Disrupting NFkB/BRD4 function in glioblastoma as a means to block tumor cell communication

Glioblastoma multiforme (GBM) is an aggressive type of cancer, whose therapeutic resistance stems from its heterogeneity which refers to diversity in mutations and cell types as well as diversity in the epigenome of cancer cells (Inda et al. 2014). A common scenario of heterogeneity in GBM is the overexpression and mutation of the Epidermal Growth Factor Receptor (EGFR) referred to as WTEGFR and EGFRvIII respectively (Gay et al. 2010).Tumor heterogeneity contributes to the recalcitrant nature of GBM, making pathway-specific and mutation-specific therapy less effective. (Neftel et al. 2019, Verhaak et al. 2010). It was found that WTEGFR and EGFRvIII-expressing GBM cancer cells both converge to signal through an NFkB and BRD4 mediated mechanism to remodel their enhancer landscapes (Zanca et al. 2017). This results in increased expression of survivin, which is known to prevent tumor death, as well as IL-6 expression, which is known to promote tumor proliferation and survival (Wheatley et al. 2019).With this information we sought to explore the molecular and epigenetic modifications that the NFkB/BRD4 interaction causes. To do so a mutation that inhibits the interaction between NFkB and BRD4 was CRISPR engineered into iPS cells which have GBM driver mutations. So far, the iPS cells were successfully engineered to express this NFkB/BRD4-disrupting mutation and differentiated into NPCs for subsequent lentiviral transduction to express WTEGFR and EGFRvIII as well as engraftment in mice for tumor development. The engineering and differentiation of these cells provides a platform for a novel approach of targeting both WTEGFR and EGFRvIII through a shared epigenome landscape facilitated by NFkB/BRD4 activity

Disrupting NFkB/BRD4 function in glioblastoma as a means to block tumor cell communication

Glioblastoma multiforme (GBM) is an aggressive type of cancer, whose therapeutic resistance stems from its heterogeneity which refers to diversity in mutations and cell types as well as diversity in the epigenome of cancer cells (Inda et al. 2014). A common scenario of heterogeneity in GBM is the overexpression and mutation of the Epidermal Growth Factor Receptor (EGFR) referred to as WTEGFR and EGFRvIII respectively (Gay et al. 2010).Tumor heterogeneity contributes to the recalcitrant nature of GBM, making pathway-specific and mutation-specific therapy less effective. (Neftel et al. 2019, Verhaak et al. 2010). It was found that WTEGFR and EGFRvIII-expressing GBM cancer cells both converge to signal through an NFkB and BRD4 mediated mechanism to remodel their enhancer landscapes (Zanca et al. 2017). This results in increased expression of survivin, which is known to prevent tumor death, as well as IL-6 expression, which is known to promote tumor proliferation and survival (Wheatley et al. 2019).With this information we sought to explore the molecular and epigenetic modifications that the NFkB/BRD4 interaction causes. To do so a mutation that inhibits the interaction between NFkB and BRD4 was CRISPR engineered into iPS cells which have GBM driver mutations. So far, the iPS cells were successfully engineered to express this NFkB/BRD4-disrupting mutation and differentiated into NPCs for subsequent lentiviral transduction to express WTEGFR and EGFRvIII as well as engraftment in mice for tumor development. The engineering and differentiation of these cells provides a platform for a novel approach of targeting both WTEGFR and EGFRvIII through a shared epigenome landscape facilitated by NFkB/BRD4 activity

Anosmia: Brighton Collaboration case definition and guidelines for data collection, analysis, and presentation of immunization safety data

<p>This is a Brighton Collaboration case definition of anosmia to be used in the evaluation of adverse events following immunization, and for epidemiologic studies for the assessment of background incidence or hypothesis testing. The case definition was developed by a group of experts convened by the Coalition for Epidemic Preparedness Innovations (CEPI) in the context of active development of SARS-CoV-2 vaccines. The case definition format of the Brighton Collaboration was followed to develop a consensus definition and defined levels of certainty, after an exhaustive review of the literature and expert consultation. The document underwent peer review by the Brighton Collaboration Network and by two expert reviewers prior to submission.</p>The SPEAC Project is funded in whole by CEPI

Anosmia: Brighton Collaboration case definition and guidelines for data collection, analysis, and presentation of immunization safety data.

This is a Brighton Collaboration case definition of anosmia to be used in the evaluation of adverse events following immunization, and for epidemiologic studies for the assessment of background incidence or hypothesis testing. The case definition was developed by a group of experts convened by the Coalition for Epidemic Preparedness Innovations (CEPI) in the context of active development of SARS-CoV-2 vaccines. The case definition format of the Brighton Collaboration was followed to develop a consensus definition and defined levels of certainty, after an exhaustive review of the literature and expert consultation. The document underwent peer review by the Brighton Collaboration Network and by two expert reviewers prior to submission