The Avatar Acceptability Study: Survivor, Parent and Community Willingness to Use Patient-Derived Xenografts to Personalize Cancer CareResearch in context

Background: Using patient-derived xenografts (PDXs) to assess chemosensitivity to anti-cancer agents in real-time may improve cancer care by enabling individualized clinical decision-making. However, it is unknown whether this new approach will be met with acceptance by patients, family and community. Methods: We used a cross-sectional structured survey to investigate PDX acceptability with 1550 individuals across Australia and New Zealand (648 survivors of adult and childhood cancer, versus 650 community comparisons; and 48 parents of childhood cancer survivors versus 204 community parents). We identified factors influencing willingness-to-use PDXs, willingness-to-pay, maximum acceptable wait-time, and maximum acceptable number of mice used per patient. Findings: PDXs were highly acceptable: >80% of those affected by cancer felt the potential advantages of PDXs outweighed the disadvantages (community participants: 68%). Survivors' and survivors' parents' most highly endorsed advantage was ‘increased chance of survival’. ‘Harm to animals’ was the least endorsed disadvantage for all groups. Cancer survivors were more willing to use PDXs than community comparisons [p < ·001]. Survivors and survivors' parents were willing to pay more [p < ·001; p = ∙004 respectively], wait longer for results [p = ·03; p = ∙01], and use more mice [p = ·01; p < ∙001] than community comparisons. Male survivors found PDXs more acceptable [p = ·01] and were willing to pay more [p < ·001] than female survivors. Survivors with higher incomes found PDXs more acceptable [p = ·002] and were willing to pay more [p < ·001] than survivors with lower incomes. Mothers found PDXs more acceptable [p = ·04] but were less willing to wait [p = ·02] than fathers. Interpretation: We found significant attitudinal support for PDX-guided cancer care. Willingness-to-pay and maximum acceptable number of mice align well with likely future usage. Maximum acceptable wait-times were lower than is currently achievable, highlighting an important area for future patient education until technology has caught up. Keywords: Patient derived xenograft, Acceptability, Oncology, Pediatric cancer, Willingness-to-pay, Informed consen

Efficacy of combined CDK9/13ET inhibition in preclinical models of MLL-rearranged acute leukemia

Abstract not availableHannah McCalmont, Ka Leung Li, Luke Jones, John Toubia, Sarah C. Bray, Debora A. Casolari ... at al

Telomerase inhibition effectively targets mouse and human AML stem cells and delays relapse following chemotherapy

Acute myeloid leukemia (AML) is an aggressive and lethal blood cancer maintained by rare populations of leukemia stem cells (LSCs). Selective targeting of LSCs is a promising approach for treating AML and preventing relapse following chemotherapy, and developing such therapeutic modalities is a key priority. Here, we show that targeting telomerase activity eradicates AML LSCs. Genetic deletion of the telomerase subunit Terc in a retroviral mouse AML model induces cell-cycle arrest and apoptosis of LSCs, and depletion of telomerase-deficient LSCs is partially rescued by p53 knockdown. Murine Terc(-/-) LSCs express a specific gene expression signature that can be identified in human AML patient cohorts and is positively correlated with patient survival following chemotherapy. In xenografts of primary human AML, genetic or pharmacological inhibition of telomerase targets LSCs, impairs leukemia progression, and delays relapse following chemotherapy. Altogether, these results establish telomerase inhibition as an effective strategy for eliminating AML LSCs

Helicopter rotor BVI airloads computation using advanced prescribed wake modeling

The miss-distance between helicopter rotor blades and their tip vortices is a key parameter for the correct prediction of blade-vortex interaction noise. Either free-wake codes (vortex lattice methods) or computational fluid dynamics codes are usually applied to compute the wake geometry and the blade-wake interactions. Prescribed wake codes are rather fast in computation, since the wake-vortex interactions are ignored therein, but they are considered not to be accurate enough due to the prescription of the geometry based on a few general parameters. They lack the effect of rotor harmonic loading and the effect of the fuselage on the wake geometry. This paper provides an approximate solution for both problems as independent extensions to classical prescribed wake codes to a first order of accuracy

Histone Deacetylase Inhibitors Trigger a G2 Checkpoint in Normal Cells That Is Defective in Tumor Cells

Important aspects of cell cycle regulation are the checkpoints, which respond to a variety of cellular stresses to inhibit cell cycle progression and act as protective mechanisms to ensure genomic integrity. An increasing number of tumor suppressors are being demonstrated to have roles in checkpoint mechanisms, implying that checkpoint dysfunction is likely to be a common feature of cancers. Here we report that histone deacetylase inhibitors, in particular azelaic bishydroxamic acid, triggers a G2 phase cell cycle checkpoint response in normal human cells, and this checkpoint is defective in a range of tumor cell lines. Loss of this G2 checkpoint results in the tumor cells undergoing an aberrant mitosis resulting in fractured multinuclei and micronuclei and eventually cell death. This histone deacetylase inhibitor-sensitive checkpoint appears to be distinct from G2/M checkpoints activated by genotoxins and microtubule poisons and may be the human homologue of a yeast G2 checkpoint, which responds to aberrant histone acetylation states. Azelaic bishydroxamic acid may represent a new class of anticancer drugs with selective toxicity based on its ability to target a dysfunctional checkpoint mechanism in tumor cells