20 results on '"Laskin, J."'
Search Results
2. EP.08F.12 Toxicity and Outcomes by Radio-Sensitizing Chemotherapy Regimen for Unresectable Stage III NSCLC in British Columbia, Canada
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Damours, M-F., Denault, M-H., Feng, J., Kuang, S., Laskin, J., Leung, B., Sun, S., Melosky, B., Liu, M., Carolan, H., and Ho, C.
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- 2024
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3. 87P Application of tissue and liquid-based next generation sequencing (NGS) for comprehensive genomic profiling: Evaluating the clinical value of ctDNA technology in treatment decision making
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Usman, F.U., Sabag, S.Y., Bhang, E., Kamali, M., Pollard, S., Hussein, A., Ko-Leong, J., Hughesman, C., Alex, D., Demarco, P., Weymann, D., Loree, J.M., Gill, K., Wang, Y., Laskin, J., Regier, D., Lim, H., Chia, S., Yip, S., and Ho, C.
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- 2024
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4. HPR129 Real-World Policy Effects of Implementing Multi-Gene Panel Sequencing for Advanced Cancers in British Columbia, Canada: An Interrupted Time Series Analysis
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Weymann, D, Krebs, E, Pollard, S, Bosdet, I, Yip, S, Karsan, A, Ho, C, Lim, H, Loree, JM, Laskin, J, Law, M, and Regier, DA
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- 2024
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5. PT30 Real-World Cost-Effectiveness of Publicly Reimbursed Multi-Gene Panel Sequencing to Inform Therapeutic Decisions for Advanced Non-Small Cell Lung Cancer in British Columbia, Canada.
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Krebs, E, Weymann, D, Ho, C, Bosdet, I, Laskin, J, Lim, H, Yip, S, Karsan, A, Hanna, T, Pollard, S, and Regier, DA
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- 2024
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6. Long-read sequencing of an advanced cancer cohort resolves rearrangements, unravels haplotypes, and reveals methylation landscapes.
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O'Neill K, Pleasance E, Fan J, Akbari V, Chang G, Dixon K, Csizmok V, MacLennan S, Porter V, Galbraith A, Grisdale CJ, Culibrk L, Dupuis JH, Corbett R, Hopkins J, Bowlby R, Pandoh P, Smailus DE, Cheng D, Wong T, Frey C, Shen Y, Lewis E, Paulin LF, Sedlazeck FJ, Nelson JMT, Chuah E, Mungall KL, Moore RA, Coope R, Mungall AJ, McConechy MK, Williamson LM, Schrader KA, Yip S, Marra MA, Laskin J, and Jones SJM
- Abstract
The Long-Read Personalized OncoGenomics (POG) dataset comprises a cohort of 189 patient tumors and 41 matched normal samples sequenced using the Oxford Nanopore Technologies PromethION platform. This dataset from the POG program and the Marathon of Hope Cancer Centres Network includes DNA and RNA short-read sequence data, analytics, and clinical information. We show the potential of long-read sequencing for resolving complex cancer-related structural variants, viral integrations, and extrachromosomal circular DNA. Long-range phasing facilitates the discovery of allelically differentially methylated regions (aDMRs) and allele-specific expression, including recurrent aDMRs in the cancer genes RET and CDKN2A. Germline promoter methylation in MLH1 can be directly observed in Lynch syndrome. Promoter methylation in BRCA1 and RAD51C is a likely driver behind homologous recombination deficiency where no coding driver mutation was found. This dataset demonstrates applications for long-read sequencing in precision medicine and is available as a resource for developing analytical approaches using this technology., Competing Interests: Declaration of interests The following authors disclose relevant potential competing interests: K.O.N., V.P., L.F.P., K.D., J.L., and S.J.M.J. received travel funding from Oxford Nanopore Technologies to present at conferences in 2022 and 2023., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2024
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7. Writing with Mass-Selected Ions Using a Dynamic Field Wien Filter.
