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Anne Rodallec,1 Guillaume Sicard,1 Sarah Giacometti,1 Manon Carré,1 Bertrand Pourroy,2 Fanny Bouquet,3 Ariel Savina,3 Bruno Lacarelle,1 Joseph Ciccolini,1 Raphaelle Fanciullino1 1SMARTc Unit, Laboratory of Pharmacokinetics and Toxicology UFR Pharmacy, Center for Research on Cancer of Marseille, Inserm UMR1068, CNRS UMR7258, Aix Marseille University, Marseille, France; 2Pharmacy Department, APHM La Conception, Marseille, France; 3Roche Institute, Boulogne Billancourt, France Purpose: Nanoparticles are of rising interest in cancer research, but in vitro canonical cell monolayer models are not suitable to evaluate their efficacy when prototyping candidates. Here, we developed three-dimensional (3D) spheroid models to test the efficacy of trastuzumab-docetaxel immunoliposomes in breast cancer prior to further testing them in vivo. Materials and methods: Immunoliposomes were synthesized using the standard thin film method and maleimide linker. Two human breast cancer cell lines varying in Her2 expression were tested: Her2+ cells derived from metastatic site: mammary breast MDA-MB-453 and triple-negative MDA-MB-231 cells. 3D spheroids were developed and tested with fluorescence detection to evaluate viability. In vivo efficacy and biodistribution studies were performed on xenograft bearing nude mice using fluorescent and bioluminescent imaging. Results: In vitro, antiproliferative efficacy was dependent upon cell type, size of the spheroids, and treatment scheduling, resulting in subsequent changes between tested conditions and in vivo results. Immunoliposomes performed better than free docetaxel + free trastuzumab and ado-trastuzumab emtansine (T-DM1). On MDA-MB-453 and MDA-MB-231 cell growth was reduced by 76% and 25%, when compared to free docetaxel + free trastuzumab and by 85% and 70% when compared to T-DM1, respectively. In vivo studies showed tumor accumulation ranging from 3% up to 15% of the total administered dose in MDA-MB-453 and MDA-MB-231 bearing mice. When compared to free docetaxel + free trastuzumab, tumor growth was reduced by 89% (MDA-MB-453) and 25% (MDA-MB-231) and reduced by 66% (MDA-MB-453) and 29% (MDA-MB-231) when compared to T-DM1, an observation in line with data collected from 3D spheroids experiments. Conclusion: We demonstrated the predictivity of 3D in vitro models when developing and testing nanoparticles in experimental oncology. In vitro and in vivo data showed efficient drug delivery with higher efficacy and prolonged survival with immunoliposomes when compared to current anti-Her2 breast cancer strategies. Keywords: docetaxel, trastuzumab, breast cancer, immunoliposome, spheroids, distribution, tumor xenograft

Background: This study aimed to determine whether implementing a rapid response system (RRS) is associated with improved short‐term outcomes in critically ill patients with haematological malignancies. Methods: Our monocentric pre‐ versus post‐intervention study was conducted between January 2012 and April 2020. RRS was activated at early signs of haemodynamic or respiratory failure. The primary outcome was the reduction in Sequential Organ Failure Assessment (SOFA) score on Day 3 after intensive care unit (ICU) admission. Secondary outcomes included time to ICU admission and mortality. Results: A total of 209 patients with a median age of 59 years were enrolled (108 in the pre‐intervention period and 101 in the post‐intervention period). 22% of them had received an allogeneic transplant. The post‐intervention period was associated with a shorter time to ICU admission (195 vs. 390 min, p <.001), a more frequent favourable trend in SOFA score (57% vs. 42%, adjusted odds ratio, 2.02, 95% confidence interval, 1.09 to 3.76), no significant changes in ICU (22% vs. 26%, p =.48) and 1‐year (62% vs. 58%, p =.62) mortality rates. Conclusion: Detection of early organ failure and activation of an RRS was associated with faster ICU admission and lower SOFA scores on Day 3 of admission in critically ill patients with haematological malignancies. [ABSTRACT FROM AUTHOR]

Stable oxygen isotopic ratios in corals (δ18Ocoral) are commonly utilized to reconstruct climate variability beyond the limit of instrumental observations. These measurements provide constraints on past seawater temperature, due to the thermodynamics of isotopic fractionation, but also past salinity, as both salinity and seawater δ18O (δ18Osw) are similarly affected by precipitation/evaporation, advection, and other processes. We use historical observations, isotope‐enabled model simulations, and the PAGES Iso2k database to assess the potential of δ18Ocoral to provide information on past salinity. Using "pseudocorals" to represent δ18Ocoral as a function of observed or simulated temperature and salinity/δ18Osw, we find that δ18Osw contributes up to 89% of δ18Ocoral variability in the Western Pacific Warm Pool. Although uncertainty in the δ18Osw‐salinity relationship influences the inferred salinity variability, corals from these sites could provide valuable δ18Osw reconstructions. Coordinated in situ monitoring of salinity and δ18Osw is vital for improving estimates of hydroclimatic change. Plain Language Summary: Seawater salinity provides valuable information about the global water cycle, including changes in precipitation, evaporation, and ocean currents. However, scientists' understanding of recent salinity change is hampered by the limited coverage of salinity measurements. Tropical corals incorporate environmental information in their skeletons as they grow, providing indirect evidence of past ocean salinity. Quantitatively estimating salinity variations requires accounting both for temperature‐ and salinity‐driven influences on the stable oxygen isotope composition (δ18O) of the coral skeleton, as well as changes in the relationship between salinity and seawater δ18O. Through comparison with instrumental records and climate models, we find that corals in the western Pacific Ocean and eastern Indian Ocean are most likely to provide reliable salinity information across seasons, years, and decades. Finally, we find that direct seawater δ18O observations are critical to improve the salinity information obtained from corals. Key Points: Seawater δ18O contributes up to 89% of the coral δ18O variability, providing critical information about salinity variability and trendsThe inferred salinity contribution to coral δ18O values is highly dependent on the salinity‐δ18O linear regression slopeInterpretation of coral δ18O values should account for both temperature and hydrological influences, which may oppose one another [ABSTRACT FROM AUTHOR]