Extracellular vesicles (EVs) are nano-sized lipid bilayer vesicles released by virtually every cell type. EVs have diverse biological activities, ranging from roles in development and homeostasis to ...cancer progression, which has spurred the development of EVs as disease biomarkers and drug nanovehicles. Owing to the small size of EVs, however, most studies have relied on isolation and biochemical analysis of bulk EVs separated from biofluids. Although informative, these approaches do not capture the dynamics of EV release, biodistribution, and other contributions to pathophysiology. Recent advances in live and high-resolution microscopy techniques, combined with innovative EV labeling strategies and reporter systems, provide new tools to study EVs in vivo in their physiological environment and at the single-vesicle level. Here we critically review the latest advances and challenges in EV imaging, and identify urgent, outstanding questions in our quest to unravel EV biology and therapeutic applications.
Abstract
Background
In MONARCH 3, a randomized, double-blind, phase 3 trial; continuous dosing of abemaciclib in combination with an AI (anastrozole or letrozole) conferred significant clinical ...benefit to postmenopausal women with HR+, HER2- ABC. We here report data from an additional 12 months of follow-up in this trial including analysis for clinically prognostic subgroups (Di Leo et al., 2018).
Methods
From the 31 October 2018 data cutoff, exploratory intermediate efficacy parameters including time to subsequent chemotherapy (TCT time from randomization to first chemotherapy CT) and time to second disease progression (PFS2 time from randomization to discontinuation date of first post-discontinuation treatment PDT, or starting date of the secondPDT, or death) were assessed. TCT and PFS2 were analyzed using the Kaplan-Meier method in the intent to treat (ITT) and subgroups previously identified as significantly prognostic.
Results
In the ITT population, updated PFS was 28.2 vs 14.8 months (HR 95% CI: 0.525 0.415, 0.665; p<.0001) in the abemaciclib vs placebo arms, respectively. A higher number of patients discontinued the study in the placebo arm as compared to the abemaciclib arm, thereby starting a PDT. Systemic PDT was received by 178 (54%) patients in the abemaciclib arm and 123 (74.5%) in the placebo arm, of which 93 (28.4%) and 82 (49.7%) received CT respectively. Addition of abemaciclib to AI deferred the initiation of CT both in the ITT (HR 95% CI: 0.513 0.380, 0.691; p<.0001) and in subgroups (Table). PFS2 was prolonged in the abemaciclib arm (HR 95% CI: 0.637 0.495, 0.819; p<.0004). Consistent with the ITT population, PFS2 favored the abemaciclib arm across all subgroups of prognostic factors (Table). Safety profile was generally consistent with previously disclosed results.
Table:326PTCTPFS2Abemaciclib + AI Events/NPlacebo + AI Events/NHR (95% CI)Abemaciclib + AI Events/NPlacebo + AI Events/NHR (95% CI)ITT93/32882/1650.513 (0.380, 0.691)152/328106/1650.637 (0.495, 0.819)ECOG PS 134/13636/610.342 (0.214, 0.548)64/13645/610.504 (0.344, 0.740) 059/19246/1040.639 (0.435, 0.940)88/19261/1040.762 (0.549, 1.059)Bone-only disease Yes13/6916/400.440 (0.211, 0.914)21/6923/400.523 (0.289, 0.945) No80/25966/1250.495 (0.357, 0.686)131/25983/1250.660 (0.501, 0.871)Liver metastases Yes21/4721/310.572 (0.313, 1.048)32/4725/310.677 (0.401, 1.142) No72/28161/1340.504 (0.358, 0.709)120/28181/1340.663 (0.500, 0.881)Progesterone receptor status Positive66/25557/1280.529 (0.371, 0.753)115/25578/1280.694 (0.520, 0.927) Negative25/7024/360.414 (0.236, 0.725)35/7027/360.537 (0.325, 0.889)Tumor grade High22/6521/320.369 (0.203, 0.672)27/6523/320.418 (0.240, 0.730)Intermediate/Low52/17948/960.512 (0.345, 0.757)86/17963/960.671 (0.484, 0.931)Treatment-free interval <36 months15/4418/320.465 (0.234, 0.924)21/4424/320.506 (0.281, 0.910) ≥36 months32/9518/410.798 (0.448, 1.422)48/9524/410.895 (0.548, 1.461)
Conclusions
Addition of abemaciclib to AI prolonged PFS2 and TCT in the ITT and all prognostic subgroups.
Clinical trial identification
NCT02246621.
Editorial acknowledgement
Medical writing support was provided by Anchal Sood and editorial assistance by Rod Everhart of Syneos Health, and funded by Eli Lilly and Company.
Legal entity responsible for the study
Eli Lilly and Company.
Funding
Eli Lilly and Company.
Disclosure
M. Martín: Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self): AstraZeneca; Honoraria (self): Pfizer; Honoraria (self): Eli Lilly and Company; Honoraria (self): Taiho Oncology; Honoraria (self): Pharmamar; Honoraria (self): Roche/Genentech. S. Johnston: Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: Eli Lilly and Company; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Research grant / Funding (self): Puma Biotechnology; Speaker Bureau / Expert testimony: Eisai. J. Huober: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Eli Lilly and Company; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy: Hexal; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Celgene; Honoraria (self), Advisory / Consultancy: Abbvie. A. Di Leo: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Celgene; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Eisai; Honoraria (self), Advisory / Consultancy: Genomic Health; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Eli Lilly and Company; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: Daiichi Sankyo; Advisory / Consultancy: Genentech; Advisory / Consultancy: Ipsen; Advisory / Consultancy, Travel / Accommodation / Expenses: Puma Biotechnology. V.A. Andre: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. H.R. Martin: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. M.C. Hardebeck: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. M.P. Goetz: Honoraria (self): Genomic Health; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly and Company; Advisory / Consultancy: Biovica; Advisory / Consultancy: Novartis; Advisory / Consultancy: Sermonix; Advisory / Consultancy: Context Pharm; Research grant / Funding (institution): Pfizer. All other authors have declared no conflicts of interest.
Versatile Applications of Metallopolymers Götz, Stefan; Zechel, Stefan; Hager, Martin D. ...
Progress in polymer science,
August 2021, 2021-08-00, Letnik:
119
Journal Article
Recenzirano
The incorporation of metal complexes into polymers leads to functional materials; whereas, the properties of polymers – easy processability, light weight or the adjustable molar mass – and those of ...metal complexes – optical properties, catalytic activity or biomedical potential – can be combined. Through the years, various different applications have been developed, depending on the needs of current techniques and society. Thus, advanced applications enabled by metallopolymers, include areas: like self-assembly, stimuli-responsive behavior, catalysis, optics, self-healing, shape-memory as well as biomedicine and further potential applications can be expected. This review will summarize and discuss these applications as well as how the interactions of metal complexes and polymers enable them.
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