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Supplementary Figures 1 and 2, Table 1 from Degradation of Fibrillar Collagen in a Human Melanoma Xenograft Improves the Efficacy of an Oncolytic Herpes Simplex Virus Vector

Oncolytic viral therapy provides a promising approach to treat certain human malignancies. These vectors improve on replication-deficient vectors by increasing the viral load within tumors through preferential viral replication within tumor cells. However, the inability to efficiently propagate throughout the entire tumor and infect cells distant from the injection site has limited the capacity of oncolytic viruses to achieve consistent therapeutic responses. Here we show that the spread of the oncolytic herpes simplex virus (HSV) vector MGH2 within the human melanoma Mu89 is limited by the fibrillar collagen in the extracellular matrix. This limitation seems to be size specific as nanoparticles of equivalent size to the virus distribute within tumors to the same extent whereas smaller particles distribute more widely. Due to limited viral penetration, tumor cells in inaccessible regions continue to grow, remaining out of the range of viral infection, and tumor eradication cannot be achieved. Matrix modification with bacterial collagenase coinjection results in a significant improvement in the initial range of viral distribution within the tumor. This results in an extended range of infected tumor cells and improved virus propagation, ultimately leading to enhanced therapeutic outcome. Thus, fibrillar collagen can be a formidable barrier to viral distribution and matrix-modifying treatments can significantly enhance the therapeutic response. (Cancer Res 2006; 66(5): 2509–13)

We present the first Chandra detection of a single X-ray cavity within the interstellar medium of the small Fanaroff-Riley type I (FRI) radio galaxy NGC 5141. The X-ray surface brightness depression, located $\approx 4$ kpc away from the galaxy center, is projected on the northern radio lobe, which is completely contained within the galaxy. The thermal gas surrounding the cavity, which extends to $\approx$ 20 kpc, has a bolometric X-ray luminosity (0.1 - 100 keV) of L${_X}\approx2\times10^{40}$ erg s$^{-1}$ and a temperature of $kT\approx0.8$ keV. We calculated the total energy (E$_{cav} = 4PV \approx 10^{55}$ erg) required to inflate the cavity and its age ($t_{cav}\approx 9$ Myrs), assuming that it is filled with relativistic particles and rises buoyantly. The inferred total cavity power is as low as P$_{cav}=E_{cav}/t_{cav}\approx6\times10^{40}$ erg s$^{-1}$, which is the lowest one among the radio-filled systems. Comparing $P_{cav}$ to the bolometric X-ray luminosity (i.e., the cooling luminosity), we conclude that NGC 5141's central active galactic nucleus can heat the interstellar medium and balance its cooling luminosity, confirming that the $P_{cav}-L_{cool}$ relation, mainly tested on groups and clusters, also works for such a low-power system., 9 pages, 6 figures, accepted for publication in A&A on 28 January 2022

DNA methylation, a key epigenetic driver of transcriptional silencing, is universally dysregulated in cancer. Reversal of DNA methylation by hypomethylating agents, such as the cytidine analogs decitabine or azacytidine, has demonstrated clinical benefit in hematologic malignancies. These nucleoside analogs are incorporated into replicating DNA where they inhibit DNA cytosine methyltransferases DNMT1, DNMT3A and DNMT3B through irreversible covalent interactions. These agents induce notable toxicity to normal blood cells thus limiting their clinical doses. Herein we report the discovery of GSK3685032, a potent first-in-class DNMT1-selective inhibitor that was shown via crystallographic studies to compete with the active-site loop of DNMT1 for penetration into hemi-methylated DNA between two CpG base pairs. GSK3685032 induces robust loss of DNA methylation, transcriptional activation and cancer cell growth inhibition in vitro. Due to improved in vivo tolerability compared with decitabine, GSK3685032 yields superior tumor regression and survival mouse models of acute myeloid leukemia.

Kidneys have one of the most complex three-dimensional cellular organizations in the body, but the spatial molecular principles of kidney health and disease are poorly understood. Here we generate high-quality single cell (sc), single nuclear (sn), spatial (sp) RNA expression and sn open chromatin datasets for 73 samples, capturing half a million cells from healthy, diabetic, and hypertensive diseased human kidneys. Combining the sn/sc and sp RNA information, we identify > 100 cell types and states and successfully map them back to their spatial locations. Computational deconvolution of spRNA-seq identifies glomerular/vascular, tubular, immune, and fibrotic spatial microenvironments (FMEs). Although injured proximal tubule cells appear to be the nidus of fibrosis, we reveal the complex, heterogenous cellular and spatial organization of human FMEs, including the highly intricate and organized immune environment. We demonstrate the clinical utility of the FME spatial gene signature for the classification of a large number of human kidneys for disease severity and prognosis. We provide a comprehensive spatially-resolved molecular roadmap for the human kidney and the fibrotic process and demonstrate the clinical utility of spatial transcriptomics.

Second-generation bromodomain and extra terminal (BET) inhibitors, which selectively target one of the two bromodomains in the BET proteins, have begun to emerge in the literature. These inhibitors aim to help determine the roles and functions of each domain and assess whether they can demonstrate an improved safety profile in clinical settings compared to pan-BET inhibitors. Herein, we describe the discovery of a novel BET BD2-selective chemotype using a structure-based drug design from a hit identified by DNA-encoded library technologies, showing a structural differentiation from key previously reported greater than 100-fold BD2-selective chemotypes GSK620, GSK046, and ABBV-744. Following a structure-based hypothesis for the selectivity and optimization of the physicochemical properties of the series, we identified 60 (GSK040), an in vitro ready and in vivo capable BET BD2-inhibitor of unprecedented selectivity (5000-fold) against BET BD1, excellent selectivity against other bromodomains, and good physicochemical properties. This novel chemical probe can be added to the toolbox used in the advancement of epigenetics research.

Domain-specific BET bromodomain ligands represent an attractive target for drug discovery with the potential to unlock the therapeutic benefits of antagonizing these proteins without eliciting the toxicological aspects seen with pan-BET inhibitors. While we have reported several distinct classes of BD2 selective compounds, namely, GSK620, GSK549, and GSK046, only GSK046 shows high aqueous solubility. Herein, we describe the lead optimization of a further class of highly soluble compounds based upon a picolinamide chemotype. Focusing on achieving >1000-fold selectivity for BD2 over BD1 ,while retaining favorable physical chemical properties, compound 36 was identified as being 2000-fold selective for BD2 over BD1 (Brd4 data) with >1 mg/mL solubility in FaSSIF media. 36 represents a valuable new in vivo ready molecule for the exploration of the BD2 phenotype.

A number of reports have recently been published describing the discovery and optimization of bromo and extraterminal inhibitors which are selective for the second bromodomain (BD2); these include our own work toward GSK046 (3) and GSK620 (5). This paper describes our approach to mitigating the genotoxicity risk of GSK046 by replacement of the acetamide functionality with a heterocyclic ring. This was followed by a template-hopping and hybridization approach, guided by structure-based drug design, to incorporate learnings from other BD2-selective series, optimize the vector for the amide region, and explore the ZA cleft, leading to the identification of potent, selective, and bioavailable compounds 28 (GSK452), 39 (GSK737), and 36 (GSK217).

The profound efficacy, yet associated toxicity of pan-BET inhibitors is well documented. The possibility of an ameliorated safety profile driven by significantly selective (>100-fold) inhibition of a subset of the eight bromodomains is enticing, but challenging given the close homology. Herein, we describe the X-ray crystal structure-directed optimization of a novel weak fragment ligand with a pan-second bromodomain (BD2) bias, to potent and highly BD2 selective inhibitors. A template hopping approach, enabled by our parallel research into an orthogonal template (15, GSK046), was the basis for the high selectivity observed. This culminated in two tool molecules, 20 (GSK620) and 56 (GSK549), which showed an anti-inflammatory phenotype in human whole blood, confirming their cellular target engagement. Excellent broad selectivity, developability, and in vivo oral pharmacokinetics characterize these tools, which we hope will be of broad utility to the field of epigenetics research.

Pan-bromodomain and extra terminal domain (BET) inhibitors interact equipotently with the eight bromodomains of the BET family of proteins and have shown profound efficacy in a number of in vitro phenotypic assays and in vivo pre-clinical models in inflammation or oncology. A number of these inhibitors have progressed to the clinic where pharmacology-driven adverse events have been reported. To better understand the contribution of each domain to their efficacy and improve their safety profile, selective inhibitors are required. This article discloses the profile of GSK046, also known as iBET-BD2, a highly selective inhibitor of the second bromodomains of the BET proteins that has undergone extensive pre-clinical in vitro and in vivo characterization.

