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"Walker, Alison"
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Precision medicine treatment in acute myeloid leukemia using prospective genomic profiling: feasibility and preliminary efficacy of the Beat AML Master Trial
Acute myeloid leukemia (AML) is the most common diagnosed leukemia. In older adults, AML confers an adverse outcome
1
,
2
. AML originates from a dominant mutation, then acquires collaborative transformative mutations leading to myeloid transformation and clinical/biological heterogeneity. Currently, AML treatment is initiated rapidly, precluding the ability to consider the mutational profile of a patient’s leukemia for treatment decisions. Untreated patients with AML ≥ 60 years were prospectively enrolled on the ongoing Beat AML trial (ClinicalTrials.gov
NCT03013998
), which aims to provide cytogenetic and mutational data within 7 days (d) from sample receipt and before treatment selection, followed by treatment assignment to a sub-study based on the dominant clone. A total of 487 patients with suspected AML were enrolled; 395 were eligible. Median age was 72 years (range 60–92 years; 38% ≥75 years); 374 patients (94.7%) had genetic and cytogenetic analysis completed within 7 d and were centrally assigned to a Beat AML sub-study; 224 (56.7%) were enrolled on a Beat AML sub-study. The remaining 171 patients elected standard of care (SOC) (103), investigational therapy (28) or palliative care (40); 9 died before treatment assignment. Demographic, laboratory and molecular characteristics were not significantly different between patients on the Beat AML sub-studies and those receiving SOC (induction with cytarabine + daunorubicin (7 + 3 or equivalent) or hypomethylation agent). Thirty-day mortality was less frequent and overall survival was significantly longer for patients enrolled on the Beat AML sub-studies versus those who elected SOC. A precision medicine therapy strategy in AML is feasible within 7 d, allowing patients and physicians to rapidly incorporate genomic data into treatment decisions without increasing early death or adversely impacting overall survival.
Preliminary results from the Beat AML umbrella trial demonstrates the feasibility and efficacy of applying prospective genomic profiling for matching newly diagnosed patients with AML with targeted therapies.
Journal Article
Potentiation of α7 nicotinic acetylcholine receptors via an allosteric transmembrane site
Positive allosteric modulators of α7 nicotinic acetylcholine receptors (nAChRs) have attracted considerable interest as potential tools for the treatment of neurological and psychiatric disorders such as Alzheimer's disease and schizophrenia. However, despite the potential therapeutic usefulness of these compounds, little is known about their mechanism of action. Here, we have examined two allosteric potentiators of α7 nAChRs (PNU-120596 and LY-2087101). From studies with a series of subunit chimeras, we have identified the transmembrane regions of α7 as being critical in facilitating potentiation of agonist-evoked responses. Furthermore, we have identified five transmembrane amino acids that, when mutated, significantly reduce potentiation of α7 nAChRs. The amino acids we have identified are located within the α-helical transmembrane domains TM1 (S222 and A225), TM2 (M253), and TM4 (F455 and C459). Mutation of either A225 or M253 individually have particularly profound effects, reducing potentiation of EC₂₀ concentrations of acetylcholine to a tenth of the level seen with wild-type α7. Reference to homology models of the α7 nAChR, based on the 4Å structure of the Torpedo nAChR, indicates that the side chains of all five amino acids point toward an intrasubunit cavity located between the four α-helical transmembrane domains. Computer docking simulations predict that the allosteric compounds such as PNU-120596 and LY-2087101 may bind within this intrasubunit cavity, much as neurosteroids and volatile anesthetics are thought to interact with GABAA and glycine receptors. Our findings suggest that this is a conserved modulatory allosteric site within neurotransmitter-gated ion channels.
Journal Article
Potentiation of alpha 7 nicotinic acetylcholine receptors via an allosteric transmembrane site
Positive allosteric modulators of alpha 7 nicotinic acetylcholine receptors (nAChRs) have attracted considerable interest as potential tools for the treatment of neurological and psychiatric disorders such as Alzheimer's disease and schizophrenia. However, despite the potential therapeutic usefulness of these compounds, little is known about their mechanism of action. Here, we have examined two allosteric potentiators of alpha 7 nAChRs (PNU-120596 and LY-2087101). From studies with a series of subunit chimeras, we have identified the transmembrane regions of alpha 7 as being critical in facilitating potentiation of agonist-evoked responses. Furthermore, we have identified five transmembrane amino acids that, when mutated, significantly reduce potentiation of alpha 7 nAChRs. The amino acids we have identified are located within the alpha -helical transmembrane domains TM1 (S222 and A225), TM2 (M253), and TM4 (F455 and C459). Mutation of either A225 or M253 individually have particularly profound effects, reducing potentiation of EC sub(20) concentrations of acetylcholine to a tenth of the level seen with wild-type alpha 7. Reference to homology models of the alpha 7 nAChR, based on the 4oe... structure of the Torpedo nAChR, indicates that the side chains of all five amino acids point toward an intrasubunit cavity located between the four alpha -helical transmembrane domains. Computer docking simulations predict that the allosteric compounds such as PNU-120596 and LY-2087101 may bind within this intrasubunit cavity, much as neurosteroids and volatile anesthetics are thought to interact with GABA sub(A) and glycine receptors. Our findings suggest that this is a conserved modulatory allosteric site within neurotransmitter-gated ion channels.
