Clonal Deletion of Tumor-Specific T Cells by Interferon-γ Confers Therapeutic Resistance to Combination Immune Checkpoint Blockade.

Resistance to checkpoint-blockade treatments is a challenge in the clinic. We found that although treatment with combined anti-CTLA-4 and anti-PD-1 improved control of established tumors, this combination compromised anti-tumor immunity in the low tumor burden (LTB) state in pre-clinical models as well as in melanoma patients. Activated tumor-specific T cells expressed higher amounts of interferon-γ (IFN-γ) receptor and were more susceptible to apoptosis than naive T cells. Combination treatment induced deletion of tumor-specific T cells and altered the T cell repertoire landscape, skewing the distribution of T cells toward lower-frequency clonotypes. Additionally, combination therapy induced higher IFN-γ production in the LTB state than in the high tumor burden (HTB) state on a per-cell basis, reflecting a less exhausted immune status in the LTB state. Thus, elevated IFN-γ secretion in the LTB state contributes to the development of an immune-intrinsic mechanism of resistance to combination checkpoint blockade, highlighting the importance of achieving the optimal magnitude of immune stimulation for successful combination immunotherapy strategies.

Effectiveness of home-based exercise for improving physical activity, quality of life and function in older adults after hospitalisation: A systematic review and meta-analysis.

OBJECTIVE: To determine if home-based exercise programmes for older adults after hospitalisation are effective at improving physical activity, quality of life, activities of daily living (ADL) and mobility compared to no intervention, standard care or centre-based exercise. METHODS: Databases were searched from inception to March 2022. Randomised controlled trials which included home-based exercise in older adults recently discharged from hospital were included. The primary outcome was physical activity. Secondary outcomes were quality of life, ADL performance, mobility, adverse events and hospital readmissions. Two reviewers independently selected relevant studies and extracted data. Quantitative synthesis with meta-analyses using a random-effects model and qualitative synthesis were performed. RESULTS: Ten trials (PEDro score 6-8) were included. Three trials reported on physical activity but meta-analysis was not possible due to heterogeneity. Home-based exercise was more effective than no intervention at improving ADL performance (SMD 0.60, 95% CI 0.03 to 1.17); and standard care at improving quality of life (SMD 0.30, 95% CI 0.11 to 0.49) and mobility (SMD 0.23, 95% CI 0.00 to 0.45). Few and minor adverse events were associated with home-based exercise. CONCLUSION: Based on individual trials, home-based exercise has the potential to improve physical activity compared to no intervention or standard care. Meta-analyses indicate that home-based exercise is more effective than no intervention at improving activities of daily living performance, and standard care at improving mobility and quality of life. It is unclear if home-based exercise is more effective than centre-based exercise at improving these outcomes.

Tuning through-bond Fe(III)/Fe(II) coupling by solvent manipulation of a central ruthenium redox couple.

The relationships between the intervalence energy (E(IT)) and the free energy difference (DeltaG) that exists between the minima of redox isomers (Fe(II)-Ru(III)/Fe(III)-Ru(II)) for various heterobimetallic complexes [(R-Fcpy)Ru(NH(3))(5)](2+/3+) (R = H, ethyl, Br, actyl; Fcpy = (4-pyridyl)ferrocenyl; Ru(NH(3))(5) = pentaam(m)ineruthenium) were examined. The changes in DeltaG for the complexes in various solvents were due to the effects of both solvent donicity and the substituents. The intervalence energy versus DeltaG, DeltaG approximately FDeltaE(1/2) (DeltaE(1/2) = E(1/2)(Fe(III/II)) - E(1/2)(Ru(III/II))), plots for the complexes in various solvents suggest a nuclear reorganization energy (lambda) of approximately 6000 cm(-1) (Chen et al. Inorg. Chem. 2000, 39, 189). For [(R-Fcpy)Ru(NH(3))(5)](2+) and [(et-Fcpy)Ru(NH(3))(4)(py)](2+) (Ru(NH(3))(4) = trans-tetraam(m)ineruthenium; py = pyridine) in various solvents, the E(1/2)(Ru(III/II)) of rutheniumam(m)ine typically was less than the E(1/2)(Fe(III/II)) of the ferrocenyl moiety. However, the low-donicity solvents resulted in relatively large values of E(1/2)(Ru(III/II)) for [(et-Fcpy)Ru(NH(3))(4)(py)](2+/3+/4+). Under our unique solvent conditions, a dramatic end-to-end interaction was observed for the trimetal cation, [(et-Fcpy)(2)Ru(NH(3))(4)](4+), in which the [(et-Fcpy)(2)Ru(NH(3))(4)](4+) included a central trans-tetraam(m)ineruthenium(III) and a terminal Fe(II)/Fe(III) pair. In general, results of electrochemical studies of [(et-Fcpy)(2)Ru(NH(3))(4)](2+) indicated both solvent-tunable E(1/2)(Ru(III/II)) (1 e(-)) and solvent-insensitive E(1/2)(Fe(III/II)) (2 e(-)) redox centers. However, in nitriles, two E(1/2)(Fe(III/II)) peaks were found with DeltaE(1/2)(Fe(III/II) - Fe(III/II)) ranging between 83 and 108 mV at a terminal metal-to-metal distance of up to 15.6 A. Furthermore, the bridging dpi orbital of the ruthenium center mediated efficient end-to-end interaction between the combinations of the terminal Fe(II)-Fe(III)/Fe(III)-Fe(II) pair. To our knowledge, this is the first example of solvent-tunable end-to-end interactions in multimetal complexes.