Dual inhibition of histone deacetylases and phosphoinositide 3-kinase enhances therapeutic activity against B cell lymphoma

Phosphoinositide 3-kinase (PI3K) and Myc are known to cooperate in promoting the survival and growth of a variety of B-cell lymphomas. While currently there are no small molecule inhibitors of Myc protein, histone deacetylase (HDAC) inhibitors have been shown to reduce levels of Myc protein by suppressing its transcription. We assessed the efficacy of CUDC-907, a new rationally designed dual inhibitor of PI3K and HDACs, in a panel of lymphoma cell lines. CUDC-907 treatment resulted in a dose- and time-dependent growth inhibition and cell death of DLBCL cell lines, irrespective of the cell of origin. CUDC-907 treatment down-regulated the phosphorylation of PI3K downstream targets, including AKT, PRAS40, S6, and 4EBP1, increased histone 3 acetylation, and decreased Myc protein levels. SILAC-based quantitative mass spectrometry demonstrated that CUDC-907 treatment decreased the protein levels of several components of the B cell receptor (BCR) and Toll like receptor (TLR) pathways, including BTK, SYK, and MyD88 proteins. These cellular changes were associated with an inhibition of NF-kB activation. CUDC-907 demonstrated in vivo efficacy with no significant toxicity in a human DLBCL xenograft mouse model. Collectively, these data provide a mechanistic rationale for evaluating CUDC-907 for the treatment of patients with Myc and PI3K-dependent lymphomas

BET Inhibition-Induced GSK3β Feedback Enhances Lymphoma Vulnerability to PI3K Inhibitors

The phosphatidylinositol 3 kinase (PI3K)-glycogen synthase kinase \u3b2 (GSK3\u3b2) axis plays a central role in MYC-driven lymphomagenesis, and MYC targeting with bromodomain and extraterminal protein family inhibitors (BETi) is a promising treatment strategy in lymphoma. In a high-throughput combinatorial drug screening experiment, BETi enhance the antiproliferative effects of PI3K inhibitors in a panel of diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma cell lines. BETi or MYC silencing upregulates several PI3K pathway genes and induces GSK3\u3b2 S9 inhibitory phosphorylation, resulting in increased \u3b2-catenin protein abundance. Furthermore, BETi or MYC silencing increases GSK3\u3b2 S9 phosphorylation levels and \u3b2-catenin protein abundance through downregulating the E2 ubiquitin conjugating enzymes UBE2C and UBE2T. In a mouse xenograft DLBCL model, BETi decrease MYC, UBE2C, and UBE2T and increase phospho-GSK3\u3b2 S9 levels, enhancing the anti-proliferative effect of PI3K inhibitors. Our study reveals prosurvival feedbacks induced by BETi involving GSK3\u3b2 regulation, providing a mechanistic rationale for combination strategies. In this study, Derenzini et al. demonstrate that BET inhibitors enhance lymphoma vulnerability to PI3K inhibitors by inducing GSK3\u3b2 feedback in a MYC-dependent manner and by downregulating E2-ubiquitin conjugating enzymes, which further enhance the feedback. These data provide the rationale for combining BET and PI3K inhibitors in lymphoma therapy

Using higher order modes in superconducting accelerating cavities for beam monitoring

Dipole modes have been shown to be successful diagnostics for the beam position in superconducting accelerating cavities at the Free Electron Laser in Hamburg (FLASH) facility at DESY. By help of downmixing electronics the signals from the two higher order mode (HOM) couplers mounted on each cavity are monitored. The calibration, based on sigular value decomposition, is more complicated than in standard position monitors. Position like signals based on this calibration are currently being in the process of being included in the control system. A second setup based on digitizing the spectrum from the HOM couplers has been used for monitoring monopole modes. The beam phase with respect to the RF has been thus monitored. The position calibration measurements and phase monitoring made at the FLASH are presented

Beam Position Monitoring with Cavity Higher Order Modes in the Superconducting Linac FLASH

FLASH (Free Electron Laser in Hamburg) is a user facility for a high intensity VUV-light source [1]. The radiation wavelength is tunable in the range from about 40 to 13 nm by changing the electron beam energy from 450 to 700 MeV. The accelerator is also a test facility for the European XFEL (X-ray Free Electron Laser) to be built in Hamburg [2] and the project study ILC (International Linear Collider) [3]. The superconducting TESLA technology is tested at this facility, together with other accelerator components

Using Higher Order Modes in Superconducting Accelerating Cavities for Beam Monitoring

Dipole modes have been shown to be successful diagnostics for the beam position in superconducting accelerating cavities at the Free Electron Laser in Hamburg (FLASH) facility at DESY. By help of downmixing electronics the signals from the two higher order mode (HOM) couplers mounted on each cavity are monitored. The calibration, based on singular value decomposition, is more complicated than in standard position monitors. Position like signals based on this calibration are currently being in the process of being included in the control system. A second setup based on digitizing the spectrum from the HOM couplers has been used for monitoring monopole modes. The beam phase with respect to the RF has been thus monitored. The position calibration measurements and phase monitoring made at the FLASH are presented

The proteomic toolbox for studying cerebrospinal fluid

Item does not contain fulltextCerebrospinal fluid (CSF) can be considered the most promising biosample for the discovery and analysis of biomarkers in neuroscience, an area of great medical need. CSF is a body fluid that surrounds the brain and provides a rich pool of biochemical markers, both proteomic and metabolomic, that reflect the state of neurological processes. Such biomarkers can either serve as diagnostic or prognostic biomarkers to improve the characterization of patients and preclinical disease models, or can be used to demonstrate drug-related exposure and efficacy. Here, we describe the proteomic toolbox for studying CSF from a drug-discovery perspective, and the trends and challenges that lie ahead

The Oncogenic Action of NRF2 Depends on De-glycation by Fructosamine-3-Kinase.

The NRF2 transcription factor controls a cell stress program that is implicated in cancer and there is great interest in targeting NRF2 for therapy. We show that NRF2 activity depends on Fructosamine-3-kinase (FN3K)-a kinase that triggers protein de-glycation. In its absence, NRF2 is extensively glycated, unstable, and defective at binding to small MAF proteins and transcriptional activation. Moreover, the development of hepatocellular carcinoma triggered by MYC and Keap1 inactivation depends on FN3K in vivo. N-acetyl cysteine treatment partially rescues the effects of FN3K loss on NRF2 driven tumor phenotypes indicating a key role for NRF2-mediated redox balance. Mass spectrometry reveals that other proteins undergo FN3K-sensitive glycation, including translation factors, heat shock proteins, and histones. How glycation affects their functions remains to be defined. In summary, our study reveals a surprising role for the glycation of cellular proteins and implicates FN3K as targetable modulator of NRF2 activity in cancer