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The 4-trifluoromethyl analog 4c shown moderate activity against Pim-1, but was surprisingly effective when tested against Pim-3 (residual activities 51% and 24%, respectively) The overall yield for the preparation of the C8 methyl derivative 17 from the common aldehyde starting material was 18%

(and mice. microenvironment and reinforce the high therapeutic value of Gal1 inhibition in PDA treatment. (25). Genetically engineered mouse models (GEMMs) are essential tools for studying the molecular mechanisms underlying PDA progression and for evaluating MRT-83 potential therapeutic targets (26). In particular, GEMMs harboring pancreas-specific mutated KRAS are currently considered the best models to mirror human pathology, as these mice develop the full spectrum of pancreatic tumor progression, from metaplastic and preneoplastic lesions to adenocarcinoma and metastasis (27C32). Moreover, tumors from Model of Pancreatic Cancer. The (herein oncogene in pancreatic acinar cells using an elastase-driven inducible Tet-Off strategy (48), is considered one of the best models for studying PDA in the preclinical setting, as it faithfully recapitulates the natural history and hallmarks of this disease (28, 48). mice develop ductal tumors displaying abundant desmoplasia with extensive extracellular matrix protein deposition and activated -SMA+ positive PSCs (Fig. 1mice with mice lacking the Gal1 gene (mice, we selected the and genotypes for further characterization, as Gal1 heterozygotes showed no phenotypic differences from mice developed ductal pancreatic tumors with histopathological hallmarks similar to those in tumors from mice (Fig. 1mice died before 3 mo, and only 20% survived more than 6 mo. In the absence of Gal1, survival changed to 5.3% for short-term survivors (a 47% decrease) and 36.8% for long-term survivors (an 84% increase) (Fig. 1and Table S1). Open in a separate window Fig. 1. Gal1 deficiency FUT3 increases lifespan in the PDA mouse model. (and mice. (Scale bars: 100 m for H&E, Gal1, and -SMA staining and 50 m for CK19.) ((= 20) and (= 19) mice. * 0.05, log-rank test. ( 0.05, 2 test. Mice. To define whether the survival phenotype observed was a consequence of delayed tumor onset and/or progression, 4-mo-old mice were killed, and tumors were analyzed. Histological characterization of pancreata showed that both and mice displayed the full spectrum of PDA progression at 4 mo, including normal pancreas, acinar-to-ductal metaplasia and precursor lesions, and fully developed ductal pancreatic tumors with one or multiple nodules (Fig. 2animals showed a less aggressive lesion distribution, characterized by an increased number of normal pancreata, precursor lesions, and uninodular tumors compared with mice (Fig. 2compared with mice (Fig. 2or mice. (and and mice. (Scale bars: 50 m MRT-83 in and (= 17) and (= 18) mice were killed. Animals were classified according to the highest histological grade lesion observed. ( 0.05. ( 0.05 (model is the generation of tumor metastases located in the liver and lung, which recapitulate those observed in the human condition. Interestingly, the presence of liver metastases was significantly and selectively reduced in mice harboring tumors compared with mice (Fig. 2Mice. Due to the high levels of Gal1 expression in the PDA stroma and the previously reported role of this lectin in the regulation of immune and endothelial cell function MRT-83 (43), we sought to examine the impact of Gal1 inactivation in the tumor microenvironment. Characterization of the primary tumors developed at 4 mo by or mice revealed that Gal1-deficient mice showed significantly smaller tumors than mice (Fig. 3tumors that developed in the absence of Gal1 showed impaired stroma activation and decreased tumor vascularization (Fig. 3and Fig. S1and mice. (and mice. (Scale bars: 1 cm.) (and mice. (Scale bars: 100 m for -SMA and 50 m for vWF.) ( 0.05. (or mice. Representative plots of tumor-infiltrating immune cells expressing CD45, CD3, CD4, and CD8 or CD11b and Gr-1 are shown. Percentages of cells of each individual subpopulation (CD3+CD4+ cells, CD3+CD8+ cells, and CD11b+Gr-1+ cells) are indicated. ** 0.01, *** 0.001 (Students test). Ten animals per group were used for the characterizations in or tumors by flow cytometry. Tumor infiltrates from mice showed a paucity of infiltrating T cells.