Faculty Opinions recommendation of IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors.

The formulation of policies constitutes a core business of political parties in modern democracies. Using the novel data of the Political Party Database (PPDB) Project and the data of the Manifesto Project (MARPOR), the authors of this chapter aim at a systematic test of the causal link between the intra-party decision mode on the electoral manifestos and the extent of programmatic change. What are the effects of the politics of manifesto formulation on the degree of policy change? Theoretically, the authors distinguish the drafting process from the final enactment of the manifesto. Empirically, they show that a higher autonomy of the party elite in formulating the manifesto leads to a higher degree of programmatic change. If party members constrain party elite’s autonomy, they tend to veto major changes.

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TAMI-23. NEUTROPHIL-TRIGGERED FERROPTOSIS PROMOTES TUMOR NECROSIS IN GLIOBLASTOMA PROGRESSION

Neuro-Oncology ◽

10.1093/neuonc/noaa215.912 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii218-ii218

Author(s):

Patricia Yee ◽

Yiju Wei ◽

Soo Yeon Kim ◽

Tong Lu ◽

Cynthia Lawson ◽

...

Keyword(s):

Tumor Cells ◽

Tumor Necrosis ◽

Treatment Resistance ◽

Binding Motif ◽

Lipid Hydroperoxides ◽

Orthotopic Mouse Model ◽

Mouse Tumors ◽

Downstream Effector ◽

Human Gbm ◽

Early Tumor

Abstract Tumor necrosis indicates poor prognoses in many cancers, including glioblastomas (GBMs). Although thought to result from chronic ischemia, the underlying nature and mechanisms driving the involved cell death remain obscured by lack of animal models recapitulating the extent of necrosis in human GBMs. The molecular and clinical heterogeneity of GBMs adds further complexity. Not all GBMs contain necrosis. Mesenchymal (MES)-GBM, the subtype correlated with worst prognosis and highest treatment resistance, is most closely associated with necrosis. MES-GBM exhibits hyperactivity of transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo tumor suppressive pathway effector whose expression in human GBMs predicts short survival. To elucidate mechanisms driving GBM necrosis, we devised a novel orthotopic mouse model recapitulating human MES-GBM phenotypically and histopathologically by expressing a constitutively-active TAZ mutant (TAZ4SA) in three human GBM cell lines (LN229, U87, and LN18) lacking MES signatures (GBM4SA). GBM4SA mice lived significantly shorter than mice implanted with GBMvector or mutant TAZ unable to bind its downstream effector, TEAD (GBM4SA-S51A). Extensive (≥30% of tumor volume) necrosis was present in GBM4SA mice but not GBMvector or GBM4SA-S51A. In GBM4SA tumors, neutrophils coincide with necrosis temporally and spatially. Neutrophil depletion dampens necrosis. Neutrophils isolated from mouse tumors killed co-cultured tumor cells. Neutrophils induce iron-dependent accumulation of lipid hydroperoxides within tumor cells by transferring myeloperoxidase-containing granules into tumor cells. Inhibiting myeloperoxidase suppresses neutrophil-induced tumor cytotoxicity. Intratumoral glutathione peroxidase 4 (GPX4) overexpression or acyl-CoA synthetase 4 (ACSL4) depletion diminishes necrosis and aggressiveness of tumors. Human GBM analysis indicates neutrophils and ferroptosis are associated with necrosis and predict poor survival. Together, we propose that certain tumor damage(s) during early tumor progression (i.e. ischemia) recruits neutrophils to damaged tissue and results in a positive feedback loop, amplifying GBM necrosis development. We show GBM necrosis involves neutrophil-triggered ferroptosis and reveal an unprecedented pro-tumorigenic role of ferroptosis.