Pan-bromodomain and extra terminal (BET) inhibitors interact equipotently with all eight bromodomains of the BET family of proteins. They have shown profound efficacy in vitro and in vivo in oncology and immunomodulatory models, and a number of them are currently in clinical trials where significant safety signals have been reported. It is therefore important to understand the functional contribution of each bromodomain to assess the opportunity to tease apart efficacy and toxicity. This article discloses the in vitro and cellular activity profiles of GSK789, a potent, cell-permeable, and highly selective inhibitor of the first bromodomains of the BET family.

[Image: see text] Pan-BET inhibitors have shown profound efficacy in a number of in vivo preclinical models and have entered the clinic in oncology trials where adverse events have been reported. These inhibitors interact equipotently with the eight bromodomains of the BET family of proteins. To better understand the contribution of each domain to their efficacy and to improve from their safety profile, selective inhibitors are required. This Letter discloses the profile of GSK973, a highly selective inhibitor of the second bromodomains of the BET proteins that has undergone extensive preclinical in vitro and in vivo characterization.

Optimization of a lead series of PI3Kδ inhibitors based on a dihydroisobenzofuran core led to the identification of potent, orally bioavailable compound 19. Selectivity profiling of compound 19 showed similar potency for class III PI3K, Vps34, and PI3Kδ, and compound 19 was not well-tolerated in a 7-day rat toxicity study. Structure-based design led to an improvement in selectivity for PI3Kδ over Vps34 and, a focus on oral phramacokinetics properties resulted in the discovery of compound 41, which showed improved toxicological outcomes at similar exposure levels to compound 19.

The use of mutant strains of oncolytic herpes simplex virus (oHSV) in early-phase human clinical trials for the treatment of glioblastoma multiforme (GBM) has proven safe, but limited efficacy suggests that more potent vector designs are required for effective GBM therapy. Inadequate vector performance may derive from poor intratumoral vector replication and limited spread to uninfected cells. Vector replication may be impaired by mutagenesis strategies to achieve vector safety, and intratumoral virus spread may be hampered by vector entrapment in the tumor-specific extracellular matrix (ECM) that in GBM is composed primarily of type IV collagen. In this report, we armed our previously described epidermal growth factor receptor (EGFR)vIII-targeted, neuronal microRNA-sensitive oHSV with a matrix metalloproteinase (MMP9) to improve intratumoral vector distribution. We show that vector-expressed MMP9 enhanced therapeutic efficacy and long-term animal survival in a GBM xenograft model. Keywords: matrix metalloproteinase 9 = MMP9, extracellular matrix = ECM, Oncolytic vectors = OVs, Glioblastoma multiforme = GBM, OVs derived from herpes simplex virus = oHSV

Herein, a series of 2,3-dihydrobenzofurans have been developed as highly potent bromo and extra-terminal domain (BET) inhibitors with 1000-fold selectivity for the second bromodomain (BD2) over the first bromodomain (BD1). Investment in the development of two orthogonal synthetic routes delivered inhibitors that were potent and selective but had raised in vitro clearance and suboptimal solubility. Insertion of a quaternary center into the 2,3-dihydrobenzofuran core blocked a key site of metabolism and improved the solubility. This led to the development of inhibitor 71 (GSK852): a potent, 1000-fold-selective, highly soluble compound with good in vivo rat and dog pharmacokinetics.

The profound efficacy of pan-BET inhibitors is well documented, but these epigenetic agents have shown pharmacology-driven toxicity in oncology clinical trials. The opportunity to identify inhibitors with an improved safety profile by selective targeting of a subset of the eight bromodomains of the BET family has triggered extensive medicinal chemistry efforts. In this article, we disclose the identification of potent and selective drug-like pan-BD2 inhibitors such as pyrazole 23 (GSK809) and furan 24 (GSK743) that were derived from the pyrrole fragment 6. We transpose the key learnings from a previous pyridone series (GSK620 2 as a representative example) to this novel class of inhibitors, which are characterized by significantly improved solubility relative to our previous research.

Domain-specific BET bromodomain ligands represent an attractive target for drug discovery with the potential to unlock the therapeutic benefits of antagonizing these proteins without eliciting the toxicological aspects seen with pan-BET inhibitors. While we have reported several distinct classes of BD2 selective compounds, namely, GSK620, GSK549, and GSK046, only GSK046 shows high aqueous solubility. Herein, we describe the lead optimization of a further class of highly soluble compounds based upon a picolinamide chemotype. Focusing on achieving1000-fold selectivity for BD2 over BD1 ,while retaining favorable physical chemical properties, compound

The 2018 annual Cambridge Healthtech Institute’s International Immuno-Oncology Summit in Boston, MA convened late August, and academic and industry researchers were allowed to debate and discuss oncolytic virology during the virus immunotherapy portion of the conference. The breakthrough agent, TVEC/IMLYGIC, as well as most other oncolytic viruses (OVs) in clinical trials, are demonstrating an immense synergy with T cell checkpoint inhibitors. To this extent, the marriage of T cell checkpoint inhibitors and OV is now vastly accepted, indicating the next phase in OVs is the recruitment of the immune system, and tailoring the immune response toward tumor clearance is a far better strategy than directly lysing the tumor outright with virus. The next field-shaping question for OVs is how to convert a patient’s immune response against their tumor. The talks this year focused on whether OVs can cause the emergence of a strong anti-tumor immunity intrinsically or whether vectors, which educate the immune system to detect tumor antigens, were more efficacious. Speakers presented novel transgenes to arm OVs and systems biology approaches to discover the best viral backbones to engineer into vectors. Here we summarize the meeting’s keynote talks, thematic principles running through the summit, and current developments in the OV field.

Background: Up to 50% of patients with muscle invasive bladder cancer (MIBC) are unable to receive neoadjuvant chemotherapy, creating an unmet clinical need for alternative systemic treatment. Results from recent neoadjuvant immune checkpoint blockade (ICB) studies signal pCR rates between 31-42%. However, there was a clear dichotomy in response between patients with high vs. low pre-treatment lymphocytic infiltration. In tumors exhibiting immune excluded or immune desert phenotypes, therapeutic strategies to attract CD8+ T cells infiltration prior to ICB may be beneficial. CG0070 is an oncolytic adenovirus designed to preferentially replicate through a transcriptionally regulated promoter that is up-regulated in RB-pathway-defective cells (>70% of MIBC). In addition, CG0070 expresses GM-CSF to attract antigen presenting cells to the tumor microenvironment. We hypothesize that combination therapy using intravesical CG0070 and systemic Nivolumab is 1) safe and 2) can enhance local and systemic treatment response in the neoadjuvant setting against MIBC. Methods: This is a phase Ib trial evaluating 2 doses of nivolumab (4 weeks apart) with 6 weekly intravesical CG0070 followed by cystectomy. Dose-limiting toxicities (DLTs) will be assessed in 6 DLT-evaluable patients in a safety lead-in phase. The combination would be declared tolerable if the incidence of DLTs is Citation Format: Roger Li, Wade Sexton, Phillipe Spiess, Scott Gilbert, Julio Pow-Sang, Jingsong Zhang, Gustavo Borjas, Paola Grandi, James Burke, Rohit Jain, Jose Conejo-Garcia. A Phase 1b Study of CG0070 combined with nivolumab in cisplatin ineligible patients with muscle invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT529.

