Abstract TP7: Association of Retrieved Thrombus Composition With Measures of Thrombectomy Success

Introduction: Emboli retrieved from stroke patients undergoing mechanical thrombectomy vastly differ in histopathologic appearance, likely reflecting varying etiologies of stroke. We investigated whether clot components correlated with clinical features and thrombectomy outcomes. Methods: Retrieved thrombi from endovascular thrombectomy in consecutive AIS-LVO patients at 2 academic medical centers were fixed in formalin and sections stained by hematoxylin and eosin. The RBC, WBC and fibrin percentages of the clot were quantified by a neuropathologist blinded to the clinical details. We evaluated the association of these clot components, patient demographic and clinical features, with TICI score (both ordinal and dichotomized at 2c), AOL score, number of thrombectomy passes, and first-pass substantial recanalization (≥TICI 2b result on the first thrombectomy device pass). Non-parametric values were computed via Spearman correlation and pairwise interaction of clinical features was analyzed by ordinal logistic regression. Results: Among the 75 analyzed patients, mean age was 71.4 (SD 17.7), 50.7% were female and presenting NIHSS mean was 16.1 (SD 7.6). Devices employed were stent retrievers in 71% of patients, aspiration in 10%, and both stent retrievers and aspiration in 19%. Number of passes per procedure was mean 2.16 (SD 1.21). Substantial reperfusion (TICI 2B-3) was achieved in 88% and excellent reperfusion (TICI 2C-3) in 44%. In retrieved thrombi, mean RBC% was 44.8% (SD 31.9) and mean fibrin% was 49.8% (SD 31.4). Rates of first-pass substantial reperfusion, final substantial reperfusion, and final excellent reperfusion were homogenous across wide ranges of retrieved thrombus RBC% and fibrin% in correlation analysis. Conclusion: RBC and fibrin composition range widely among retrieved thrombi causing acute ischemic stroke. Current generation thrombectomy devices perform well across a broad range of clot compositions

EGFR Mutation Promotes Glioblastoma through Epigenome and Transcription Factor Network Remodeling

Epidermal growth factor receptor (EGFR) gene amplification and mutations are the most common oncogenic events in glioblastoma (GBM), but the mechanisms by which they promote aggressive tumor growth are not well understood. Here, through integrated epigenome and transcriptome analyses of cell lines, genotyped clinical samples, and TCGA data, we show that EGFR mutations remodel the activated enhancer landscape of GBM, promoting tumorigenesis through a SOX9 and FOXG1-dependent transcriptional regulatory network in vitro and in vivo. The most common EGFR mutation, EGFRvIII, sensitizes GBM cells to the BET-bromodomain inhibitor JQ1 in a SOX9, FOXG1-dependent manner. These results identify the role of transcriptional/epigenetic remodeling in EGFR-dependent pathogenesis and suggest a mechanistic basis for epigenetic therapy

Target Selection for the DESI Peculiar Velocity Survey

International audienceWe describe the target selection and characteristics of the DESI Peculiar Velocity Survey, the largest survey of peculiar velocities (PVs) using both the fundamental plane (FP) of galaxies and the Tully-Fisher (TF) relationship planned to date. We detail how we identify suitable early-type galaxies for the FP and suitable late-type galaxies for the TF relation using the photometric data provided by the DESI Legacy Imaging Survey DR9. Subsequently, we provide targets for 373 533 early-type galaxies and 118 637 late-type galaxies within the DESI 5-year footprint. We validate these photometric selections using existing morphological classifications. Furthermore, we demonstrate using survey validation data that DESI is able to measure the spectroscopic properties to sufficient precision to obtain PVs for our targets. Based on realistic DESI fiber assignment simulations and spectroscopic success rates, we predict the final DESI Peculiar Velocity Survey will obtain $\sim$133 000 FP-based and $\sim$53 000 TF-based PV measurements over an area of 14 000 $\mathrm{deg^{2}}$. Each of these components will be a factor of 4--5 larger than other recent samples. We forecast the ability of using these data to measure the clustering of galaxy positions and peculiar velocities from the combined DESI PV and Bright Galaxy Surveys (BGS), which allows for cancellation of cosmic variance at low redshifts. With these forecasts, we anticipate a $4\%$ statistical measurement on the growth rate of structure at $z<0.15$. This is over two times better than achievable with redshifts from the BGS alone. The combined DESI PV and Bright Galaxy surveys will enable the most precise tests to date of the time and scale dependence of large-scale structure growth at $z<0.15$