Journal Article
Optical Spike Detection and Connectivity Analysis With a Far-Red Voltage-Sensitive Fluorophore Reveals Changes to Network Connectivity in Development and Disease
The ability to optically record dynamics of neuronal membrane potential promises to revolutionize our understanding of neurobiology. In this study, we show that the far-red voltage sensitive fluorophore, Berkeley Red Sensor of Transmembrane potential-1, or BeRST 1, can be used to monitor neuronal membrane potential changes across dozens of neurons at a sampling rate of 500 Hz. Notably, voltage imaging with BeRST 1 can be implemented with affordable, commercially available illumination sources, optics, and detectors. BeRST 1 is well-tolerated in cultures of rat hippocampal neurons and provides exceptional optical recording fidelity, as judged by dual fluorescence imaging and patch-clamp electrophysiology. We developed a semi-automated spike-picking program to reduce user bias when calling action potentials and used this in conjunction with BeRST 1 to develop an optical spike and connectivity analysis (OSCA) for high-throughput dissection of neuronal activity dynamics. The high temporal resolution of BeRST 1 enables dissection of firing rate changes in response to acute, pharmacological interventions with commonly used inhibitors like gabazine and picrotoxin. Over longer periods of time, BeRST 1 also tracks chronic perturbations to neurons exposed to amyloid beta 1–42 (Aβ 1–42 ), revealing modest changes to spiking frequency but profound changes to overall network connectivity. Finally, we use OSCA to track changes in neuronal connectivity during maturation in culture, providing a functional readout of network assembly. We envision that use of BeRST 1 and OSCA described here will be of use to the broad neuroscience community.
Journal Article
Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine
A phase II clinical trial with single-agent decitabine was conducted in older patients (≥60 years) with previously untreated acute myeloid leukemia (AML) who were not candidates for or who refused intensive chemotherapy. Subjects received low-dose decitabine at 20 mg/m² i.v. over 1 h on days 1 to 10. Fifty-three subjects enrolled with a median age of 74 years (range, 60-85). Nineteen (36%) had antecedent hematologic disorder or therapy-related AML; 16 had complex karyotypes (≥3 abnormalities). The complete remission rate was 47% (n = 25), achieved after a median of three cycles of therapy. Nine additional subjects had no morphologic evidence of disease with incomplete count recovery, for an overall response rate of 64% (n = 34). Complete remission was achieved in 52% of subjects presenting with normal karyotype and in 50% of those with complex karyotypes. Median overall and disease-free survival durations were 55 and 46 weeks, respectively. Death within 30 days of initiation of treatment occurred in one subject (2%), death within 8 weeks in 15% of subjects. Given the DNA hypomethylating effect of decitabine, we examined the relationship of clinical response and pretreatment level of miR-29b, previously shown to target DNA methyltransferases. Higher levels of miR-29b were associated with clinical response (P = 0.02). In conclusion, this schedule of decitabine was highly active and well tolerated in this poor-risk cohort of older AML patients. Levels of miR-29b should be validated as a predictive factor for stratification of older AML patients to decitabine treatment.
Journal Article
Distance-dependent gradient in NMDAR-driven spine calcium signals along tapering dendrites
Neurons receive a multitude of synaptic inputs along their dendritic arbor, but how this highly heterogeneous population of synaptic compartments is spatially organized remains unclear. By measuring N-methyl-D-aspartic acid receptor (NMDAR)-driven calcium responses in single spines, we provide a spatial map of synaptic calcium signals along dendritic arbors of hippocampal neurons and relate this to measures of synapse structure. We find that quantal NMDAR calcium signals increase in amplitude as they approach a thinning dendritic tip end. Based on a compartmental model of spine calcium dynamics, we propose that this biased distribution in calcium signals is governed by a gradual, distance-dependent decline in spine size, which we visualized using serial block-face scanning electron microscopy. Our data describe a cell-autonomous feature of principal neurons, where tapering dendrites show an inverse distribution of spine size and NMDAR-driven calcium signals along dendritic trees, with important implications for synaptic plasticity rules and spine function.
