribute to the temporal changes in Cdc2-cyclin B activity. E2F target genes are constitutively active throughout the cell cycle, reflecting the low activity of pocket proteins such as p107 and pRb and constitutive activity of pRb-kinases. These results show that rapid cell division cycles in primitive cells of embryonic origin are driven by extreme levels of Cdk activity that lack normal cell cycle periodicity.
Asunto(s)
Quinasas CDC2-CDC28 , Proteínas de Ciclo Celular , División Celular/fisiología , Ciclina A/fisiología , Ciclina E/fisiología , Quinasas Ciclina-Dependientes/fisiología , Proteínas de Unión al ADN , Proteínas Serina-Treonina Quinasas/fisiología , Células Madre/citología , Factores de Transcripción/fisiología , Animales , Línea Celular , Quinasa 2 Dependiente de la Ciclina , Quinasas Ciclina-Dependientes/química , Quinasas Ciclina-Dependientes/metabolismo , Factores de Transcripción E2F , Embrión de Mamíferos/citología , Ratones , Fosforilación , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Tirosina/metabolismoRESUMEN
To develop an automated approach for 3D quantitative assessment and measurement of alpha angles from the femoral head-neck (FHN) junction using bone models derived from magnetic resonance (MR) images of the hip joint.Bilateral MR images of the hip joints were acquired from 30 male volunteers (healthy active individuals and high-performance athletes, aged 1849 years) using a water-excited 3D dual echo steady state (DESS) sequence. In a subset of these subjects (18 water-polo players), additional True Fast Imaging with Steady-state Precession (TrueFISP) images were acquired from the right hip joint. For both MR image sets, an active shape model based algorithm was used to generate automated 3D bone reconstructions of the proximal femur. Subsequently, a local coordinate system of the femur was constructed to compute a 2D shape map to project femoral head sphericity for calculation of alpha angles around the FHN junction. To evaluate automated alpha angle measures, manual analyses were performed on anterosuperior and anterior radial MR slices from the FHN junction that were automatically reformatted using the constructed coordinate system.High intra- and inter-rater reliability (intra-class correlation coefficients > 0.95) was found for manual alpha angle measurements from the auto-extracted anterosuperior and anterior radial slices. Strong correlations were observed between manual and automatic measures of alpha angles for anterosuperior (r = 0.84) and anterior (r = 0.92) FHN positions. For matched DESS and TrueFISP images, there were no significant differences between automated alpha angle measures obtained from the upper anterior quadrant of the FHN junction (two-way repeated measures ANOVA, F < 0.01, p = 0.98).Our automatic 3D method analysed MR images of the hip joints to generate alpha angle measures around the FHN junction circumference with very good reliability and reproducibility. This work has the potential to improve analyses of cam-type lesions of the FHN junction for large-scale morphometric and clinical MR investigations of the human hip region.
Asunto(s)
Algoritmos , Cabeza Femoral/diagnóstico por imagen , Cabeza Femoral/patología , Imagenología Tridimensional/métodos , Cuello/diagnóstico por imagen , Cuello/patología , Adolescente , Adulto , Automatización , Humanos , Interpretación de Imagen Asistida por Computador , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Radiografía , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
Kinesin spindle protein (KSP/Eg5) inhibitors are novel anticancer agents that have thus far shown only modest activity in the clinic. Understanding how to identify patients who may be most sensitive to treatment is clearly needed to improve the development of these molecules. We studied four multiple myeloma cell lines treated with the KSP inhibitor ARRY-520 to identify factors important for initiating apoptosis while cells are arrested in mitosis. The majority (three of four) of cell lines underwent mitotic arrest, with apoptosis occurring in mitosis within 24 to 30 hours. The remaining line (NCI H929) is temporally refractory to ARRY-520 treatment, undergoing mitotic slippage and subsequently peaking in apoptotic markers after 72 hours of treatment, while most cells are in interphase. Interestingly, loss of the antiapoptotic protein myeloid cell leukemia 1 (Mcl-1) coincided with mitotic cell death. Stabilization of Mcl-1 resulted in a delayed onset of apoptosis, whereas enforced downregulation of Mcl-1 increased cell death in response to KSP inhibition. Thus, variation in responses to KSP inhibition is governed by a balance between survival proteins and spindle checkpoint integrity. Cells relying on short-lived survival proteins during mitosis are more likely to undergo apoptosis in response to KSP inhibition. We propose that patients with hematologic malignancies, which rely on Mcl-1, would therefore be good candidates for treatment with KSP inhibitors.
Asunto(s)
Cinesinas/antagonistas & inhibidores , Mieloma Múltiple/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Tiadiazoles/farmacología , Animales , Apoptosis/efectos de los fármacos , Western Blotting , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Femenino , Humanos , Cinesinas/metabolismo , Ratones , Ratones SCID , Mitosis/efectos de los fármacos , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Proteínas Proto-Oncogénicas c-bcl-2/genética , Interferencia de ARN , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: SNS-032 (formerly BMS-387032) is a potent, selective inhibitor of cyclin-dependent kinases (CDK) 2, 7 and 9, currently in phase 1 clinical trial for chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). We used the MM cell line RPMI-8226 to evaluate the relationship between duration of SNS-032 exposure, target modulation of CDKs 2, 7 and 9, and induction of apoptosis. We also assessed target modulation in patient peripheral blood mononuclear cells (PBMCs) from phase 1 solid tumor patients treated with SNS-032. METHODS: Proliferation and colony forming assays were used to evaluate cytotoxicity, Western blot analyses to evaluate target modulation, FACS analysis to assess cell cycle distribution, RT-PCR to evaluate transcriptional inhibition. RESULTS: SNS-032 blocks the cell cycle via inhibition of CDKs 2 and 7, and transcription via inhibition of CDKs 7 and 9. Treatment of RPMI-8226 MM cells at 300 nM (IC(90)) for 6 h was sufficient for commitment to apoptosis. This correlated with inhibition of CDKs 2, 7 and 9, as reflected in substrate signaling molecules. SNS-032 activity was unaffected by human serum. Target modulation was observed in PBMC from treated patients. CONCLUSIONS: These results demonstrate SNS-032 target modulation of CDKs 2, 7 and 9, and establish 6 h exposure as sufficient to commit RPMI-8226 MM cells to apoptosis. Combined with the demonstration of target modulation in PBMC from phase 1 solid tumor patients treated with SNS-032, these data support the ongoing clinical study of SNS-032 in MM and CLL.