A-to-G), but cannot produce base transversions. Here we present BEs that cause C-to-A transversions in E. coli and C-to-G transversions in mammalian cells. Our glycosylase base editors (GBEs) consist of a Cas9 nickase, a cytidine deaminase and a Uracil-DNA glycosylase (Ung). Ung excises the U base created by the deaminase, creating an apurinic/apyrimidinic (AP) site that initiates the DNA repair process. [AU: unclear how this results in a transversion. Can this be

Most cancers preserve functional retinoblastoma (Rb) and may, therefore, respond to inhibition of D-cyclin-dependent Rb kinases, CDK4 and CDK6. To date, CDK4/6 inhibitors have shown promising clinical activity in breast cancer and lymphomas, but it is not clear which additional Rb-positive cancers might benefit from these agents. No systematic survey to compare relative sensitivities across tumor types and define molecular determinants of response has been described. We report a subset of cancers highly sensitive to CDK4/6 inhibition and characterized by various genomic aberrations known to elevate D-cyclin levels and describe a recurrent CCND1 3'UTR mutation associated with increased expression in endometrial cancer. The results suggest multiple additional classes of cancer that may benefit from CDK4/6-inhibiting drugs such as abemaciclib.

Exosomes are nanosized membrane vesicles (30–100 nm) that can easily penetrate the blood–brain barrier, safely deliver therapeutic drugs, and be modified with target ligands. Embryonic stem cells (ESCs) provide abundant exosome sources for clinical application due to their almost unlimited self‐renewal. Previous studies show that exosomes secreted by ESCs (ESC‐exos) have antitumor properties. However, it is not known whether ESC‐exos inhibit glioblastoma (GBM) growth. In this study, the anti‐GBM effect of ESC‐exos is confirmed and then c(RGDyK)‐modified and paclitaxel (PTX)‐loaded ESC‐exos, named cRGD‐Exo‐PTX are prepared. It is then investigated whether the engineered exosomes deliver more efficiently to GBM cells versus free drug alone and drug‐loaded ESC‐exos using an in vitro GBM model and in vivo subcutaneous and orthotopic xenografts model. The results show that cRGD‐Exo‐PTX significantly improves the curative effects of PTX in GBM via enhanced targeting. These data indicate that ESC‐exos are potentially powerful therapeutic carriers for GBM and could have utility in many other diseases.

The protein kinase Cθ (PKCθ) serine/threonine kinase has been implicated in signaling of T cell activation, proliferation, and cytokine production. However, the in vivo consequences of ablation of PKCθ on T cell function in inflammatory autoimmune disease have not been thoroughly examined. In this study we used PKCθ-deficient mice to investigate the potential involvement of PKCθ in the development of experimental autoimmune encephalomyelitis, a prototypic T cell-mediated autoimmune disease model of the CNS. We found that PKCθ−/− mice immunized with the myelin oligodendrocyte glycoprotein (MOG) peptide MOG35–55 were completely resistant to the development of clinical experimental autoimmune encephalomyelitis compared with wild-type control mice. Flow cytometric and histopathological analysis of the CNS revealed profound reduction of both T cell and macrophage infiltration and demyelination. Ex vivo MOG35–55 stimulation of splenic T lymphocytes from immunized PKCθ−/− mice revealed significantly reduced production of the Th1 cytokine IFN-γ as well as the T cell effector cytokine IL-17 despite comparable levels of IL-2 and IL-4 and similar cell proliferative responses. Furthermore, IL-17 expression was dramatically reduced in the CNS of PKCθ−/− mice compared with wild-type mice during the disease course. In addition, PKCθ−/− T cells failed to up-regulate LFA-1 expression in response to TCR activation, and LFA-1 expression was also significantly reduced in the spleens of MOG35–55-immunized PKCθ−/− mice as well as in in vitro-stimulated CD4+ T cells compared with wild-type mice. These results underscore the importance of PKCθ in the regulation of multiple T cell functions necessary for the development of autoimmune disease.