Introduction: CG0070, is an Ad5-based oncolytic vaccine engineered to express GM-CSF and replicate selectively in tumor cells with mutated or deficient RB. The CG0070 mechanism of action includes cell lysis and immunogenic cell death which is enhanced in the presence of GM-CSF. In an open label ph. 2 study, an overall CR rate of 62% and a CR at 12 months (m) of 29% have been observed in patients with high risk NMIBC previously treated with BCG. IV pembrolizumab, was recently approved by the FDA for patients with BCG-unresponsive CIS (with or without papillary tumors) with an overall complete RR of 41% and a 12 m CR rate of ~20%.This ph. 2 study will assess the potential synergy of the two agents in the treatment of BCG-unresponsive NMIBC. Methods:35 pts with BCG-unresponsive CIS with or without concurrent Ta or T1 disease will be treated with intravescical CG0070 (1x1012 vp) in combination with pembrolizumab at a dose of 400 mg IV q6 weeks. CG0070 will be administered weekly x 6 as induction followed by weekly x 3 maintenance instillations at months 3, 6, 9, 12, and 18. Pts with persistent CIS or HG Ta at 3 m may receive re-induction with weekly x 6 of CG0070. Pembrolizumab will be administered up to 24 m. Assessment of response will include q 3 m cystoscopy with biopsy of areas suspicious for disease, urine cytology, CTU/MRU, and mandatory bladder mapping biopsies at 12 m. Recurrence of HG disease will be enumerated as disease recurrence. The primary endpoint of the study is CR at 12 m. Secondary endpoints will include CR at any time, progression free survival, duration of response, cystectomy free survival and the safety of the combination. Correlate assessments will include changes in the tumor immune microenvironment, systemic immune induction, viral replication and transgene expression. Baseline expression of PD-L1, coxsackie adenovirus receptor, E2F transcription factor as well as anti-Ad5 Ab titer will be correlated with tumor response. Results: Thus far, 10 patients are evaluable at the 3 m timepoint for efficacy. Assessment of these 10 pts demonstrates 100% CR at 3 mos. Six of the 10 pts have also reached the 6 m hallmark in a CR as well as 2 at the 12 mos timepoint. Treatment related AE have been limited to transient grade 1-2 local-regional genitourinary adverse events with no grade 3 or 4 treatment related AE reported date. Conclusions: This initial data on the efficacy and safety of CG0070 plus pembrolizumab for the treatment of BCG unresponsive NMIBC is encouraging. An update on the study will be provided at the time of presentation. Citation Format: Roger Li, Gary Steinberg, Paras Shah, Ed Uchio, Donald Lamm, Trinity Bivalacqua, Vignesh Packiam, Ashish Kamat, Michael Chisamore, John McAdory, Paola Grandi, Jee-Hyun Kim, James Burke. CORE1: Phase 2, single arm study of CG0070 combined with pembrolizumab in patients with non-muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guerin (BCG) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT036.

4597 Background: CG0070, is an Ad5-based oncolytic vaccine engineered to express GM-CSF and replicate selectively in tumor cells with mutated or deficient RB. The CG0070 mechanism of action includes cell lysis and immunogenic cell death which is enhanced in the presence of GM-CSF. In an open label ph. 2 study, an overall CR rate of 62% and a CR at 12 months (m) of 29% have been observed in patients with high risk NMIBC previously treated with BCG. IV pembrolizumab, was recently approved by the FDA for patients with BCG-unresponsive CIS (with or without papillary tumors) with an overall complete RR of 41% and a 12 m CR rate of ̃20%. This ph. 2 study will assess the potential synergy of the two agents in the treatment of BCG-unresponsive NMIBC. Methods: 35 pts with BCG-unresponsive CIS with or without concurrent Ta or T1 disease will be treated with intravescical CG0070 (1x1012 vp) in combination with pembrolizumab at a dose of 400 mg IV q6 weeks. CG0070 will be administered weekly x 6 as induction followed by weekly x 3 maintenance instillations at months 3, 6, 9, 12, and 18. Pts with persistent CIS or HG Ta at 3 m may receive re-induction with weekly x 6 of CG0070. Pembrolizumab will be administered up to 24 m. Assessment of response will include q 3 m cystoscopy with biopsy of areas suspicious for disease, urine cytology, CTU/MRU, and mandatory bladder mapping biopsies at 12 m. Recurrence of HG disease will be enumerated as disease recurrence. The primary endpoint of the study is CR at 12 m. Secondary endpoints will include CR at any time, progression free survival, duration of response, cystectomy free survival and the safety. Correlate assessments will include changes in the tumor immune microenvironment, systemic immune induction,viral replication and transgene expression. Baseline expression of PD-L1, coxsackie adenovirus receptor, E2F transcription factor as well as anti-Ad5 Ab titer will be correlated with tumor response. Results: A CR rate of 87.5% (14/16) at the 3 m assessment timepoint has been observed thus far. All patients in CR at 3 m remain in CR at downstream timepoints including: 9/9 at 6 m, 6/6 at 9 m, and 3/3 at 12 m. Treatment related AE have been generally limited to transient grade 1-2 local-regional genitourinary adverse events with no reports of grade 3, 4 or SAE attributed to treatment with CG0070/Pembroluzimab. Conclusions: This initial data on the efficacy and safety of CG0070 plus pembrolizumab for the treatment of BCG unresponsive NMIBC is encouraging. Additional data on efficacy as well as safety and biomarker (CAR, E2F, and PDL1) assessment will be presented for at least 25 of the projected 35 patients at the time of the conference. Clinical trial information: NCT04387461.

4574 Background: CG0070 is a replication-competent oncolytic adenovirus engineered to target RB deficient tumor cells and to express GM-CSF. CG0070 has previously demonstrated safety and efficacy against BCG-exposed high risk non-muscle invasive bladder cancer through tumor lysis and anti-tumor immune activation. We tested the safety and efficacy of CG0070 in combination with N as neoadjuvant therapy for MIBC in C-ineligible patients in this study (NCT04610671). Methods: C-ineligible pts with MIBC (cT2-4a, N≤1) were enrolled. Pts received 6 weekly intravesical CG0070 (1x1012vp) and 2 doses of N at wks 2 and 6, followed by radical cystectomy (RC). The primary objective is safety of CG0070+N as measured by CTCAEv5.0. Secondary objective is to assess pathologic response (PaR) (pT0N0). Exploratory objectives include the assessment of correlation between PaR with baseline 1) E2F expression; 2) immune infiltration; 3) PD-L1 expression; and 4) TLS expression. Results from a prespecified interim analysis following accrual of 15 patients is reported herein. Results: Between Nov 2020 and Jan 2022, 15 pts were enrolled with median age 75.5yrs, 73% male, 47% > cT2; 1 patient refused RC but was included in the ITT population. No DLTs were encountered. The overall rate of grade 3-4 AEs was 10/15 (75%), and the vast majority were related to RC (90%). Immune related AEs were seen in one pt, who had grade 2 autoimmune thyroiditis. There was no delay in time to RC and no unexpected surgical complications from treatment. PaR was observed in 6/13 (46%) evaluable pts, and an additional pt had negative post-treatment biopsy but refused RC. Conclusions: Neoadjuvant CG0070+N is safe and effective in C-ineligible pts with MIBC. This combination was well tolerated without any delays in RC and induced an overall response rate of 54%. Clinical trial information: NCT04610671. [Table: see text]

The past few years have witnessed important breakthroughs in the identification of compounds that specifically bind and regulate RNAs and in optimizing them for therapeutic use. Here, we review successful and unsuccessful approaches in screening for RNA-targeted small molecules. We discuss advantages and disadvantages of the different screening techniques and variables that affect the outcome of RNA-screening projects. We also highlight key challenges that hamper the development of quality RNA ligands, especially the still-low availability of RNA-specific compound libraries and the poor understanding of RNA structural dynamics. We conclude that the development of new RNA-targeting drugs would greatly benefit from integration of the power of high-throughput screening technologies with improved biochemical, structural, and computational characterization of RNA targets.

It is generally thought that FRII Radio Galaxies host thin optically thick disks, while FRIs are powered by Advected Dominated Accretion Flows. The sources with an efficient engine are optically classified as High Excitation Radio Galaxies (HERGs) and those with an inefficient motor as Low Excitation Radio Galaxies (LERGs). Recently, the study of Radio Galaxies down to mJy fluxes has cast serious doubts on the LERG-FRI and HERG-FRII correspondence, revealing that many LERGs show FRII radio morphologies. The FR catalogs recently compiled by Capetti et al. (2017a,b) and Baldi et al. (2018) have allowed us to explore this issue in the local ($z\le 0.15$) mJy Universe. Our statistical study shows that the majority of nearby mJy objects are in a late stage of their life. FRII-LERGs appear more similar to the old FRI-LERGs than to the young FRII-HERGs. FRII-LERGs may be aged HERGs that, exhausted the cold fuel, have changed their accretion regime or a separate LERG class particularly efficient in launching jets. Exploiting the empirical relations which convert L$_{\rm [OIII]}$ and L$_{\rm 1.4~GHz}$ into accretion power and jet kinetic power, respectively, we observed that LERGs with similar masses and accretion rates seem to expel jets of different power. We speculate that intrinsic differences related to the black hole properties (spin and magnetic field at its horizon) can determine the observed spread in jet luminosity. In this view, FRII-LERGs should have the fastest spinning black holes and/or the most intense magnetic fluxes. On the contrary, compact LERGs (i.e. FR0s) should host extremely slow black holes and/or weak magnetic fields., 16 pages, 5 figures. Accepted for publication in ApJ