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Espenship MF and Laskin J
- Abstract
We have designed and constructed a low-cost Wien filter based on strong permanent magnets and integrated it into an ion soft-landing instrument to enable parallel deposition as well as one- and two-dimensional surface patterning of mass-selected ions using dynamic fields. We show the capabilities of this device for separating ions from a multicomponent high-flux continuous ion beam and simultaneous deposition of ions of different mass-to-charge ratios onto discrete locations on a surface. When a dynamic electric field is applied parallel to the magnetic field, ions are deposited in one-dimensional arrays, laterally separated by mass. The field's strength, frequency, and waveform type determine both the lengths of the arrays and the density of ions across the 1-D pattern. Additionally, a second dynamic field from user-defined waveforms orthogonal to the magnetic field enables two-dimensional surface patterning of ions while maintaining mass separation. These experiments demonstrate the practical utility of a Wien filter for the controlled fabrication of interfaces with arbitrary patterns of mass-selected ions.
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- 2024
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8. MSIGen: An Open-Source Python Package for Processing and Visualizing Mass Spectrometry Imaging Data.
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Hernly E, Hu H, and Laskin J
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Mass spectrometry imaging (MSI) provides information about the spatial localization of molecules in complex samples with high sensitivity and molecular selectivity. Although point-wise data acquisition, in which mass spectra are acquired at predefined points in a grid pattern, is common in MSI, several MSI techniques use line-wise data acquisition. In line-wise mode, the imaged surface is continuously sampled along consecutive parallel lines and MSI data are acquired as a collection of line scans across the sample. Furthermore, aside from the standard imaging mode in which full mass spectra are acquired, other acquisition modes have been developed to enhance molecular specificity, enable separation of isobaric and isomeric species, and improve sensitivity to facilitate the imaging of low abundance species. These methods, including MS/MS-MSI in both MS
2 and MS3 modes, multiple-reaction monitoring (MRM)-MSI, and ion mobility spectrometry (IMS)-MSI have all demonstrated their capabilities, but their broader implementation is limited by the existing MSI analysis software. Here, we present MSIGen, an open-source Python package for the visualization of MSI experiments performed in line-wise acquisition mode containing MS1 , MS2 , MRM, and IMS data, which is available at https://github.com/LabLaskin/MSIGen. The package supports multiple vendor-specific and open-source data formats and contains tools for targeted extraction of ion images, normalization, and exportation as images, arrays, or publication-style images. MSIGen offers multiple interfaces, allowing for accessibility and easy integration with other workflows. Considering its support for a wide variety of MSI imaging modes and vendor formats, MSIGen is a valuable tool for the visualization and analysis of MSI data.- Published
- 2024
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9. Correlative Imaging for Comprehensive Molecular Mapping of Individual Cell Types in Biological Tissues.
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Yang M, Iqfath M, Meke FN, Qu Z, Hernly EL, Su P, Zhang ZY, and Laskin J
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Mass spectrometry imaging (MSI) is a powerful technique for label-free spatial mapping of multiple classes of biomolecules in tissue sections. However, differences in desorption and ionization efficiency of different classes of molecules make it challenging to simultaneously map biomolecules at each omics layer in the same tissue sample. Herein, we present a correlative imaging method using nanospray desorption electrospray ionization (nano-DESI) MSI, which enables the spatial mapping of lipids, metabolites, peptides, and proteins with cellular-level spatial resolution in a single tissue section. We demonstrate the molecular profiling of specific cell types and identify truncated peptides in mouse pancreatic tissue. Distinct chemical gradients of peptides and lipids extending from endocrine cells to exocrine cells indicate their different roles in endocrine-exocrine crosstalk and intracellular signaling. The results underscore the power of the developed imaging approach for spatial multi-omics analysis that provides deep insights into cellular diversity and the intricate molecular interactions that occur within heterogenous biological tissues.
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- 2024
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10. Diagnostic and Therapeutic Implications of a FUS::TFCP2 Fusion and ALK Activation in a Metastatic Rhabdomyosarcoma.
