7 research outputs found
Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system philadelphia chromosome positive leukemia
Although imatinib, a BCR-ABL tyrosine kinase inhibitor, is used to treat acute Philadelphia chromosome-positive (Ph+) leukemia, it does not prevent central nervous system (CNS) relapses resulting from poor drug penetration through the blood-brain barrier. Imatinib and dasatinib (a dual-specific SRC/BCR-ABL kinase inhibitor) were compared in a pre-clinical mouse model of intracranial Ph+ leukemia. Clinical dasatinib treatment in patients with CNS Ph+ leukemia was assessed. In preclinical studies, dasatinib increased survival, whereas imatinib failed to inhibit intracranial tumor growth. Stabilization and regression of CNS disease were achieved with continued dasatinib administration. The drug also demonstrated substantial activity in 11 adult and pediatric patients with CNS Ph+ leukemia. Eleven evaluable patients had clinically significant, long-lasting responses, which were complete in 7 patients. In 3 additional patients, isolated CNS relapse occurred during dasatinib therapy; and in 2 of them, it was caused by expansion of a BCR-ABL-mutated dasatinib-resistant clone, implying selection pressure exerted by the compound in the CNS. Dasatinib has promising therapeutic potential in managing intracranial leukemic disease and substantial clinical activity in patients who experience CNS relapse while on imatinib therapy. This study is registered at ClinicalTrials. gov as CA180006 (#NCT00108719) and CA180015 (#NCT00110097)
Targeting Huntington鈥檚 disease through histone deacetylases
Huntington鈥檚 disease (HD) is a debilitating neurodegenerative condition with significant burdens on both patient and healthcare costs. Despite extensive research, treatment options for patients with this condition remain limited. Aberrant post-translational modification (PTM) of proteins is emerging as an important element in the pathogenesis of HD. These PTMs include acetylation, phosphorylation, methylation, sumoylation and ubiquitination. Several families of proteins are involved with the regulation of these PTMs. In this review, I discuss the current evidence linking aberrant PTMs and/or aberrant regulation of the cellular machinery regulating these PTMs to HD pathogenesis. Finally, I discuss the evidence suggesting that pharmacologically targeting one of these protein families the histone deacetylases may be of potential therapeutic benefit in the treatment of HD
Recommended from our members
Perfusion Assessment in Left-Sided/Low Anterior Resection (PILLAR III): A Randomized, Controlled, Parallel, Multicenter Study Assessing Perfusion Outcomes With PINPOINT Near-Infrared Fluorescence Imaging in Low Anterior Resection.
BackgroundIndocyanine green fluoroscopy has been shown to improve anastomotic leak rates in early phase trials.ObjectiveWe hypothesized that the use of fluoroscopy to ensure anastomotic perfusion may decrease anastomotic leak after low anterior resection.DesignWe performed a 1:1 randomized controlled parallel study. Recruitment of 450 to 1000 patients was planned over 2 years.SettingsThis was a multicenter trial.PatientsIncluded patients were those undergoing resection defined as anastomosis within 10 cm of the anal verge.InterventionPatients underwent standard evaluation of tissue perfusion versus standard in conjunction with perfusion evaluation using indocyanine green fluoroscopy.Main outcome measuresPrimary outcome was anastomotic leak, with secondary outcomes of perfusion assessment and the rate of postoperative abscess requiring intervention.ResultsThis study was concluded early because of decreasing accrual rates. A total of 25 centers recruited 347 patients, of whom 178 were randomly assigned to perfusion and 169 to standard. The groups had comparable tumor-specific and patient-specific demographics. Neoadjuvant chemoradiation was performed in 63.5% of perfusion and 65.7% of standard (p > 0.05). Mean level of anastomosis was 5.2 卤 3.1 cm in perfusion compared with 5.2 卤 3.3 cm in standard (p > 0.05). Sufficient visualization of perfusion was reported in 95.4% of patients in the perfusion group. Postoperative abscess requiring surgical management was reported in 5.7% of perfusion and 4.2% of standard (p = 0.75). Anastomotic leak was reported in 9.0% of perfusion compared with 9.6% of standard (p = 0.37). On multivariate regression analysis, there was no difference in anastomotic leak rates between perfusion and standard (OR = 0.845 (95% CI, 0.375-1.905); p = 0.34).LimitationsThe predetermined sample size to adequately reduce the risk of type II error was not achieved.ConclusionsSuccessful visualization of perfusion can be achieved with indocyanine green fluoroscopy. However, no difference in anastomotic leak rates was observed between patients who underwent perfusion assessment versus standard surgical technique. In experienced hands, the addition of routine indocyanine green fluoroscopy to standard practice adds no evident clinical benefit. See Video Abstract at http://links.lww.com/DCR/B560.Valoracin de la irrigacin