We present a detailed study of the galaxy cluster Abell 795 and of its central Fanaroff-Riley Type 0 (FR0) radio galaxy. From an archival Chandra observation, we found a dynamically disturbed environment with evidences for sloshing of the intracluster medium. We argue that the environment alone cannot explain the compactness of the radio galaxy, as similar conditions are also found around extended sources. We identified a pair of putative X-ray cavities in the proximity of the center: These could have been created in a past outburst of the FR0, and dragged away by the large-scale gas movement. The presence of X-ray cavities associated with a FR0 could open a new window on the study of jet power and feedback properties of this recently discovered class of compact radio galaxies., Comment: 5 pages, 2 figures. Accepted for publication in Astronomische Nachrichten. Contribution to the proceedings of the 6th Workshop on CSS and GPS radio sources, held in Toru\'n (Poland) in May 2015 (online meeting)

Aims. The collimation of relativistic jets in galaxies is a poorly understood process. Detailed radio studies of the jet collimation region have been performed so far in few individual objects, providing important constraints for jet formation models. However, the extent of the collimation zone as well as the nature of the external medium possibly confining the jet are still debated. Methods. In this article we present a multi-frequency and multi-scale analysis of the radio galaxy NGC 315, including the use of mm-VLBI data up to 86 GHz, aimed at revealing the evolution of the jet collimation profile. We then consider results from the literature to compare the jet expansion profile in a sample of 27 low-redshift sources, mainly comprising radio galaxies and BL Lacs, classified based on the accretion properties as low-excitation (LEG) and high-excitation (HEG) galaxies. Results.The jet collimation in NGC 315 is completed on sub-parsec scales. A transition from a parabolic to conical jet shape is detected at $z_{t}=0.58\pm0.28$ parsecs or ${\sim}5\times 10^3$ Schwarzschild radii ($R_{S}$) from the central engine, a distance which is much smaller than the Bondi radius, $r_{B}{\sim}92$ $\rm pc$, estimated based on X-ray data. The jet in this and in few other LEGs in our sample may be initially confined by a thick disk extending out to ${\sim}10^3$-$10^4$ $R_{S}$. A comparison between the mass-scaled jet expansion profiles of all sources indicates that jets in HEGs are surrounded by thicker disk-launched sheaths and collimate on larger scales with respect to jets in LEGs. These results suggest that disk winds play an important role in the jet collimation mechanism, particularly in high-luminosity sources. The impact of winds for the origin of the FRI/FRII dichotomy in radio galaxies is also discussed., 14 pages plus appendix, 6 figures. Accepted for publication in A&A

Giant Radio Galaxies (GRGs) are the largest single structures in the Universe. Exhibiting extended radio morphology, their projected sizes range from 0.7 Mpc up to 4.9 Mpc. LOFAR has opened a new window on the discovery and investigation of GRGs and, despite the hundreds that are today known, their main growth catalyst is still debated. One natural explanation for the exceptional size of GRGs is their old age. In this context, hard X-ray selected GRGs show evidence of restarting activity, with the giant radio lobes being mostly disconnected from the nuclear source, if any. In this paper, we present the serendipitous discovery of a distant ($z=0.629$), medium X-ray selected GRG in the Bo\"otes field. High-quality, deep Chandra and LOFAR data allow a robust study of the connection between the nucleus and the lobes, at a larger redshift so far inaccessible to coded-mask hard X-ray instruments. The radio morphology of the GRG presented in this work does not show evidence for restarted activity, and the nuclear radio core spectrum does not appear to be GPS-like. On the other hand, the X-ray properties of the new GRG are perfectly consistent with the ones previously studied with Swift/BAT and INTEGRAL at lower redshift. In particular, the bolometric luminosity measured from the X-ray spectrum is a factor of six larger than the one derived from the radio lobes, although the large uncertainties make them formally consistent at $1\sigma$. Finally, the moderately dense environment around the GRG, traced by the spatial distribution of galaxies, supports recent findings that the growth of GRGs is not primarily driven by underdense environments., Comment: 8 pages, 5 figures. Accepted for publication in A&A