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Csizmok V, Grisdale CJ, Williamson LM, Lim HJ, Lee L, Renouf DJ, Jones SJM, Marra MA, Laskin J, and Smrke A
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- Humans, Male, Adult, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Anaplastic Lymphoma Kinase genetics, Rhabdomyosarcoma genetics, Rhabdomyosarcoma pathology, Rhabdomyosarcoma drug therapy, RNA-Binding Protein FUS genetics, Oncogene Proteins, Fusion genetics, Transcription Factors genetics
- Abstract
The identification of gene fusions in rare sarcoma subtypes can have diagnostic, prognostic, and therapeutic impacts for advanced cancer patients. Here, we present a case of a 31-year-old male with a lytic lesion of the left mandible initially diagnosed as an osteosarcoma but found to have a TFCP2 fusion and ALK alteration, redefining the diagnosis and providing rationale for a novel treatment strategy. Histologically, the tumor displayed hypercellular, spindled to epithelioid neoplasm and nuclear pleomorphism, while immunohistochemistry showed diffuse SATB2 and focal desmin staining. Whole genome and transcriptome analysis revealed a FUS::TFCP2 fusion, the defining alteration of a rare molecularly characterized subtype of soft tissue sarcoma termed intraosseous rhabdomyosarcoma. An internal ALK deletion and extremely high ALK RNA expression were also identified, suggesting potential benefit of an ALK inhibitor. This patient displayed a rapid and dramatic clinical and radiographic response to an ALK inhibitor, alectinib. Unfortunately, the response was short-lived, likely due to the advanced stage and aggressiveness of the disease. This report describes genome and transcriptome characterization of an intraosseous rhabdomyosarcoma, few of which exist in the literature, as well as providing evidence that inhibition of ALK may be a rational treatment strategy for patients with this exceedingly rare soft tissue sarcoma subtype characterized by TFCP2 fusions and ALK activation., (© 2024 The Author(s). Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.)
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- 2024
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11. Enhancing Energy Storage Capacity of 3D Carbon Electrodes Using Soft Landing of Molecular Redox Mediators.
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Das A, Samayoa-Oviedo HY, Mohapatra M, Basu S, and Laskin J
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The incorporation of redox-active species into the electric double layer is a powerful strategy for enhancing the energy density of supercapacitors. Polyoxometalates (POM) are a class of stable, redox-active species with multielectron activity, which is often used to tailor the properties of electrochemical interfaces. Traditional synthetic methods often result in interfaces containing a mixture of POM anions, unreactive counter ions, and neutral species. This leads to degradation in electrochemical performance due to aggregation and increased interfacial resistance. Another significant challenge is achieving the uniform and stable anchoring of POM anions on substrates to ensure the long-term stability of the electrochemical interface. These challenges are addressed by developing a mass spectrometry-based subambient deposition strategy for the selective deposition of POM anions onto engineered 3D porous carbon electrodes. Furthermore, positively charged functional groups are introduced on the electrode surface for efficient trapping of POM anions. This approach enables the deposition of purified POM anions uniformly through the pores of the 3D porous carbon electrode, resulting in unprecedented increase in the energy storage capacity of the electrodes. The study highlights the critical role of well-defined electrochemical interfaces in energy storage applications and offers a powerful method to achieve this through selective ion deposition., (© 2024 The Authors. Small published by Wiley‐VCH GmbH.)
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- 2024
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12. Nanospray Desorption Electrospray Ionization Mass Spectrometry Imaging (nano-DESI MSI): A Tutorial Review.
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Iqfath M, Wali SN, Amer S, Hernly E, and Laskin J
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Nanospray desorption electrospray ionization (nano-DESI) is a liquid-based ambient mass spectrometry imaging (MSI) technique that enables visualization of analyte distributions in biological samples down to cellular-level spatial resolution. Since its inception, significant advancements have been made to the nano-DESI experimental platform to facilitate molecular imaging with high throughput, deep molecular coverage, and spatial resolution better than 10 μm. The molecular selectivity of nano-DESI MSI has been enhanced using new data acquisition strategies, the development of separation and online derivatization approaches for isobar separation and isomer-selective imaging, and the optimization of the working solvent composition to improve analyte extraction and ionization efficiency. Furthermore, nano-DESI MSI research has underscored the importance of matrix effects and established normalization methods for accurately measuring concentration gradients in complex biological samples. This tutorial offers a comprehensive guide to nano-DESI experiments, detailing fundamental principles and data acquisition and processing methods and discussing essential operational parameters., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)
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- 2024
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13. Hardware and software solutions for implementing nanospray desorption electrospray ionization (nano-DESI) sources on commercial mass spectrometers.