de lado izquierdo/reseccin anterior baja pilar iii un estudio aleatorizado, controlado, paralelo y multicntrico que evala los resultados de la irrigacin con pinpoint imgenes de fluorescencia cercana al infrarrojo en la reseccin anterior bajaANTECEDENTES:Se ha demostrado que la fluoroscopia con verde de indocianina mejora las tasas de fuga anastom贸tica en ensayos en fases iniciales.OBJETIVO:Nuestra hip贸tesis es que la utilizaci贸n de fluoroscopia para asegurar la irrigaci贸n anastom贸tica puede disminuir la fuga anastom贸tica luego de una resecci贸n anterior baja.DISE脩O:Realizamos un estudio paralelo, controlado, aleatorizado 1:1. Se planific贸 el reclutamiento de 450-1000 pacientes durante 2 a帽os.AMBITO:Multic茅ntrico.PACIENTES:Pacientes sometidos a resecci贸n definida como una anastomosis dentro de los 10cm del margen anal.INTERVENCI脫N:Pacientes que se sometieron a la evaluaci贸n est谩ndar de la irrigaci贸n tisular contra la est谩ndar en conjunto con la valoraci贸n de la irrigaci贸n mediante fluoroscopia con verde indocianina.PRINCIPALES VARIABLES EVALUADAS:El principal resultado fue la fuga anastom贸tica, y los resultados secundarios fueron la evaluaci贸n de la perfusi贸n y la tasa de absceso posoperatorio que requiri贸 intervenci贸n.RESULTADOS:Este estudio se cerr贸 anticipadamente debido a la disminuci贸n de las tasas de acumulaci贸n. Un total de 25 centros reclutaron a 347 pacientes, de los cuales 178 fueron, de manera aleatoria, asignados a perfusi贸n y 169 a est谩ndar. Los grupos ten铆an datos demogr谩ficos espec铆ficos del tumor y del paciente similares. Recibieron quimio-radioterapia neoadyuvante el 63,5% de la perfusi贸n y el 65,7% del est谩ndar (p> 0,05). La anastomosis estuvo en un nivel promedio de 5,2 + 3,1 cm en perfusi贸n en comparaci贸n con 5,2 + 3,3 cm en est谩ndar (p> 0,05). Se report贸 una visualizaci贸n suficiente de la perfusi贸n en el 95,4% de los pacientes del grupo de perfusi贸n. El absceso posoperatorio que requiri贸 tratamiento quir煤rgico fue de 5,7% de los perfusion y en el 4,2% del est谩ndar (p = 0,75). Se inform贸 fuga anastom贸tica en el 9,0% de la perfusi贸n en comparaci贸n con el 9,6% del est谩ndar (p = 0,37). En el an谩lisis de regresi贸n multivariante, no hubo diferencias en las tasas de fuga anastom贸tica entre la perfusi贸n y el est谩ndar (OR 0,845; IC del 95% (0,375; 1,905); p = 0,34).LIMITACIONES:No se logr贸 el tama帽o de muestra predeterminado para reducir satisfactoriamente el riesgo de error tipo II.CONCLUSI脫N:Se puede obtener una visualizaci贸n adecuada de la perfusi贸n con ICG-F. Sin embargo, no se observaron diferencias en las tasas de fuga anastom贸tica entre los pacientes que se sometieron a evaluaci贸n de la perfusi贸n versus la t茅cnica quir煤rgica est谩ndar. En manos expertas, agregar ICG-F a la rutina de la pr谩ctica est谩ndar no agrega ning煤n beneficio cl铆nico evidente. Consulte Video Resumen en http://links.lww.com/DCR/B560. (Traducci贸n-Dr Juan Antonio Villanueva-Herrero)
NCI Imaging Data Commons
The National Cancer Institute (NCI) Cancer Research Data Commons (CRDC) aims to establish a national cloud-based data science infrastructure. Imaging Data Commons (IDC) is a new component of CRDC supported by the Cancer Moonshot. The goal of IDC is to enable a broad spectrum of cancer researchers, with and without imaging expertise, to easily access and explore the value of deidentified imaging data and to support integrated analyses with nonimaging data. We achieve this goal by colocating versatile imaging collections with cloud-based computing resources and data exploration, visualization, and analysis tools. The IDC pilot was released in October 2020 and is being continuously populated with radiology and histopathology collections. IDC provides access to curated imaging collections, accompanied by documentation, a user forum, and a growing number of analysis use cases that aim to demonstrate the value of a data commons framework applied to cancer imaging research. Significance: This study introduces NCI Imaging Data Commons, a new repository of the NCI Cancer Research Data Commons, which will support cancer imaging research on the cloud
NCI Imaging Data Commons
The National Cancer Institute (NCI) Cancer Research Data Commons (CRDC) aims to establish a national cloud-based data science infrastructure. Imaging Data Commons (IDC) is a new component of CRDC supported by the Cancer Moonshot{trade mark, serif}. The goal of IDC is to enable a broad spectrum of cancer researchers, with and without imaging expertise, to easily access and explore the value of de-identified imaging data and to support integrated analyses with non-imaging data. We achieve this goal by co-locating versatile imaging collections with cloud-based computing resources and data exploration, visualization, and analysis tools. The IDC pilot was released in October 2020 and is being continuously populated with radiology and histopathology collections. IDC provides access to curated imaging collections, accompanied by documentation, a user forum, and a growing number of analysis use cases that aim to demonstrate the value of a data commons framework applied to cancer imaging research