Journal Article
Preclinical activity and a pilot phase I study of pacritinib, an oral JAK2/FLT3 inhibitor, and chemotherapy in FLT3-ITD-positive AML
SummaryActivating FLT3 internal tandem duplication (FLT3-ITD) mutations in acute myeloid leukemia (AML) associate with inferior outcomes. We determined that pacritinib, a JAK2/FLT3 inhibitor, has in vitro activity against FLT3-ITD and tyrosine kinase domain (TKD) mutations. Therefore, we conducted a phase I study of pacritinib in combination with chemotherapy in AML patients with FLT3 mutations to determine the pharmacokinetics and preliminary toxicity and clinical activity. Pacritinib was administered at a dose of 100 mg or 200 mg twice daily following a 3 + 3 dose-escalation in combination with cytarabine and daunorubicin (cohort A) or with decitabine induction (cohort B). A total of thirteen patients were enrolled (five in cohort A; eight in cohort B). Dose limiting toxicities include hemolytic anemia and grade 3 QTc prolongation in two patients who received 100 mg. Complete remission was achieved in two patients in cohort A, one of whom had a minor D835Y clone at baseline. One patient in cohort B achieved morphologic leukemia free state. Seven patients (two in cohort A; five in cohort B) had stable disease. In conclusion, pacritinib, an inhibitor of FLT3-ITD and resistant-conferring TKD mutations, was well tolerated and demonstrated preliminary anti-leukemic activity in combination with chemotherapy in patients with FLT3 mutations.
Journal Article
Bayesian parameter estimation for characterising mobile ion vacancies in perovskite solar cells
To overcome the challenges associated with poor temporal stability of perovskite solar cells, methods are required that allow for fast iteration of fabrication and characterisation, such that optimal device performance and stability may be actively pursued. Currently, establishing the causes of underperformance is both complex and time-consuming, and optimisation of device fabrication is thus inherently slow. Here, we present a means of computational device characterisation of mobile halide ion parameters from room temperature current–voltage ( J − V ) measurements only , requiring ∼2 h of computation on basic computing resources. With our approach, the physical parameters of the device may be reverse-modelled from experimental J − V measurements. In a drift-diffusion (DD) model, the set of coupled DD partial differential equations cannot be inverted explicitly, so a method for inverting the DD simulation is required. We show how Bayesian Parameter Estimation coupled with a DD perovskite solar cell model can determine the extent to which device parameters affect performance measured by J − V characteristics. Our method is demonstrated by investigating the extent to which device performance is influenced by mobile halide ions for a specific fabricated device. The ion vacancy density N 0 and diffusion coefficient D I were found to be precisely characterised for both simulated and fabricated devices. This result opens up the possibility of pinpointing origins of degradation by finding which parameters most influence device J − V curves as the cell degrades.
Journal Article
A cancer disparities curriculum in a hematology/oncology fellowship program
Background
After George Floyd’s murder in 2020, the Center for Disease Control and Prevention (CDC) called systemic racism a public health crisis. This health crisis is connected to the already-documented racial and socioeconomic disparities in cancer care. Ensuring hematologists and oncologists are aware of these disparities through their medical education can help to address these disparities.
Methods
The authors implemented a healthcare disparities-focused curriculum in a Hematology/Oncology fellowship program during the 2020–2021 academic year at The Ohio State University Hematology/Oncology Fellowship Program. They implemented a pre- and post- survey to evaluate the efficacy of the program.
Results
Fifteen fellows completed the pre-curriculum survey and 14 completed the post-survey. Before the curriculum, 12 fellows (80%) noted a “Fair” or “Good” understanding of healthcare disparities, and 6 (40%) had a “Fair” understanding of disparities in clinical trials and access to novel therapies. Fourteen fellows (93.3%) had not previously participated in a research project focused on identifying or overcoming healthcare disparities. After the curriculum, 12 (85%) fellows strongly agreed or agreed that the information presented in the curriculum was useful for training as a hematologist/oncologist. Twelve fellows (85%) noted “Agree” or “Strongly Agree” that the information presented was relevant to their practice. Eleven fellows (92%) noted that they plan to incorporate healthcare disparities into a future research or clinical project. The majority of fellows, 11 (79%) recommended that the fellowship program continue to have a formal health disparities curriculum in the future.
Discussion/Conclusion
There is utility in incorporating cancer disparities education into a hematology/oncology academic curriculum. We recommend further analysis of such curricula to improve fellowship education and patient outcomes with these interventions.
Journal Article