Target selection for the DESI Peculiar Velocity Survey

We describe the target selection and characteristics of the DESI Peculiar Velocity Survey, the largest survey of peculiar velocities (PVs) using both the fundamental plane (FP) and the Tully-Fisher (TF) relationship planned to date. We detail how we identify suitable early-type galaxies (ETGs) for the FP and suitable late-type galaxies (LTGs) for the TF relation using the photometric data provided by the DESI Legacy Imaging Survey DR9. Subsequently, we provide targets for 373 533 ETGs and 118 637 LTGs within the Dark Energy Spectroscopic Instrument (DESI) 5-yr footprint. We validate these photometric selections using existing morphological classifications. Furthermore, we demonstrate using survey validation data that DESI is able to measure the spectroscopic properties to sufficient precision to obtain PVs for our targets. Based on realistic DESI fibre assignment simulations and spectroscopic success rates, we predict the final DESI PV Survey will obtain ∼133 000 FP-based and ∼53 000 TF-based PV measurements over an area of 14 000 deg2. We forecast the ability of using these data to measure the clustering of galaxy positions and PVs from the combined DESI PV and Bright Galaxy Surveys (BGS), which allows for cancellation of cosmic variance at low redshifts. With these forecasts, we anticipate a 4 per cent statistical measurement on the growth rate of structure at z &lt; 0.15. This is over two times better than achievable with redshifts from the BGS alone. The combined DESI PV and BGS will enable the most precise tests to date of the time and scale dependence of large-scale structure growth at z &lt; 0.15

EGFR Mutation Promotes Glioblastoma through Epigenome and Transcription Factor Network Remodeling

Epidermal Growth Factor Receptor (EGFR) gene amplification and mutations are the most common oncogenic events in Glioblastoma (GBM), but the mechanisms by which they promote aggressive tumor growth are not well understood. Here, through integrated epigenome and transcriptome analyses of cell lines, genotyped clinical samples and TCGA data, we show that EGFR mutations remodel the activated enhancer landscape of GBM, promoting tumorigenesis through a SOX9 and FOXG1-dependent transcriptional regulatory network in vitro and in vivo. The most common EGFR mutation, EGFRvIII, sensitizes GBM cells to the BET-bromodomain inhibitor JQ1 in a SOX9, FOXG1-dependent manner. These results identify the role of transcriptional/epigenetic remodeling in EGFR-dependent pathogenesis and suggest a mechanistic basis for epigenetic therapy

IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma

In many cancers, high proliferation rates correlate with elevation of rRNA and tRNA levels, and nucleolar hypertrophy. However, the underlying mechanisms linking increased nucleolar transcription and tumorigenesis are only minimally understood. Here we show that IMP dehydrogenase-2 (IMPDH2), the rate-limiting enzyme for de novo guanine nucleotide biosynthesis, is overexpressed in the highly lethal brain cancer glioblastoma. This leads to increased rRNA and tRNA synthesis, stabilization of the nucleolar GTP-binding protein nucleostemin, and enlarged, malformed nucleoli. Pharmacological or genetic inactivation of IMPDH2 in glioblastoma reverses these effects and inhibits cell proliferation, whereas untransformed glia cells are unaffected by similar IMPDH2 perturbations. Impairment of IMPDH2 activity triggers nucleolar stress and growth arrest of glioblastoma cells even in the absence of functional p53. Our results reveal that upregulation of IMPDH2 is a prerequisite for the occurance of aberrant nucleolar function and increased anabolic processes in glioblastoma, which constitutes a primary event in gliomagenesis

HIV-associated distal neuropathic pain is associated with smaller total cerebral cortical gray matter

Despite modern antiretroviral therapy, HIV-associated sensory neuropathy affects over 50% of HIV patients. The clinical expression of HIV neuropathy is highly variable: many individuals report few symptoms, but about half report distal neuropathic pain (DNP), making it one of the most prevalent, disabling and treatment-resistant complications of HIV disease. The presence and intensity of pain is not fully explained by the degree of peripheral nerve damage, making it unclear why some patients do, and others do not, report pain. To better understand central nervous system contributions to HIV DNP, we performed a cross-sectional analysis of structural magnetic resonance imaging (MRI) volumes in 241 HIV-infected participants from an observational multi-site cohort study at five US sites (CNS HIV Antiretroviral Treatment Effects Research Study, CHARTER). The association between DNP and the structural imaging outcomes was investigated using both linear and nonlinear (Gaussian Kernel support vector) multivariable regression, controlling for key demographic and clinical variables. Severity of DNP symptoms was correlated with smaller total cerebral cortical gray matter volume (R = −0.24; p = 0.004). Understanding the mechanisms for this association between smaller total cortical volumes and DNP may provide insight into HIV DNP chronicity and treatment-resistance