Li Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome caused by germline mutations in TP53. TP53 is the most common mutated gene in human cancer, occurring in 30-50% of ...glioblastomas (GBM). Here, we highlight a precision medicine platform to identify potential targets for a GBM patient with LFS. We used a comparative transcriptomics approach to identify genes that are uniquely overexpressed in the LFS GBM patient relative to a cancer compendium of 12,747 tumor RNA sequencing data sets, including 200 GBMs. STAT1 and STAT2 were identified as being significantly overexpressed in the LFS patient, indicating ruxolitinib, a Janus kinase 1 and 2 inhibitors, as a potential therapy. The LFS patient had the highest level of STAT1 and STAT2 expression in an institutional high-grade glioma cohort of 45 patients, further supporting the cancer compendium results. To empirically validate the comparative transcriptomics pipeline, we used a combination of adherent and organoid cell culture techniques, including ex vivo patient-derived organoids (PDOs) from four patient-derived cell lines, including the LFS patient. STAT1 and STAT2 expression levels in the four patient-derived cells correlated with levels identified in the respective parent tumors. In both adherent and organoid cultures, cells from the LFS patient were among the most sensitive to ruxolitinib compared to patient-derived cells with lower STAT1 and STAT2 expression levels. A spheroid-based drug screening assay (3D-PREDICT) was performed and used to identify further therapeutic targets. Two targeted therapies were selected for the patient of interest and resulted in radiographic disease stability. This manuscript supports the use of comparative transcriptomics to identify personalized therapeutic targets in a functional precision medicine platform for malignant brain tumors.
Current lithium-oxygen (Li-O2) batteries suffer from large charge overpotentials related to electronic resistivity of the insulating lithium peroxide (Li2O2) discharge product. One potential solution ...to this challenge is the stabilization of the lithium superoxide (LiO2) discharge intermediate, which has much higher electronic conductivity compared to Li2O2. Cathodes based on small iridium (Ir) nanoparticles have been recently used in a Li-O2 battery to successfully stabilize the LiO2 product, however, the LiO2 had a short lifetime. In the previous study, researchers found that the LiO2 was stabilized on Ir3Li surfaces which were formed from Ir nanoparticles during battery operation. Little is known about the electronic properties of Ir3Li and its role in stabilizing LiO2 product formation. This work provides the first study of the electronic properties of Ir3Li, which was thermally synthesized in bulk prior to implementation on the reduced graphene oxide (rGO) cathode of a Li-O2 cell. The bulk Ir3Li was found to have comparable electrical conductivity to Ir metal, possess metal-like magnetic properties, and has an affinity towards O2 adsorption. The LiO2 discharge product formed from the Li-O2 battery discharge was characterized using Raman spectroscopy, titration, along with a comprehensive transmission electron microscopy (TEM) study. This analysis revealed the formation of ultra-nanocrystalline LiO2 particles greater than 200 nm. This result was attributed to the use of large micron sized Ir3Li particles, which could stabilize larger LiO2 particles compared to previous cathodes that utilized Ir nanoparticles that partially converted to Ir3Li during cycling. These results demonstrate that cathode properties can be modified to stabilize the bulk LiO2 discharge product, which can be useful for the further development of LiO2-based Li-O2 batteries.
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•Bulk synthesis and characterization of Ir3Li as Li-O2 battery cathode material.•Reduced Li-O2 battery charge overpotentials using Ir3Li-rGO cathodes.•Formation of stable, > 200 nm particles of lithium superoxide as discharge product.
Research studies on Lithium Oxygen (Li-O2) batteries is expected to have a far-reaching impact on industry, the environment and society. Exploring the one electron transfer process, studying the ...fundamental physical and chemical properties of the new LiO2 material and investigating potential stabilizing catalysts could lead to a LiO2, or lithium superoxide battery, which then could be developed into a solid state battery. It is therefore crucial to further research the reaction mechanism, the properties of LiO 2, and to characterize the discharge products of Li-O2 batteries. Li-O2 batteries are an excellent candidate for many electronic devices and for Electric Vehicles (EVs) due to their high theoretical energy density. However, there are many obstacles to overcome before the commercialization of this battery becomes a viable reality. The problems that are currently being researched are: poor cyclability, low practical energy density and power density, electrolytic decomposition, instability of the cathode and high overpotentials, among others. Much research and effort has been put forth to find an optimized cathode material and an efficient electrolyte for the Li-O2 battery. Specific catalysts are also being investigated to further enhance the performance of these batteries. The characterization of the discharge products is a vital part of the research effort for the Li-O 2 battery. Scanning Electron Microscopy (SEM), Raman Spectroscopy, Atomic Force Microscopy (AFM), Conductive-Atomic Force Microscopy (C-AFM) and many other characterization techniques are being employed to probe the basic properties of the discharge product at the cathode. The use of C-AFM will be emphasized as the main characterization technique to carry out conductivity measurments. The investigation of the electronic, magnetic, structural, and interfacial properties of the discharge product is a very important step forward in making the use of Li-O2 batteries a reality. In this work, different techniques for improving the overall performance of the Li-O2 battery will be discussed. New catalysts and cathode materials will be presented, their effect on battery performance, and characterization of associated discharge products.
