In this study, we performed both electrochemical measurements, such as the rotating disk electrode and the rotating ring-disk electrode techniques, and density functional theory (DFT) calculations to investigate oxygen reduction reaction (ORR) on nonprecious transition metal/nitrogen doped carbon nanofiber (Fe/N/C and Co/N/C) catalysts in acid medium. The nanofiber catalysts were synthesized by electrospinning and subsequent heat treatment procedures. Our electrochemical measurements showed that the pyrolyzed Fe/N/C catalyst possesses higher activity for ORR than the pyrolyzed Co/N/C catalyst and could promote four-electron (4e−) ORR. In comparison, O2 electroreduction was found to proceed mainly with 2e− pathway on the Co/N/C catalyst. To gain insights into underlying catalytic mechanisms, we calculated the adsorption energies of all possible chemical species and the activation energies for O–O bond dissociation reactions involved in ORR on the FeN4 and CoN4 active sites embedded in graphene. Our DFT calculations predicted that the ORR could happen through 4e− associative pathway on the FeN4 site, whereas it might end with a 2e− pathway on the CoN4 site due to high activation energy for O–O bond splitting and extremely weak adsorption of H2O2 on the CoN4 site. Complementary experimental and theoretical results suggest that the FeN4 and CoN4 clusters might be the main active sites for promoting ORR on the transition metal/nitrogen doped carbon nanofiber catalysts in acidic medium.
A series of structurally diverse alcoholamine-and alkoxyalkylamine-functionalized variants of the metal-organic framework Mg2(dobpdc) are shown to exhibit selective, step-shaped adsorption of carbon dioxide (CO2). Optimized structures obtained from vdW-corrected DFT calculations indicate that the observed adsorption profiles can be attributed to carbamic acid (for alcoholamines) or ammonium carbamate (for alkoxyalkylamines) chain-like structures stabilized by hydrogen bonding interactions within the framework pores, as corroborated by solid state NMR. As the first report of materials exhibiting cooperative CO2 chemisorption without the use of diamines, this finding provides the foundation for expanding the scope of cooperative CO2 capture in porous materials.[a]
Background: The identification of patients with homologous recombination deficiency (HRD) beyond BRCA1/2 mutations is an urgent task, as they may benefit from PARP inhibitors. We have previously developed a method to detect mutational signature 3 (Sig3), termed SigMA, associated with HRD from clinical panel sequencing data, that is able to reliably detect HRD from the limited sequencing data derived from gene-focused panel sequencing. Methods: We apply this method to patients from two independent datasets: (1) high-grade serous ovarian cancer and triple-negative breast cancer (TNBC) from a Phase 1b trial of the PARP inhibitor olaparib in combination with the PI3K inhibitor buparlisib (BKM120) (NCT01623349), and (2) TNBC patients who received neoadjuvant olaparib in the Phase II PETREMAC trial (NCT02624973). Results: We find that Sig3 as detected by SigMA is positively associated with improved progression-free survival and objective responses. In addition, comparison of Sig3 detection in panel and exome sequencing data from the same patient samples demonstrated highly concordant results and superior performance in comparison with the genomic instability score. Conclusion: Our analyses demonstrate that HRD can be detected reliably from panel sequencing data that are obtained as part of routine clinical care, and that this approach can identify patients beyond those with germline BRCA12 mut who might benefit from PARP inhibitors. Prospective clinical utility testing is warranted.
A series of structurally diverse alcoholamine-and alkoxyalkylamine-functionalized variants of the metal-organic framework Mg2(dobpdc) are shown to exhibit selective, step-shaped adsorption of carbon dioxide (CO2). Optimized structures obtained from vdW-corrected DFT calculations indicate that the observed adsorption profiles can be attributed to carbamic acid (for alcoholamines) or ammonium carbamate (for alkoxyalkylamines) chain-like structures stabilized by hydrogen bonding interactions within the framework pores, as corroborated by solid state NMR. As the first report of materials exhibiting cooperative CO2 chemisorption without the use of diamines, this finding provides the foundation for expanding the scope of cooperative CO2 capture in porous materials.