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Jiang LX, Hilger RT, and Laskin J
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Nanospray desorption electrospray ionization (nano-DESI) is an ambient ionization mass spectrometry imaging (MSI) approach that enables spatial mapping of biological and environmental samples with high spatial resolution and throughput. Because nano-DESI has not yet been commercialized, researchers develop their own sources and interface them with different commercial mass spectrometers. Previously, several protocols focusing on the fabrication of nano-DESI probes have been reported. In this tutorial, we discuss different hardware requirements for coupling the nano-DESI source to commercial mass spectrometers, such as the safety interlock, inlet extension, and contact closure. In addition, we describe the structure of our custom software for controlling the nano-DESI MSI platform and provide detailed instructions for its usage. With this tutorial, interested researchers should be able to implement nano-DESI experiments in their labs., (© 2024 The Author(s). Journal of Mass Spectrometry published by John Wiley & Sons Ltd.)
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- 2024
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14. The effect of host size on binding in host-guest complexes of cyclodextrins and polyoxometalates.
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Su P, Zhu X, Wilson SM, Feng Y, Samayoa-Oviedo HY, Sonnendecker C, Smith AJ, Zimmermann W, and Laskin J
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Harnessing flexible host cavities opens opportunities for the design of novel supramolecular architectures that accommodate nanosized guests. This research examines unprecedented gas-phase structures of Keggin-type polyoxometalate PW
12 O40 3- (WPOM) and cyclodextrins (X-CD, X = α, β, γ, δ, ε, ζ) including previously unexplored large, flexible CDs. Using ion mobility spectrometry coupled to mass spectrometry (IM-MS) in conjunction with molecular dynamics (MD) simulations, we provide first insights into the binding modes between WPOM and larger CD hosts as isolated structures. Notably, γ-CD forms two distinct structures with WPOM through binding to its primary and secondary faces. We also demonstrate that ε-CD forms a deep inclusion complex, which encapsulates WPOM within its annular inner cavity. In contrast, ζ-CD adopts a saddle-like conformation in its complex with WPOM, which resembles its free form in solution. More intriguingly, the gas-phase CD-WPOM structures are highly correlated with their counterparts in solution as characterized by nuclear magnetic resonance (NMR) spectroscopy. The strong correlation between the gas- and solution phase structures of CD-WPOM complexes highlight the power of gas-phase IM-MS for the structural characterization of supramolecular complexes with nanosized guests, which may be difficult to examine using conventional approaches., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)- Published
- 2024
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15. Spontaneous ligand loss by soft landed [Ni(bpy) 3 ] 2+ ions on perfluorinated self-assembled monolayer surfaces.