Full list of authors: Abdalla, H.; Abe, H.; Acero, F.; Acharyya, A.; Adam, R.; Agudo, I; Aguirre-Santaella, A.; Alfaro, R.; Alfaro, J.; Alispach, C.; Aloisio, R.; Batista, R. Alves; Amati, L.; Amato, E.; Ambrosi, G.; Anguner, E. O.; Araudo, A.; Armstrong, T.; Arqueros, F.; Arrabito, L.; Asano, K.; Ascasibar, Y.; Ashley, M.; Backes, M.; Balazs, C.; Balbo, M.; Balmaverde, B.; Baquero Larriva, A.; Martins, V. Barbosa; Barkov, M.; Baroncelli, L.; de Almeida, U. Barres; Barrio, J. A.; Batista, P-, I; Becerra Gonzalez, J.; Becherini, Y.; Beck, G.; Tjus, J. Becker; Belmont, R.; Benbow, W.; Bernardini, E.; Berti, A.; Berton, M.; Bertucci, B.; Beshley, V; Bi, B.; Biasuzzi, B.; Biland, A.; Bissaldi, E.; Biteau, J.; Blanch, O.; Bocchino, F.; Boisson, C.; Bolmont, J.; Bonanno, G.; Arbeletche, L. Bonneau; Bonnoli, G.; Bordas, P.; Bottacini, E.; Bottcher, M.; Bozhilov, V; Bregeon, J.; Brill, A.; Brown, A. M.; Bruno, P.; Bruno, A.; Bulgarelli, A.; Burton, M.; Buscemi, M.; Caccianiga, A.; Cameron, R.; Capasso, M.; Caprai, M.; Caproni, A.; Capuzzo-Dolcetta, R.; Caraveo, P.; Carosi, R.; Carosi, A.; Casanova, S.; Cascone, E.; Cauz, D.; Cerny, K.; Cerruti, M.; Chadwick, P.; Chaty, S.; Chen, A.; Chernyakova, M.; Chiaro, G.; Chiavassa, A.; Chytka, L.; Conforti, V; Conte, F.; Contreras, J. L.; Coronado-Blazquez, J.; Cortina, J.; Costa, A.; Costantini, H.; Covino, S.; Cristofari, P.; Cuevas, O.; D'Ammando, F.; Daniel, M. K.; Davies, J.; Dazzi, F.; De Angelis, A.; de Lavergne, M. de Bony; De Caprio, V; dos Anjos, R. de Cassia; Dal Pino, E. M. de Gouveia; De Lotto, B.; De Martino, D.; de Naurois, M.; Wilhelmi, E. de Ona; De Palma, F.; de Souza, V; Delgado, C.; Della Ceca, R.; della Volpe, D.; Depaoli, D.; Di Girolamo, T.; Di Pierro, F.; Diaz, C.; Diaz-Bahamondes, C.; Diebold, S.; Djannati-Atai, A.; Dmytriiev, A.; Dominguez, A.; Donini, A.; Dorner, D.; Doro, M.; Dournaux, J.; Dwarkadas, V. V.; Ebr, J.; Eckner, C.; Einecke, S.; Ekoume, T. R. N.; Elsaesser, D.; Emery, G.; Evoli, C.; Fairbairn, M.; Falceta-Goncalves, D.; Fegan, S.; Feng, Q.; Ferrand, G.; Fiandrini, E.; Fiasson, A.; Fioretti, V; Foffano, L.; Fonseca, M., V; Font, L.; Fontaine, G.; Franco, F. J.; Freixas Coromina, L.; Fukami, S.; Fukazawa, Y.; Fukui, Y.; Gaggero, D.; Galanti, G.; Gammaldi, V; Garcia, E.; Garczarczyk, M.; Gascon, D.; Gaug, M.; Gent, A.; Ghalumyan, A.; Ghirlanda, G.; Gianotti, F.; Giarrusso, M.; Giavitto, G.; Giglietto, N.; Giordano, F.; Glicenstein, J.; Goldoni, P.; Gonzalez, J. M.; Gourgouliatos, K.; Grabarczyk, T.; Grandi, P.; Granot, J.; Grasso, D.; Green, J.; Grube, J.; Gueta, O.; Gunji, S.; Halim, A.; Harvey, M.; Collado, T. Hassan; Hayashi, K.; Heller, M.; Cadena, S. Hernandez; Hervet, O.; Hinton, J.; Hiroshima, N.; Hnatyk, B.; Hnatyk, R.; Hoffmann, D.; Hofmann, W.; Holder, J.; Horan, D.; Horandel, J.; Horvath, P.; Hovatta, T.; Hrabovsky, M.; Hrupec, D.; Hughes, G.; Hutten, M.; Iarlori, M.; Inada, T.; Inoue, S.; Insolia, A.; Ionica, M.; Iori, M.; Jacquemont, M.; Jamrozy, M.; Janecek, P.; Jimenez Martinez, I; Jin, W.; Jung-Richardt, I; Jurysek, J.; Kaaret, P.; Karas, V; Karkar, S.; Kawanaka, N.; Kerszberg, D.; Khelifi, B.; Kissmann, R.; Knodlseder, J.; Kobayashi, Y.; Kohri, K.; Komin, N.; Kong, A.; Kosack, K.; Kubo, H.; La Palombara, N.; Lamanna, G.; Lang, R. G.; Lapington, J.; Laporte, P.; Lefaucheur, J.; Lemoine-Goumard, M.; Lenain, J.; Leone, F.; Leto, G.; Leuschner, F.; Lindfors, E.; Lloyd, S.; Lohse, T.; Lombardi, S.; Longo, F.; Lopez, A.; Lopez, M.; Lopez-Coto, R.; Loporchio, S.; Lucarelli, F.; Luque-Escamilla, P. L.; Lyard, E.; Maggio, C.; Majczyna, A.; Makariev, M.; Mallamaci, M.; Mandat, D.; Maneva, G.; Manganaro, M.; Manico, G.; Marcowith, A.; Marculewicz, M.; Markoff, S.; Marquez, P.; Marti, J.; Martinez, O.; Martinez, M.; Martinez, G.; Martinez-Huerta, H.; Maurin, G.; Mazin, D.; Mbarubucyeye, J. D.; Miranda, D. Medina; Meyer, M.; Micanovic, S.; Miener, T.; Minev, M.; Miranda, J. M.; Mitchell, A.; Mizuno, T.; Mode, B.; Moderski, R.; Mohrmann, L.; Molina, E.; Montaruli, T.; Moralejo, A.; Morales Merino, J.; Morcuende-Parrilla, D.; Morselli, A.; Mukherjee, R.; Mundell, C.; Murach, T.; Muraishi, H.; Nagai, A.; Nakamori, T.; Nemmen, R.; Niemiec, J.; Nieto, D.; Nievas, M.; Nikolajuk, M.; Nishijima, K.; Noda, K.; Nosek, D.; Nozaki, S.; Ohira, Y.; Ohishi, M.; Oka, T.; Ong, R. A.; Orienti, M.; Orito, R.; Orlandini, M.; Orlando, E.; Osborne, J. P.; Ostrowski, M.; Oya, I; Pagliaro, A.; Palatka, M.; Paneque, D.; Pantaleo, F. R.; Paredes, J. M.; Parmiggiani, N.; Patricelli, B.; Pavletic, L.; Pe'er, A.; Pech, M.; Pecimotika, M.; Peresano, M.; Persic, M.; Petruk, O.; Pfrang, K.; Piatteli, P.; Pietropaolo, E.; Pillera, R.; Pilszyk, B.; Pimentel, D.; Pintore, F.; Pita, S.; Pohl, M.; Poireau, V; Polo, M.; Prado, R. R.; Prast, J.; Principe, G.; Produit, N.; Prokoph, H.; Prouza, M.; Przybilski, H.; Pueschel, E.; Puehlhofer, G.; Pumo, M. L.; Punch, M.; Queiroz, F.; Quirrenbach, A.; Rando, R.; Razzaque, S.; Rebert, E.; Recchia, S.; Reichherzer, P.; Reimer, O.; Reimer, A.; Renier, Y.; Reposeur, T.; Rhode, W.; Ribeiro, D.; Ribo, M.; Richtler, T.; Rico, J.; Rieger, F.; Rizi, V; Rodriguez, J.; Fernandez, G. Rodriguez; Ramirez, J. C. Rodriguez; Rodriguez Vazquez, J. J.; Romano, P.; Romeo, G.; Roncadelli, M.; Rosado, J.; de Leon, A. Rosales; Rowell, G.; Rudak, B.; Rujopakarn, W.; Russo, F.; Sadeh, I; Saha, L.; Saito, T.; Greus, F. Salesa; Sanchez, D.; Sanchez-Conde, M.; Sangiorgi, P.; Sano, H.; Santander, M.; Santos, E. M.; Sanuy, A.; Sarkar, S.; Saturni, F. G.; Sawangwit, U.; Scherer, A.; Schleicher, B.; Schovanek, P.; Schussler, F.; Schwanke, U.; Sciacca, E.; Scuderi, S.; Arroyo, M. Seglar; Sergijenko, O.; Servillat, M.; Seweryn, K.; Shalchi, A.; Sharma, P.; Shellard, R. C.; Siejkowski, H.; Sinha, A.; Sliusar, V; Slowikowska, A.; Sokolenko, A.; Sol, H.; Specovius, A.; Spencer, S.; Spiga, D.; Stamerra, A.; Starling, R.; Stolarczyk, T.; Straumann, U.; Striskovic, J.; Suda, Y.; Tagliaferri, G.; Takahashi, H.; Takahashi, M.; Tavecchio, F.; Taylor, L.; Tejedor, L. A.; Temnikov, P.; Terrier, R.; Terzic, T.; Testa, V; Tian, W.; Tibaldo, L.; Tonev, D.; Torres, D. F.; Torresi, E.; Tosti, L.; Tothill, N.; Tovmassian, G.; Travnicek, P.; Truzzi, S.; Tuossenel, F.; Umana, G.; Vacula, M.; Vagelli, V.; Valentino, M.; Vallage, B.; Vallania, P.; van Eldik, C.; Varner, G. S.; Vassiliev, V.; Vazquez Acosta, M.; Vecchi, M.; Veh, J.; Vercellone, S.; Vergani, S.; Verguilov, V.; Vettolani, G. P.; Viana, A.; Vigorito, C. F.; Vitale, V.; Vorobiov, S.; Vovk, I; Vuillaume, T.; Wagner, S. J.; Walter, R.; Watson, J.; White, M.; White, R.; Wiemann, R.; Wierzcholska, A.; Will, M.; Williams, D. A.; Wischnewski, R.; Wolter, A.; Yamazaki, R.; Yanagita, S.; Yang, L.; Yoshikoshi, T.; Zacharias, M.; Zaharijas, G.; Zaric, D.; Zavrtanik, M.; Zavrtanik, D.; Zdziarski, A. A.; Zech, A.; Zechlin, H.; Zhdanov, V., I; Zivec, M., The Cherenkov Telescope Array (CTA), the new-generation ground-based observatory for γ astronomy, provides unique capabilities to address significant open questions in astrophysics, cosmology, and fundamental physics. We study some of the salient areas of γ cosmology that can be explored as part of the Key Science Projects of CTA, through simulated observations of active galactic nuclei (AGN) and of their relativistic jets. Observations of AGN with CTA will enable a measurement of γ absorption on the extragalactic background light with a statistical uncertainty below 15% up to a redshift z=2 and to constrain or