Cancer trials often start investigational therapy at diagnosis or after a selected number of relapses.These are the usual core inclusion criteria in clinical trials.Hence it is helpful when planning a trial to know th...Cancer trials often start investigational therapy at diagnosis or after a selected number of relapses.These are the usual core inclusion criteria in clinical trials.Hence it is helpful when planning a trial to know the likely percentages of patients receiving standard therapy at clinics and hospitals who meet this key inclusion criteria of being newly diagnosed during a period or having just had their first,second or third relapse during an anticipated enrollment time frame.Often regulatory agencies will have approvals tied to the use of a therapy in a relapsed context or in a newly diagnosed context.We provide details on calculations to help those in clinical trial operations make realistic assessments on the number of sites and likely enrollment at clinical trial sites,and the enrollment time frames that might be needed to complete planned total patient enrollment.The estimates complement site feasibility questionnaires which are often sent to gauge patient availability and site interest.展开更多
5q-syndrome is a distinct form of myelodysplastic syndrome（MDS） where a deletion on chromosome 5 is the underlying cause.MDS is characterized by bone marrow failures,including macrocytic anemia.Genetic mapping and s...5q-syndrome is a distinct form of myelodysplastic syndrome（MDS） where a deletion on chromosome 5 is the underlying cause.MDS is characterized by bone marrow failures,including macrocytic anemia.Genetic mapping and studies using various models support the notion that ribosomal protein S14（RPS14） is the candidate gene for the erythroid failure.Targeted disruption of RPS14 causes an increase in p53 activity and p53-mediated apoptosis,similar to what is observed with other ribosomal proteins.However,due to the higher risk for cancer development in patients with ribosome deficiency,targeting the p53 pathway is not a viable treatment option.To better understand the pathology of RPS14 deficiency in 5q-deletion,we generated a zebrafish model harboring a mutation in the RPS14 gene.This model mirrors the anemic phenotype seen in 5q-syndrome.Moreover,the anemia is due to a late-stage erythropoietic defect,where the erythropoietic defect is initially p53-independent and then becomes p53-dependent.Finally,we demonstrate the versatility of this model to test various pharmacological agents,such as RAP-011,L-leucine,and dexamethasone in order to identify molecules that can reverse the anemic phenotype.展开更多
文摘Cancer trials often start investigational therapy at diagnosis or after a selected number of relapses.These are the usual core inclusion criteria in clinical trials.Hence it is helpful when planning a trial to know the likely percentages of patients receiving standard therapy at clinics and hospitals who meet this key inclusion criteria of being newly diagnosed during a period or having just had their first,second or third relapse during an anticipated enrollment time frame.Often regulatory agencies will have approvals tied to the use of a therapy in a relapsed context or in a newly diagnosed context.We provide details on calculations to help those in clinical trial operations make realistic assessments on the number of sites and likely enrollment at clinical trial sites,and the enrollment time frames that might be needed to complete planned total patient enrollment.The estimates complement site feasibility questionnaires which are often sent to gauge patient availability and site interest.
基金supported by Celgene(Nov022011)National Institutes of Health(R56 DK107286)
文摘5q-syndrome is a distinct form of myelodysplastic syndrome（MDS） where a deletion on chromosome 5 is the underlying cause.MDS is characterized by bone marrow failures,including macrocytic anemia.Genetic mapping and studies using various models support the notion that ribosomal protein S14（RPS14） is the candidate gene for the erythroid failure.Targeted disruption of RPS14 causes an increase in p53 activity and p53-mediated apoptosis,similar to what is observed with other ribosomal proteins.However,due to the higher risk for cancer development in patients with ribosome deficiency,targeting the p53 pathway is not a viable treatment option.To better understand the pathology of RPS14 deficiency in 5q-deletion,we generated a zebrafish model harboring a mutation in the RPS14 gene.This model mirrors the anemic phenotype seen in 5q-syndrome.Moreover,the anemia is due to a late-stage erythropoietic defect,where the erythropoietic defect is initially p53-independent and then becomes p53-dependent.Finally,we demonstrate the versatility of this model to test various pharmacological agents,such as RAP-011,L-leucine,and dexamethasone in order to identify molecules that can reverse the anemic phenotype.