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Samayoa-Oviedo HY, Knorke H, Warneke J, and Laskin J
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Transition metal (TM) complexes are widely used in catalysis, photochemical energy conversion, and sensing. Understanding factors that affect ligand loss from TM complexes at interfaces is important both for generating catalytically-active undercoordinated TM complexes and for controlling the degradation pathways of photosensitizers and photoredox catalysts. Herein, we demonstrate that well-defined TM complexes prepared on surfaces using ion soft landing undergo substantial structural rearrangements resulting in ligand loss and formation of both stable and reactive undercoordinated species. We employ nickel bipyridine (Ni-bpy) cations as a model system and explore their structural reorganization on surfaces using a combination of experimental and computational approaches. The controlled preparation of surface layers by mass-selected deposition of [Ni(bpy)
3 ]2+ cations provides insights into the chemical reactivity of these species on surfaces. Both surface characterization using mass spectrometry and electronic structure calculations using density functional theory (DFT) indicate that [Ni(bpy)3 ]2+ undergoes a substantial geometry distortion on surfaces in comparison with its gas-phase structure. This distortion reduces the ligand binding energy and facilitates the formation of the undercoordinated [Ni(bpy)2 ]2+ . Additionally, charge reduction by the soft landed [Ni(bpy)3 ]2+ facilitates ligand loss. We observe that ligand loss is inhibited by co-depositing [Ni(bpy)3 ]2+ with a stable anion such as closo -dodecaborate dianion, [B12 F12 ]2- . The strong electrostatic interaction between [Ni(bpy)3 ]2+ and [B12 F12 ]2- diminishes the distortion of the cation due to interactions with the surface. This interaction stabilizes the soft landed cation by reducing the extent of charge reduction and its structural reorganization. Overall, this study shows the intricate interplay of charge state, ion surface interactions, and stabilization by counterions on the structure and reactivity of metal complexes on surfaces. The combined experimental and computational approach used in this study offers detailed insights into factors that affect the integrity and stability of active species relevant to energy production and catalysis., Competing Interests: The authors declare that they have no conflict of interest., (This journal is © The Royal Society of Chemistry.)- Published
- 2024
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16. Whole genome and transcriptome integrated analyses guide clinical care of pediatric poor prognosis cancers.
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Deyell RJ, Shen Y, Titmuss E, Dixon K, Williamson LM, Pleasance E, Nelson JMT, Abbasi S, Krzywinski M, Armstrong L, Bonakdar M, Ch'ng C, Chuah E, Dunham C, Fok A, Jones M, Lee AF, Ma Y, Moore RA, Mungall AJ, Mungall KL, Rogers PC, Schrader KA, Virani A, Wee K, Young SS, Zhao Y, Jones SJM, Laskin J, Marra MA, and Rassekh SR
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- Humans, Child, Female, Adolescent, Male, Child, Preschool, Prognosis, Infant, Transcriptome, Young Adult, Whole Genome Sequencing, Germ-Line Mutation, Mutation, Genome, Human genetics, Genetic Predisposition to Disease, Neoplasms genetics, Neoplasms therapy, Gene Expression Profiling methods, DNA Copy Number Variations
- Abstract
The role for routine whole genome and transcriptome analysis (WGTA) for poor prognosis pediatric cancers remains undetermined. Here, we characterize somatic mutations, structural rearrangements, copy number variants, gene expression, immuno-profiles and germline cancer predisposition variants in children and adolescents with relapsed, refractory or poor prognosis malignancies who underwent somatic WGTA and matched germline sequencing. Seventy-nine participants with a median age at enrollment of 8.8 y (range 6 months to 21.2 y) are included. Germline pathogenic/likely pathogenic variants are identified in 12% of participants, of which 60% were not known prior. Therapeutically actionable variants are identified by targeted gene report and whole genome in 32% and 62% of participants, respectively, and increase to 96% after integrating transcriptome analyses. Thirty-two molecularly informed therapies are pursued in 28 participants with 54% achieving a clinical benefit rate; objective response or stable disease ≥6 months. Integrated WGTA identifies therapeutically actionable variants in almost all tumors and are directly translatable to clinical care of children with poor prognosis cancers., (© 2024. The Author(s).)
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- 2024
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17. Reductive Doping Inhibits the Formation of Isomerization-Derived Structural Defects in N-doped Poly(benzodifurandione) (n-PBDF).