Background: Poly (ADP-ribose) polymerase (PARP) inhibitors target cancers with homologous recombination deficiency (HRD). Preclinical data showed PI3K inhibitors impair homologous recombination (HR) pathways; exposure may sensitize HR-proficient cancers to PARP inhibition. Single-base substitution mutational signature 3 (Sig3) is strongly associated with HRD. We report correlative analysis of Sig3 as predictor of response from a Phase Ib trial of the PARP inhibitor olaparib in combination with the PI3K inhibitor buparlisib (BKM120) in patients (pts) with advanced high-grade serous ovarian cancer (HGSOC) and triple-negative breast cancer (TNBC). Methods The parent trial (NCT01623349) is a multicenter phase 1b trial of escalating doses of olaparib and buparlisib. Eligible pts enrolled in the trial carried a diagnosis of advanced TNBC, HGSOC, or recurrent breast cancer of any histology with a germline BRCA1 or BRCA2 (BRCA1/2) mutation. Archival tumor tissue was available from 39 pts, and was analyzed by panel sequencing and whole-exome sequencing (WES). A score for the Sig3 was calculated from panel sequencing data and WES using SigMA. Genomic Instability Score (GIS) based on copy-number variation (CNV) were also calculated from WES data using scarHRD. Survival analyses and Cox regression were performed.Results: Our cohort comprised 39 pts (28 pts with HGSOC and 11 pts with TNBC). The median age was 58 years (range 34 - 78). Pts with Sig3+ tumors had a progression-free survival (PFS) of 7.7 months vs 5.6 months for those with Sig3- tumors (log-rank test; p = 0.036). CNV+ group did not differ significantly from CNV- group (log-rank test; p = 0.18). Even though Sig3 identified the majority of cancers with BRCA1/2 mutations (18/24), the PFS for pts with BRCA1/2 mutations was not statistically different from those with BRCA wild type tumors (log-rank test; p = 0.15). In our Cox regression model, Sig3+ had a significant positive impact on PFS (HR 0.27, CI 0.092 - 0.77, p = 0.015) while GIS did not (HR 0.41, CI 0.13 - 1.3, p = 0.14). We tested the influence of copy number alterations of genes associated with PARPi resistance on PFS, and identified ATR amplification as a feature of PARPi resistance (HR 4.48, p = 0.002).Conclusions: Within a trial that combined the PARP inhibitor olaparib and the PI3K inhibitor BKM120 in advanced ovarian and breast cancer, Sig3 positivity from panel sequencing data was associated with longer PFS while the CNV-based HRD prediction score (i.e. GIS) from WES was not. SigMA identified Sig3 from readily-available clinical sequencing as a candidate biomarker to refine patient selection for therapy with PARP inhibitors. Mutational signatures may improve HRD identification compared to a selection solely based on the mutation status of BRCA1/2 genes. Clinical utility should be explored in the setting of a confirmatory clinical trial. Citation Format: Felipe Batalini, Doga Gulhan, Victor Mao, Madeline Polak, Eric P. Winer, Erica L. Mayer, Ursula A. Matulonis, Panagiotis A. Konstantinopoulos, Peter Park, Gerburg M. Wulf. Mutational signature 3 predicts responses to olaparib plus buparlisib in triple-negative breast cancer and high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 156.
<div>AbstractPurpose:<p>The identification of patients with homologous recombination deficiency (HRD) beyond <i>BRCA1/2</i> mutations is an urgent task, as they may benefit from PARP inhibitors. We have previously developed a method to detect mutational signature 3 (Sig3), termed SigMA, associated with HRD from clinical panel sequencing data, that is able to reliably detect HRD from the limited sequencing data derived from gene-focused panel sequencing.</p>Experimental Design:<p>We apply this method to patients from two independent datasets: (i) high-grade serous ovarian cancer and triple-negative breast cancer (TNBC) from a phase Ib trial of the PARP inhibitor olaparib in combination with the PI3K inhibitor buparlisib (BKM120; NCT01623349), and (ii) TNBC patients who received neoadjuvant olaparib in the phase II PETREMAC trial (NCT02624973).</p>Results:<p>We find that Sig3 as detected by SigMA is positively associated with improved progression-free survival and objective responses. In addition, comparison of Sig3 detection in panel and exome-sequencing data from the same patient samples demonstrated highly concordant results and superior performance in comparison with the genomic instability score.</p>Conclusions:<p>Our analyses demonstrate that HRD can be detected reliably from panel-sequencing data that are obtained as part of routine clinical care, and that this approach can identify patients beyond those with germline <i>BRCA1</i>/<i>2</i>mut who might benefit from PARP inhibitors. Prospective clinical utility testing is warranted.</p></div>
Supplementary Figure from Mutational Signature 3 Detected from Clinical Panel Sequencing is Associated with Responses to Olaparib in Breast and Ovarian Cancers
Supplementary Table from Mutational Signature 3 Detected from Clinical Panel Sequencing is Associated with Responses to Olaparib in Breast and Ovarian Cancers
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