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Metastasis is altered through multiple processes regulated by the E2F1 transcription factor

Scientific Reports ◽

10.1038/s41598-021-88924-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Matthew R. Swiatnicki ◽

Eran R. Andrechek

Keyword(s):

Breast Cancer ◽

Transgenic Mouse Models ◽

Cellular Processes ◽

Mouse Tumors ◽

Mutation Burden ◽

Multiple Processes ◽

Metastatic Process ◽

Cycle Regulation ◽

Bioinformatic Approach ◽

Complicated Nature

AbstractThe E2F family of transcription factors is important for many cellular processes, from their canonical role in cell cycle regulation to other roles in angiogenesis and metastasis. Alteration of the Rb/E2F pathway occurs in various forms of cancer, including breast cancer. E2F1 ablation has been shown to decrease metastasis in MMTV-Neu and MMTV-PyMT transgenic mouse models of breast cancer. Here we take a bioinformatic approach to determine the E2F1 regulated genomic alterations involved in the metastatic cascade, in both Neu and PyMT models. Through gene expression analysis, we reveal few transcriptome changes in non-metastatic E2F1−/− tumors relative to transgenic tumor controls. However investigation of these models through whole genome sequencing found numerous differences between the models, including differences in the proposed tumor etiology between E2F1−/− and E2F1+/+ tumors induced by Neu or PyMT. For example, loss of E2F1 within the Neu model led to an increased contribution of the inefficient double stranded break repair signature to the proposed etiology of the tumors. While the SNV mutation burden was higher in PyMT mouse tumors than Neu mouse tumors, there was no statistically significant differences between E2F WT and E2F1 KO mice. Investigating mutated genes through gene set analysis also found a significant number of genes mutated in the cell adhesion pathway in E2F1−/− tumors, indicating this may be a route for disruption of metastasis in E2F1−/− tumors. Overall, these findings illustrate the complicated nature of uncovering drivers of the metastatic process.

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Irradiation of subcutaneous mouse tumors with a clinical linear accelerator validated by alanine dosimetry

Radiation Measurements ◽

10.1016/j.radmeas.2021.106636 ◽

2021 ◽

pp. 106636

Author(s):

C. Ankjærgaard ◽

A.Z. Johansen ◽

M.M.K. von Staffeldt ◽

C.E. Andersen ◽

D.H. Madsen ◽

...

Keyword(s):

Linear Accelerator ◽

Mouse Tumors

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In Vitro and In Vivo Multispectral Photoacoustic Imaging for the Evaluation of Chromophore Concentration

Sensors ◽

10.3390/s21103366 ◽

2021 ◽

Vol 21 (10) ◽

pp. 3366

Author(s):

Aneline Dolet ◽

Rita Ammanouil ◽

Virginie Petrilli ◽

Cédric Richard ◽

Piero Tortoli ◽

...

Keyword(s):

Remote Sensing ◽

Photoacoustic Imaging ◽

Hyperspectral Remote Sensing ◽

Reference Spectrum ◽

In Vivo Experiments ◽

Mouse Tumors ◽

Chromophore Concentration ◽

Saturation Rate

Multispectral photoacoustic imaging is a powerful noninvasive medical imaging technique that provides access to functional information. In this study, a set of methods is proposed and validated, with experimental multispectral photoacoustic images used to estimate the concentration of chromophores. The unmixing techniques used in this paper consist of two steps: (1) automatic extraction of the reference spectrum of each pure chromophore; and (2) abundance calculation of each pure chromophore from the estimated reference spectra. The compared strategies bring positivity and sum-to-one constraints, from the hyperspectral remote sensing field to multispectral photoacoustic, to evaluate chromophore concentration. Particularly, the study extracts the endmembers and compares the algorithms from the hyperspectral remote sensing domain and a dedicated algorithm for segmentation of multispectral photoacoustic data to this end. First, these strategies are tested with dilution and mixing of chromophores on colored 4% agar phantom data. Then, some preliminary in vivo experiments are performed. These consist of estimations of the oxygen saturation rate (sO2) in mouse tumors. This article proposes then a proof-of-concept of the interest to bring hyperspectral remote sensing algorithms to multispectral photoacoustic imaging for the estimation of chromophore concentration.

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