Background
Retrospective analyses of randomized trials suggest that Black men with metastatic castration‐resistant prostate cancer (mCRPC) have longer survival than White men. The authors conducted a ...prospective study of abiraterone acetate plus prednisone to explore outcomes by race.
Methods
This race‐stratified, multicenter study estimated radiographic progression‐free survival (rPFS) in Black and White men with mCRPC. Secondary end points included prostate‐specific antigen (PSA) kinetics, overall survival (OS), and safety. Exploratory analysis included genome‐wide genotyping to identify single nucleotide polymorphisms associated with progression in a model incorporating genetic ancestry. One hundred patients self‐identified as White (n = 50) or Black (n = 50) were enrolled. Eligibility criteria were modified to facilitate the enrollment of individual Black patients.
Results
The median rPFS for Black and White patients was 16.6 and 16.8 months, respectively; their times to PSA progression (TTP) were 16.6 and 11.5 months, respectively; and their OS was 35.9 and 35.7 months, respectively. Estimated rates of PSA decline by ≥50% in Black and White patients were 74% and 66%, respectively; and PSA declines to <0.2 ng/mL were 26% and 10%, respectively. Rates of grade 3 and 4 hypertension, hypokalemia, and hyperglycemia were higher in Black men.
Conclusions
Multicenter prospective studies by race are feasible in men with mCRPC but require less restrictive eligibility. Despite higher comorbidity rates, Black patients demonstrated rPFS and OS similar to those of White patients and trended toward greater TTP and PSA declines, consistent with retrospective reports. Importantly, Black men may have higher side‐effect rates than White men. This exploratory genome‐wide analysis of TTP identified a possible candidate marker of ancestry‐dependent treatment outcomes.
This is the first prospective, race‐stratified study in advanced prostate cancer demonstrating important trends in outcomes previously only observed in retrospective reports. These results demonstrate the feasibility of this approach in a multicenter setting and establish important preliminary data with regard to differences in toxicity profiles and predictive biomarkers by race.
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Background: Pivotal trials of AAP for patients with mCRPC enrolled few B pts, a population with a higher mortality from prostate cancer. Retrospective data suggests B pts may ...have higher PSA response rates than W pts treated with AAP for mCRPC. Therefore, we prospectively investigated AAP in B vs. W pts with mCRPC. Methods: Abi Race (NCT01940276) is a prospective, multicenter, parallel group study of AP in 100 men (50 B, 50 W) with mCRPC, self-identified by race. All pts received AA 1000 mg/D and P 10 mg/D (AAP) until disease progression or unacceptable adverse events (AE). The primary objective was radiographic progression-free survival (rPFS); key secondary endpoints include PSA kinetics and safety. Exploratory analyses include SNP, metabolomics and hormonal differences by race. Results: Baseline characteristics among pts were similar. The median rPFS for B and W pts was 16.8 months (mo) in each. However, PSA PFS varied by race; median PSA PFS for B and W pts were 16.6 and 11.5 mo Table. B pts also had numerically higher rates of ≥30%, ≥50% and ≥90% PSA decline Table. AEs were similar in frequency and severity by race including hypertension (42 vs 40%); however, fatigue was higher in W pts (40 vs 26%), and hypokalemia was higher in B pts (36 vs 18%). SNP profiling revealed differences in key genes involved in androgen metabolism and transport. Conclusions: This is the first prospective multicenter study by race of secondary hormonal therapy in mCRPC. B pts may have greater and more durable PSA response to AAP than W pts. SNP patterns vary by race and will be evaluated for prognostic significance. Further prospective studies in B pts are possible and needed to understand the impact of racial determinants on outcome of new hormonal regimens. Clinical trial information: NCT01940276. Table: see text
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