detect γ halos up to intergalactic-magnetic-field strengths of at least 0.3 pG . Extragalactic observations with CTA also show promising potential to probe physics beyond the Standard Model. The best limits on Lorentz invariance violation from γ astronomy will be improved by a factor of at least two to three. CTA will also probe the parameter space in which axion-like particles could constitute a significant fraction, if not all, of dark matter. We conclude on the synergies between CTA and other upcoming facilities that will foster the growth of γ cosmology. © 2021 IOP Publishing Ltd and Sissa Medialab., We gratefully acknowledge financial support from the following agencies and organizations: State Committee of Science of Armenia, Armenia; The Australian Research Council, Astronomy Australia Ltd, The University of Adelaide, Australian National University, Monash University, The University of New South Wales, The University of Sydney, Western Sydney University, Australia; Federal Ministry of Education, Science and Research, and Innsbruck University, Austria; Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Ministry of Science, Technology, Innovations and Communications (MCTIC), Brasil; Ministry of Education and Science, National RI Roadmap Project DO1-153/28.08.2018, Bulgaria; The Natural Sciences and Engineering Research Council of Canada and the Canadian Space Agency, Canada; CONICYT-Chile grants CATA AFB 170002, ANID PIA/APOYO AFB 180002, ACT 1406, FONDECYT-Chile grants, 1161463, 1170171, 1190886, 1171421, 1170345, 1201582, Gemini-ANID 32180007, Chile; Croatian Science Foundation, Rudjer Boskovic Institute, University of Osijek, University of Rijeka, University of Split, Faculty of Electrical Engineering, Mechanical Engineering and Naval Architecture, University of Zagreb, Faculty of Electrical Engineering and Computing, Croa tia; Ministry of Education, Youth and Sports, MEYS M2015046, LM2018105, LTT17006, EU/MEYS CZ.02.1.01/0.0/0.0/16_013/0001403, CZ.02.1.01/0.0/0.0/18_046/0016007 and CZ.02.1.01/0.0/0.0/16_019/0000754, Czech Republic; Academy of Finland (grant nr.317636 and 320045), Finland; Ministry of Higher Education and Research, CNRS-INSU and CNRS-IN2P3, CEA-Irfu, ANR, Regional Council Ile de France, Labex ENIGMASS, OCEVU, OSUG2020 and P2IO, France; Max Planck Society, BMBF, DESY, Helmholtz Association, Germany; Department of Atomic Energy, Department of Science and Technology, India; Istituto Nazionale di Astrofisica (INAF), Istituto Nazionale di Fisica Nucleare (INFN), MIUR, Istituto Nazionale di Astrofisica (INAF-OABRERA) Grant Fondazione Cariplo/Regione Lombardia ID 2014-1980/RST_ERC, Italy; ICRR, University of Tokyo, JSPS, MEXT, Japan; Netherlands Research School for Astronomy (NOVA), Netherlands Organization for Scientific Research (NWO), Netherlands; University of Oslo, Norway; Ministry of Science and Higher Education, DIR/WK/2017/12, the National Centre for Research and Development and the National Science Centre, UMO-2016/22/M/ST9/00583, Poland; Slovenian Research Agency, grants P1-0031, P1-0385, I0-0033, J1-9146, J1-1700, N1-0111, and the Young Researcher program, Slovenia; South African Department of Science and Technology and National Research Foundation through the South African Gamma-Ray Astronomy Programme, South Africa; The Spanish groups acknowledge the Spanish Ministry of Science and Innovation and the Spanish Research State Agency (AEI) through grants AYA2016-79724-C4-1-P, AYA2016-80889-P, AYA2016-76012-C3-1-P, BES-2016-076342, FPA2017-82729-C6-1-R, FPA2017-82729-C6-2-R, FPA2017-82729-C6-3-R, FPA2017-82729-C6-4-R, FPA2017-82729-C6-5-R, FPA2017-82729-C6-6-R, PGC2018-095161-B-I00, PGC2018-095512-B-I00, PID2019-107988GB-C22; the “Centro de Excelencia Severo Ochoa” program through grants no. SEV-2016-0597, SEV-2016-0588, SEV-2017-0709, CEX2019-000920-S; the “Unidad de Excelencia María de Maeztu” program through grant no. MDM-2015-0509; the “Ramón y Cajal” programme through grants RYC-2013-14511, RYC-2017-22665; and the MultiDark Consolider Network FPA2017-90566-REDC. They also acknowledge the Atracción de Talento contract no. 2016-T1/TIC-1542 granted by the Comunidad de Madrid; the “Postdoctoral Junior Leader Fellowship” programme from La Caixa Bank ing Foundation, grants no. LCF/BQ/LI18/11630014 and LCF/BQ/PI18/11630012; the “Programa Operativo” FEDER 2014-2020, Consejería de Economía y Conocimiento de la Junta de Andalucía (Ref. 1257737), PAIDI 2020 (Ref. P18-FR-1580) and Universidad de Jaén; “Programa Operativo de Crecimiento Inteligente” FEDER 2014-2020 (Ref. ESFRI-2017-IAC-12), Ministerio de Ciencia e Innovación, 15% co-financed by Consejería de Economía, Industria, Comercio y Conocimiento del Gobierno de Canarias; the Spanish AEI EQC2018-005094-P FEDER 2014-2020; the European Union’s “Horizon 2020” research and innovation programme under Marie Skłodowska-Curie grant agreement no. 665919; and the ESCAPE project with grant no. GA:824064; Swedish Research Council, Royal Physiographic Society of Lund, Royal Swedish Academy of Sciences, The Swedish National Infrastructure for Computing (SNIC) at Lunarc (Lund), Sweden; State Secretariat for Education, Research and Innovation (SERI) and Swiss National Science Foundation (SNSF), Switzerland; Durham University, Leverhulme Trust, Liverpool University, University of Leicester, University of Oxford, Royal Soci ety, Science and Technology Facilities Council, UK; U.S. National Science Foundation, U.S. Department of Energy, Argonne National Laboratory, Barnard College, University of California, University of Chicago, Columbia University, Georgia Institute of Technology, Institute for Nuclear and Particle Astrophysics (INPAC-MRPI program), Iowa State University, the Smithsonian Institution, Washington University McDonnell Center for the Space Sciences, The University of Wisconsin and the Wisconsin Alumni Research Foundation, USA. The research leading to these results has received funding from the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreements No 262053 and No 317446. This project is receiving funding from the European Union’s Horizon 2020 research and innovation programs under agreement No 676134. The research leading to these results has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement GammaRayCascades No 843800. The Fermi LAT Collaboration acknowledges generous ongoing support from a number of agencies and institutes that have supported both the development and the operation of the LAT as well as scientific data analysis. These include the National Aeronautics and Space Administration and the Department of Energy in the United States, the Commissariat à l’Energie Atomique and the Centre National de la Recherche Scientifique / Institut National de Physique Nucléaire et de Physique des Particules in France, the Agenzia Spaziale Italiana and the Istituto Nazionale di Fisica Nucleare in Italy, the Ministry of Education, Culture, Sports, Science and Technology (MEXT), High Energy Accelerator Research Organization (KEK) and Japan Aerospace Exploration Agency (JAXA) in Japan, and the K. A. Wallenberg Foundation, the Swedish Research Council and the Swedish National Space Board in Sweden. Additional support for science analysis during the operations phase is gratefully acknowledged from the Istituto Nazionale di Astrofisica in Italy and the Centre National d’Études Spatiales in France. This work performed in part under DOE Contract DE-AC02-76SF00515.