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Hwang J, Zhao Q, Ahmed M, Yakisan AC, Espenship MF, Laskin J, Savoie BM, and Mei J
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Recently, solution-processable n-doped poly(benzodifurandione) (n-PBDF) has been made through in-situ oxidative polymerization and reductive doping, which exhibited exceptionally high electrical conductivities and optical transparency. The discovery of n-PBDF is considered a breakthrough in the field of organic semiconductors. In the initial report, the possibility of structural defect formation in n-PBDF was proposed, based on the observation of structural isomerization from (E)-2H,2'H-[3,3'-bibenzofuranylidene]-2,2'-dione (isoxindigo) to chromeno[4,3-c]chromene-5,11-dione (dibenzonaphthyrone) in the dimer model reactions. In this study, we present clear evidence that structural isomerization is inhibited during polymerization. We reveal that the dimer (BFD1) and the trimer (BFD2) can be reductively doped by several mechanisms, including hydride transfer, forming charge transfer complexes (CTC) or undergoing an integer charge transfer (ICT) with reactants available during polymerization. Once the hydride transfer adducts, the CTC, or the ICT product forms, structural isomerization can be effectively prevented even at elevated temperatures. Our findings provide a mechanistic understanding of why isomerization-derived structural defects are absent in n-PBDF backbone. It lays a solid foundation for the future development of n-PBDF as a benchmark polymer for organic electronics and beyond., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
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- 2024
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18. Outcomes of patients with advanced epithelial growth factor receptor mutant lung cancer treated with first-line osimertinib who would not have met the eligibility criteria for the FLAURA clinical trial.
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Connor Wells J, Mullin MM, Ho C, Melosky B, Laskin J, Wang Y, and Sun S
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- Humans, Retrospective Studies, Protein Kinase Inhibitors adverse effects, ErbB Receptors genetics, Aniline Compounds therapeutic use, Aniline Compounds adverse effects, Receptors, Growth Factor therapeutic use, Mutation genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms chemically induced, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Acrylamides, Indoles, Pyrimidines
- Abstract
Objectives: Osimertinib is largely used as first-line therapy for metastatic epithelial growth factor receptor (EGFR) mutant lung cancers based on the FLAURA clinical trial. Real-world patient outcomes often differ from clinical trial outcomes. This study evaluated the efficacy of first-line osimertinib in patients treated in British Columbia (BC), Canada. Furthermore, we compared the outcomes of patients who would and would not have been eligible for the original FLAURA trial., Methods: Consecutive patients receiving first-line osimertinib for metastatic EGFR exon19 or L858R lung cancer were identified using the BC Cancer Pharmacy Database. Patient eligibility for the FLAURA clinical trial were retrospectively reviewed based on the following criteria: ECOG ≥ 2, symptomatic brain metastases or on steroids, hemoglobin < 90 g/L, platelets < 100x10
9 /L, or a creatinine clearance < 50 mL/min. mOS was assessed for the entire population and compared between patients who would have been eligible and ineligible for FLAURA., Results: From January 2020 to October 2021, 311 patients received first-line osimertinib; 44 % (137/311) were deemed FLAURA ineligible, predominantly due to low ECOG (n = 120). After a median follow-up of 26.5 months, the mOS for the entire cohort was 27.4 months (95 %CI 23.8-30.1). The mOS for ineligible patients was 18 months shorter than eligible patients (15.8 vs 34.2, p < 0.001). Ineligible patients had higher rates of de novo stage IV disease, higher rates of stage IVB disease, and more sites of disease than eligible patients., Conclusion: In this real-world population, nearly half of patients would have been ineligible for FLAURA. The mOS was one year shorter than reported in FLAURA. However, patients who would have been eligible for the FLAURA clinical trial had similar OS to patients enrolled in FLAURA. Trial ineligible patients had a higher burden of disease at baseline which may have led to inferior outcomes. Further research is needed to improve outcomes in these patients., Competing Interests: Declaration of competing interest JC Wells, M Mullin, and S Sun have no COIs to report. C Ho has received: Grants/Research funding - Astra Zeneca, Roche. Honoraria - Abbvie, Amgen, Astra Zeneca, Bayer, BMS, CADTH, Eisai, Jazz, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi. B Melosky has received speaker honoraria or attended advisory boards for Astra Zeneca, BMS, Merck, Roche, Pfizer, Takeda, Sanofi, EMD Serono, and Janssen J Laskin has received honoraria from Roche, Pfizer, Takeda and Lilly; she has also received research funding to her institution from Roche., (Copyright © 2024 Elsevier B.V. All rights reserved.)- Published
- 2024
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19. Regulation of β-cell death by ADP-ribosylhydrolase ARH3 via lipid signaling in insulitis.
