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Patient‐derived cancer models that reconstitute the characteristics of the tumor microenvironment may facilitate efforts in precision immune‐oncology and the discovery of effective anticancer therapies. Organoids that have recently emerged as robust preclinical models typically contain tumor epithelial cells and lack the native tumor immune microenvironment. A patient‐derived organotypic tumor spheroid (PDOTS) is a novel and innovative ex vivo system that retains key features of the native tumor immune microenvironment. Here, we established and characterized a series of colorectal cancer PDOTS models for use as a preclinical platform for testing effective immunotherapy and its combinations with other drugs. Partially dissociated (> 100 μm in diameter) tumor tissues were embedded in Matrigel‐containing organoid media and subsequently formed into organoid structures within 3 to 7 days of culture. The success rate of growing PDOTS from fresh tissues was ~86%. Morphological analysis showed that the PDOTSs varied in size and structure. Immunofluorescence and flow cytometry analysis revealed that the PDOTSs retained autologous tumor‐infiltrating lymphoid cells and tumor‐infiltrating lymphoid cells were continually decreased through serial passages. Notably, PDOTSs from tumors from a high‐level microsatellite instability‐harboring patient were sensitive to anti‐PD‐1 or anti‐PD‐L1 antibodies. Our results demonstrate that the PDOTS model in which the tumor immune microenvironment is preserved may represent an advantageous ex vivo system to develop effective immune therapeutics.

17Fiber reinforced polymer composites are commonly bonded to concrete structures for 18 strengthening reasons, even though little is known about the evolution of bond strength 19 while the strengthening systems are subject to sustained loads and elevated temperatures. 20This investigation uses single-lap shear specimens to examine the effects of sustained 21 load and elevated temperature on the time-dependent deformation of a carbon fiber 22 reinforced polymer (CFRP) composite bonded to concrete as well as the pull-off strength 23 of the composite after the sustained loading period. Increased temperature during the 24 sustained loading period led to increased slip of the CFRP, whereas increased curing time 25 of the polymer resin prior to the sustained loading period led to reduced slip. Specimens 26 that underwent sustained loading had increased pull-off strength and interfacial fracture 27 energy following the sustained loading period. This beneficial effect was most significant 28 for roughly 30 days of sustained loading. The analysis of strain distributions and fracture 29 surfaces indicated that stress relaxation of the adhesive occurred in the 30 mm closest to 30 the loaded end of the CFRP during sustained loading, which increased the pull-off 31 strength provided the failure locus remained mostly in the concrete. For longer sustained 32 loading times, the bond failure locus shifted to the epoxy/concrete interface, which 33 diminished part of the strength increase brought on by the stress relaxation of the 34 adhesive. 35

Peroxiredoxin I (Prx I), an antioxidant enzyme, has multiple functions in human cancer. However, the role of Prx I in hepatic tumorigenesis has not been characterized. Here we investigated the relevance and underlying mechanism of Prx I in hepatic tumorigenesis. Prx I increased in tumors of hepatocellular carcinoma (HCC) patients that aligned with overexpression of oncogenic H-ras. Prx I also increased in H-rasG12V transfected HCC cells and liver tumors of H-rasG12V transgenic (Tg) mice, indicating that Prx I may be involved in Ras-induced hepatic tumorigenesis. When Prx I was knocked down or deleted in HCC-H-rasG12V cells or H-rasG12V Tg mice, cell colony or tumor formation was significantly reduced that was associated with downregulation of pERK pathway as well as increased intracellular reactive oxygen species (ROS) induced DNA damage and cell death. Overexpressing Prx I markedly increased Ras downstream pERK/FoxM1/Nrf2 signaling pathway and inhibited oxidative damage in HCC cells and H-rasG12V Tg mice. In this study, we found Nrf2 was transcriptionally activated by FoxM1, and Prx I was activated by the H-rasG12V/pERK/FoxM1/Nrf2 pathway and suppressed ROS-induced hepatic cancer-cell death along with formation of a positive feedback loop with Ras/ERK/FoxM1/Nrf2 to promote hepatic tumorigenesis.