Lysine methylation of BRD4 selectively determines the recruitment of E2F1 to specific target genes to regulate mRNA translation., The transcriptional coactivator BRD4 has a fundamental role in transcription regulation and thus became a promising epigenetic therapeutic candidate to target diverse pathologies. However, the regulation of BRD4 by posttranslational modifications has been largely unexplored. Here, we show that BRD4 is methylated on chromatin at lysine-99 by the protein lysine methyltransferase SETD6. BRD4 methylation negatively regulates the expression of genes that are involved in translation and inhibits total mRNA translation in cells. Mechanistically, we provide evidence that supports a model where BRD4 methylation by SETD6 does not have a direct role in the association with acetylated histone H4 at chromatin. However, this methylation specifically determines the recruitment of the transcription factor E2F1 to selected target genes that are involved in mRNA translation. Together, our findings reveal a previously unknown molecular mechanism for BRD4 methylation–dependent gene-specific targeting, which may serve as a new direction for the development of therapeutic applications.

TPS598 Background: CG0070 is a serotype 5 adenovirus engineered to express GM-CSF and replicate in cells with mutated or deficient RB, with response rates (RR) of approximately 45% observed in patients with recurrent NMIBC after BCG (J Urol. 2012;188:2391–7; Urol Oncol. 2018;36(10):440–7). This single arm phase 3 study (NCT04452591) was launched to confirm the clinical activity of CG0070 in patients with BCG Unresponsive NMIBC. Methods: 110 patients with BCG-unresponsive CIS with or without concurrent Ta or T1 disease will be treated with intravesical (IVe) CG0070 at a dose of 1x1012 vp. CG0070 will be administered as follows: induction weekly x 6 followed by weekly x 3 maintenance instillations at months 3, 6, 9, 12, and 18. Patients with persistent CIS or HG Ta at 3 months (m) may receive re-induction with weekly x 6 CG0070. Assessment of response will include q 3 m cystoscopy with biopsy of areas suspicious for disease, urine cytology, CTU/MRU, and mandatory bladder mapping at 12 m. Detection of high grade disease within the bladder will be enumerated as recurrence or non-response. The primary endpoint of the study is CR at any time on study as assessed by biopsy (directed to cystoscopic abnormalities and mandatory mapping at 12 m), urine cytology, and radiography, as above. Secondary endpoints include CR at 12 m, duration of response, progression free survival, cystectomy free survival and safety. Correlative assessments include changes in the tumor immune microenvironment, systemic immune induction as reflected in the peripheral blood and urine, as well as viral replication and transgene expression. Baseline expression of coxsackie adenovirus receptor, E2F transcription factor as well as anti-adenovirus antibody titer will be correlated with tumor response. Study enrollment globally is ongoing including in North America, Taiwan, Japan, and South Korea. Refs. Burke JM, Lamm DL, Meng MV, Nemunaitis JJ, Stephenson JJ, Arseneau JC, Aimi J, Lerner S, Yeung AW, Kazarian T, Maslyar DJ, McKiernan JM. A first in human phase 1 study of CG0070, a GM-CSF expressing oncolytic adenovirus, for the treatment of nonmuscle invasive bladder cancer. Clinical trial information: NCT04452591.

Pan-bromodomain and extra terminal domain (BET) inhibitors interact equipotently with the eight bromodomains of the BET family of proteins and have shown profound efficacy in a number of

CRISPR/Cas9–based gene knockouts (KOs) enable precise perturbation of target gene function in human cells, which is ideally assessed in an unbiased fashion by molecular omics readouts. Typically, this requires the lengthy process of isolating KO subclones. We show here that KO subclones are phenotypically heterogenous, regardless of the guide RNA used. We present an experimental strategy that avoids subcloning and achieves fast and efficient gene silencing on cell pools, based on the synergistic combination of two guide RNAs mapping at close (40–300 bp) genomic proximity. Our strategy results in better predictable indel generation with a low allelic heterogeneity, concomitant with low or undetectable residual target protein expression, as determined by MS3 mass spectrometry proteomics. Our method is compatible with nondividing primary cells and can also be used to study essential genes. It enables the generation of high confidence omics data which solely reflect the phenotype of the target ablation.

Bromodomain inhibitors revisited Bromodomain and extraterminal domain (BET) proteins contribute to the pathogenesis of cancer and immune diseases through their effects on transcriptional regulation. BET proteins contain two nearly identical bromodomains, BD1 and BD2, structural modules that have attracted great interest as targets for drug development. First-generation drugs that inhibited both BD1 and BD2 showed promising therapeutic activity in preclinical models but proved to be less efficacious in clinical trials. Gilan et al. took a different approach and designed drugs that selectively inhibited BD1 or BD2 (see the Perspective by Filippakopoulos and Knapp). They found that BD1 and BD2 inhibitors altered gene expression in different ways and that BD2 inhibitors had greater therapeutic activity than BD1 inhibitors in preclinical models of inflammation and autoimmune disease. Science , this issue p. 387 ; see also p. 367

We present the final observations of a complete sample of 37 radio galaxies from the Third Cambridge Catalog (3C) with redshift, 29 pages; accepted for publication on A&A

Fanaroff–Riley type II (FR II) low-excitation radio galaxies (LERGs) are characterized by weak nuclear excitation on parsec-scales and properties typical of powerful FR IIs (defined as high-excitation radio galaxies, hereafter HERGs/BLRGs) on kiloparsec-scales. Since a link between the accretion properties and the power of the produced jets is expected both from theory and observations, their nature is still debated. In this work, we investigate the X-ray properties of a complete sample of 19 FR II-LERGs belonging to the 3CR catalogue, exploiting Chandra and XMM–Newton archival data. We also analyse 32 FR II-HERGs/BLRGs with Chandra data as a control sample. We compared FR II-LERG and FR II-HERG/BLRG X-ray properties and optical data available in literature to obtain a wide outlook of their behaviour. The low accretion rate estimates for FR II-LERGs, from both X-ray and optical bands, allow us to firmly reject the hypothesis as they are the highly obscured counterpart of powerful FR II-HERGs/BLRGs. Therefore, at least two hypothesis can be invoked to explain the FR II-LERG nature: (i) they are evolving from classical FR IIs because of the depletion of accreting cold gas in the nuclear region, while the extended radio emission is the heritage of a past efficiently accreting activity; and (ii) they are an intrinsically distinct class of objects with respect to classical FR Is/FR IIs. Surprisingly, in this direction, a correlation between accretion rates and environmental richness is found in our sample. The richer the environment is, the more inefficient is the accretion. In this framework, the FR II-LERGs are intermediate between FR Is and FR II-HERGs/BLRGs both in terms of accretion rate and environment.

We present observations obtained with the VLT/MUSE optical integral field spectrograph of the radio source 3C277.3, located at a redshift of 0.085 and associated with the galaxy Coma A. An emission line region fully enshrouds the double-lobed radio source, which is ~60 kpc x 90 kpc in size. Based on the emission line ratios, we identified five compact knots in which the gas ionization is powered by young stars located as far as ~60 kpc from the host. The emission line filaments surrounding the radio emission are compatible with ionization from fast shocks (with a velocity of 350-500 km/s), but a contribution from star formation occurring at the edges of the radio source is likely. Coma A might be a unique example in the local Universe in which the expanding outflow triggers star formation throughout the whole radio source., Pre-proofs version - Accepted for publication in A&A

Cancer and inflammation are strongly interconnected processes. Chronic inflammatory pathologies can be at the heart of tumor development; similarly, tumor-elicited inflammation is a consequence of many cancers. The mechanistic interdependence between cancer and inflammatory pathologies points toward common protein effectors which represent potential shared targets for pharmacological intervention. Epigenetic mechanisms often drive resistance to cancer therapy and immunomodulatory strategies. The bromodomain and extraterminal domain (BET) proteins are epigenetic adapters which play a major role in controlling cell proliferation and the production of inflammatory mediators. A plethora of small molecules aimed at inhibiting BET protein function to treat cancer and inflammatory diseases have populated academic and industry efforts in the last 10 years. In this review, we will discuss recent pharmacological approaches aimed at targeting a single or a subset of the eight bromodomains within the BET family which have the potential to tease apart clinical efficacy and safety signals of BET inhibitors.

The sources responsible for the emission of high-energy ($\gtrsim$ 100 TeV) neutrinos detected by IceCube are still unknown. Among the possible candidates, active galactic nuclei with relativistic jets are often examined, since the outflowing plasma seems to offer the ideal environment to accelerate the required parent high-energy cosmic rays. The non-detection of single point sources or -- almost equivalently -- the absence, in the IceCube events, of multiplets originating from the same sky position, constrains the cosmic density and the neutrino output of these sources, pointing to a numerous population of faint sources. Here we explore the possibility that FR0 radiogalaxies, the population of compact sources recently identified in large radio and optical surveys and representing the bulk of radio-loud AGN population, can represent suitable candidates for neutrino emission. Modeling the spectral energy distribution of a FR0 radiogalaxy recently associated to a $\gamma$-ray source detected by the Large Area Telescope onboard Fermi, we derive the physical parameters of its jet, in particular the power carried by it. We consider the possible mechanisms of neutrino production, concluding that $p\gamma$ reactions in the jet between protons and ambient radiation is too inefficient to sustain the required output. We propose an alternative scenario, in which protons, accelerated in the jet, escape from it and diffuse in the host galaxy, producing neutrinos as a result of $pp$ scattering with the interstellar gas, in strict analogy with the processes taking place in star-forming galaxies., Comment: 5 pages, 3 figures, accepted for publication in MNRAS

Em 2015, a constituição dos 17 Objetivos de Desenvolvimento Sustentável (ODS), e as 169 metas a serem implementadas até 2030, instigaram organizações, governos e pessoas a buscarem meios de garantir a redução das desigualdades, o desenvolvimento sustentável e a conservação do meio ambiente. Tomando como referência este cenário, este artigo objetiva analisar a carteira de crédito do Banco Regional de Desenvolvimento do Extremo Sul (BRDE), e apresentar os impactos dos financiamentos desse banco sobre os ODS 8 no Paraná. Para isso, o método escolhido foi o estudo de caso, com coleta de dados em bases do BRDE, IBGE, Ipardes, Celepar e Ipea. Para verificar os impactos financeiros no alcance dos ODS, selecionaram-se os municípios paranaenses que recebem fomento do BRDE, agrupando-os de acordo com seu IFDM. Para avaliar o impacto do BRDE no ODS 8, meta 8.3 no Paraná, considerou-se a média dos empregos formais anuais. A quantidade de empregos criados no BRDE foi avaliada ano a ano, calculando-se o acumulado desde 2016, logo se identificou que o impacto no ODS 8, meta 8.3, foi de 9,50% no estado. O ano mais relevante foi 2018, com impacto de 3,15%. Aponta-se que, no ODS 8, o impacto do BRDE é de até 3% na meta anual, no estado do Paraná. Conclui-se que, apesar de o percentual ser pequeno, quando uma instituição consegue atingir 2 a 3% dos empregos formais no Estado considera-se uma atuação relevante, pois para o atingimento dos ODS é necessário o esforço integrado de diversas instituições.