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Sarkar S, Deiter C, Kyle JE, Guney MA, Sarbaugh D, Yin R, Li X, Cui Y, Ramos-Rodriguez M, Nicora CD, Syed F, Juan-Mateu J, Muralidharan C, Pasquali L, Evans-Molina C, Eizirik DL, Webb-Robertson BM, Burnum-Johnson K, Orr G, Laskin J, Metz TO, Mirmira RG, Sussel L, Ansong C, and Nakayasu ES
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- Mice, Animals, Humans, Cell Death, Cytokines metabolism, Fatty Acids, Unsaturated, Phosphatidylcholines metabolism, Islets of Langerhans metabolism, Fatty Acids, Omega-3 metabolism, N-Glycosyl Hydrolases
- Abstract
Background: Lipids are regulators of insulitis and β-cell death in type 1 diabetes development, but the underlying mechanisms are poorly understood. Here, we investigated how the islet lipid composition and downstream signaling regulate β-cell death., Methods: We performed lipidomics using three models of insulitis: human islets and EndoC-βH1 β cells treated with the pro-inflammatory cytokines interlukine-1β and interferon-γ, and islets from pre-diabetic non-obese mice. We also performed mass spectrometry and fluorescence imaging to determine the localization of lipids and enzyme in islets. RNAi, apoptotic assay, and qPCR were performed to determine the role of a specific factor in lipid-mediated cytokine signaling., Results: Across all three models, lipidomic analyses showed a consistent increase of lysophosphatidylcholine species and phosphatidylcholines with polyunsaturated fatty acids and a reduction of triacylglycerol species. Imaging assays showed that phosphatidylcholines with polyunsaturated fatty acids and their hydrolyzing enzyme phospholipase PLA2G6 are enriched in islets. In downstream signaling, omega-3 fatty acids reduce cytokine-induced β-cell death by improving the expression of ADP-ribosylhydrolase ARH3. The mechanism involves omega-3 fatty acid-mediated reduction of the histone methylation polycomb complex PRC2 component Suz12, upregulating the expression of Arh3, which in turn decreases cell apoptosis., Conclusions: Our data provide insights into the change of lipidomics landscape in β cells during insulitis and identify a protective mechanism by omega-3 fatty acids. Video Abstract., (© 2024. Battelle Memorial Institute.)
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- 2024
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20. Lipid Isobar and Isomer Imaging Using Nanospray Desorption Electrospray Ionization Combined with Triple Quadrupole Mass Spectrometry.
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Weigand MR, Unsihuay Vila DM, Yang M, Hu H, Hernly E, Muhoberac M, Tichy S, and Laskin J
- Abstract
Mass spectrometry imaging (MSI) is widely used for examining the spatial distributions of molecules in biological samples. Conventional MSI approaches, in which molecules extracted from the sample are distinguished based on their mass-to-charge ratio, cannot distinguish between isomeric species and some closely spaced isobars. To facilitate isobar separation, MSI is typically performed using high-resolution mass spectrometers. Nevertheless, the complexity of the mixture of biomolecules observed in each pixel of the image presents a challenge, even for modern mass spectrometers with the highest resolving power. Herein, we implement nanospray desorption electrospray ionization (nano-DESI) MSI on a triple quadrupole (QqQ) mass spectrometer for the spatial mapping of isobaric and isomeric species in biological tissues. We use multiple reaction monitoring acquisition mode (MRM) with unit mass resolution to demonstrate the performance of this new platform by imaging lipids in mouse brain and rat kidney tissues. We demonstrate that imaging in MRM mode may be used to distinguish between isobaric phospholipids requiring a mass resolving power of 3,800,000. Additionally, we have been able to image eicosanoid isomers, a largely unexplored class of signaling molecules present in tissues at low concentrations, in rat kidney tissue. This new capability substantially enhances the specificity and selectivity of MSI, enabling spatial localization of species that remain unresolved in conventional MSI experiments.
- Published
- 2024
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