4 research outputs found
Inhibition of the Wnt/β-catenin pathway enhances anti-tumor immunity in ovarian cancer
Background: The Wnt/β-catenin pathway is linked to tumorigenesis in a variety of tumors and
promotes T cell exclusion and resistance to checkpoint inhibitors. We sought to determine whether a small molecule inhibitor of this pathway, WNT974, would impair tumor growth, affect gene expression patterns, and improve the immune response in human and murine ovarian cancer models.
Methods: Human ovarian cancer cells were treated with WNT974 in vitro. RNAseq libraries were constructed and differences in gene expression patterns between responders and nonresponders were compared to The Cancer Genome Atlas (TCGA). Mice with subcutaneous or intraperitoneal ID8 ovarian cancer tumors were treated with WNT974, paclitaxel, combination, or control. Tumor growth and survival were measured. Flow cytometry and β-TCR repertoire analysis were used to determine the immune response.
Results: Gene expression profiling revealed distinct signatures in responders and nonresponders,
which strongly correlated with T cell infiltration patterns in the TCGA analysis of ovarian cancer.
WNT974 inhibited tumor growth, prevented ascites formation, and prolonged survival in mouse models. WNT974 increased the ratio of CD8+ T cells to T regulatory cells (Tregs) in tumors and enhanced the effector functions of infiltrating CD4+ and CD8+ T cells. Treatment also decreased the expression of inhibitory receptors on CD8+ T cells. Combining WNT974 with paclitaxel further reduced tumor growth, prolonged survival, and expanded the T cell repertoire.
Conclusions: These findings suggest that inhibiting the Wnt/β-catenin pathway may have a potent immunomodulatory effect in the treatment of ovarian cancer, particularly when combined with paclitaxel
Design of Factor XIII V34X activation peptides to control ability to interact with thrombin mutants
Wnt/β-catenin signalling in ovarian cancer: Insights into its hyperactivation and function in tumorigenesis
Coronal Heating as Determined by the Solar Flare Frequency Distribution Obtained by Aggregating Case Studies
Flare frequency distributions represent a key approach to addressing one of
the largest problems in solar and stellar physics: determining the mechanism
that counter-intuitively heats coronae to temperatures that are orders of
magnitude hotter than the corresponding photospheres. It is widely accepted
that the magnetic field is responsible for the heating, but there are two
competing mechanisms that could explain it: nanoflares or Alfv\'en waves. To
date, neither can be directly observed. Nanoflares are, by definition,
extremely small, but their aggregate energy release could represent a
substantial heating mechanism, presuming they are sufficiently abundant. One
way to test this presumption is via the flare frequency distribution, which
describes how often flares of various energies occur. If the slope of the power
law fitting the flare frequency distribution is above a critical threshold,
as established in prior literature, then there should be a
sufficient abundance of nanoflares to explain coronal heating. We performed
600 case studies of solar flares, made possible by an unprecedented number
of data analysts via three semesters of an undergraduate physics laboratory
course. This allowed us to include two crucial, but nontrivial, analysis
methods: pre-flare baseline subtraction and computation of the flare energy,
which requires determining flare start and stop times. We aggregated the
results of these analyses into a statistical study to determine that . This is below the critical threshold, suggesting that Alfv\'en
waves are an important driver of coronal heating.Comment: 1,002 authors, 14 pages, 4 figures, 3 tables, published by The
Astrophysical Journal on 2023-05-09, volume 948, page 7