BackgroundCG0070, an oncolytic vaccine available as an intravesical therapy, is a serotype 5 adenovirus engineered to express GM-CSF and replicate in tumor cells with mutated or deficient RB (which results in increased of the transcription factor E2F). The CG0070 mechanism of action includes direct cell lysis in conjunction with immunogenic cell death which is enhanced in the presence of GM-CSF. In an initial phase 1 study as well as a subsequent phase 2 study, an overall CR rate of ~62% and a CR at 12 months (m) of 29% have been observed in patients with high risk NMIBC previously treated with BCG. Intravenous Pembrolizumab was recently approved by the FDA for patients with BCG-unresponsive CIS (with or without papillary tumors) with an overall complete RR of 41% and a 12m CR rate of ~20%. This phase 2 study (NCT04387461) will assess the potential synergy of the two agents in the treatment of BCG-unresponsive NMIBC.Methods35 patients with BCG-unresponsive CIS with or without concurrent Ta or T1 disease will be treated with intravesical (IVE) CG0070 at a dose of 1x10e12 vp in combination with pembrolizumab at a dose of 400 mg IV q6 weeks. CG0070 will be administered weekly x 6 as induction followed by weekly x 3 maintenance instillations at 3, 6, 9, 12, and 18m. Patients with persistent CIS or HG Ta at 3 m may receive re-induction with weekly x 6 CG0070. Pembrolizumab will be administered up to 24m. Assessment of response will include q 3m cystoscopy with biopsy, urine cytology, CTU/MRU, and mandatory bladder mapping biopsies at 12m.ResultsThe primary endpoint is CR at 12 m. Secondary endpoints will include CR at any time, progression free survival, duration of response, cystectomy free survival and the safety of the combination. Correlate assessments will include changes in the TME, systemic immune induction, viral replication and transgene expression. Baseline expression of PD-L1, coxsackie adenovirus receptor, E2F transcription factor as well as anti-adenovirus antibody titer will be correlated with tumor response. At this time the first 5 patients demonstrates 100% 3 m CR. Treatment related AE have been limited to transient grade 1-2 urinary frequency (3 patients) and grade 1 bladder spasm, hematuria, painful urination, thyroiditis, and flu-like symptoms (one patient/each). No grade 3, 4, 5 AE or SAE were observed.ConclusionsThe study is currently enrolling. Preliminary safety and efficacy data on 8 patients will be available by November 2021Trial RegistrationNCT04387461Ethics ApprovalIRB: CG2003C

BackgroundCG0070 is a serotype 5 adenovirus engineered to express GM-CSF and replicate in cells with mutated or deficient RB, with response rates (RR) of approximately 45% observed in patients with recurrent NMIBC after BCG.1 2 This single arm phase 3 study (NCT04452591) was launched to confirm the clinical activity of CG0070 in patients with BCG Unresponsive NMIBC.Methods110 patients with BCG-unresponsive CIS with or without concurrent Ta or T1 disease will be treated with intravesical (IVe) CG0070 at a dose of 1x10e12 vp. CG0070 will be administered as follows: induction weekly x 6 followed by weekly x 3 maintenance instillations at months 3, 6, 9, 12, and 18. Patients with persistent CIS or HG Ta at 3 m may receive re-induction with weekly x 6 CG0070. Assessment of response will include q 3 m cystoscopy with biopsy of areas suspicious for disease, urine cytology, CTU/MRU, and mandatory bladder mapping at 12 m. Detection of high grade disease within the bladder will be enumerated as recurrence or non-response. The primary endpoint of the study is CR at any time on study as assessed by biopsy (directed to cystoscopic abnormalities and mandatory mapping at 12 m), urine cytology, and radiography, as above. Secondary endpoints include CR at 12 m, duration of response, progression free survival, cystectomy free survival and safety. Correlative assessments include changes in the tumor immune microenvironment, systemic immune induction as reflected in the peripheral blood and urine, as well as viral replication and transgene expression. Baseline expression of coxsackie adenovirus receptor, E2F transcription factor as well as anti-adenovirus antibody titer will be correlated with tumor response. Study enrollment globally is ongoing.Trial RegistrationNCT04452591ReferencePackiam VT, Lamm DL, Barocas DA, Trainer A, Fand B, Davis RL 3rd, Clark W, Kroeger M, Dumbadze I, Chamie K, Kader AK, Curran D, Gutheil J, Kuan A, Yeung AW, Steinberg GD. An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non-muscle-invasive bladder cancer: Interim results. Urol Oncol 2018;36:440–447.Ethics ApprovalCASTLE IRB: BOND-003 (CG3002S)

We analyze VLT/MUSE observations of 37 radio galaxies from the Third Cambridge catalogue (3C) with redshift $, Comment: 40 pages; accepted for publication on A&A

Are better drugs just a click away? Drugs that show promise in preclinical models often fail in the clinic, in part because of limited information on drug localization within cells and across tissues. In a proof-of-concept study, Tyler et al. applied click chemistry methods to study the localization of bromodomain inhibitors. These are cancer drugs that alter chromatin structure and gene expression. Clickable derivatives of the drugs localized within chromatin and showed that the drugs exhibit distinct modes of binding at responsive and unresponsive genes. In a mouse leukemia model, the click-probes revealed that the drugs accumulate to different extents in the spleen and bone marrow, which are two tissue sources of leukemic cells. Science , this issue p. 1397

Quasi-simultaneous observations of the Flat Spectrum Radio Quasar PKS 2326-502 were carried out in the gamma-ray, X-ray, UV, optical, near-infrared, and radio bands. Thanks to these observations we are able to characterize the spectral energy distribution of the source during two flaring and one quiescent gamma-ray states. These data were used to constrain one-zone leptonic models of the spectral energy distributions of each flare and investigate the physical conditions giving rise to them. While modeling one flare only required changes to the electron spectrum, the other flare needed changes in both the electron spectrum and the size of the emitting region with respect to the quiescent state. These results are consistent with an emerging pattern of two broad classes of flaring states seen in blazars., Comment: 18 pages, 3 figures. Accepted in the Astrophysical Journal

The bromodomain of ATAD2 has proved to be one of the least-tractable proteins within this target class. Here, we describe the discovery of a new class of inhibitors by high-throughput screening and show how the difficulties encountered in establishing a screening triage capable of finding progressible hits were overcome by data-driven optimization. Despite the prevalence of nonspecific hits and an exceptionally low progressible hit rate (0.001%), our optimized hit qualification strategy employing orthogonal biophysical methods enabled us to identify a single active series. The compounds have a novel ATAD2 binding mode with noncanonical features including the displacement of all conserved water molecules within the active site and a halogen-bonding interaction. In addition to reporting this new series and preliminary structure-activity relationship, we demonstrate the value of diversity screening to complement the knowledge-based approach used in our previous ATAD2 work. We also exemplify tactics that can increase the chance of success when seeking new chemical starting points for novel and less-tractable targets.

Gene knockouts (KOs) are efficiently engineered through CRISPR-Cas9-induced frameshift mutations. While DNA editing efficiency is readily verified by DNA sequencing, a systematic understanding of the efficiency of protein elimination has been lacking. Here, we devised an experimental strategy combining RNA-seq and triple-stage mass spectrometry (SPS-MS3) to characterize 193 genetically verified deletions targeting 136 distinct genes generated by CRISPR-induced frameshifts in HAP1 cells. We observed residual protein expression for about one third of the quantified targets, at variable levels from low to original, and identified two causal mechanisms, translation reinitiation leading to N-terminally truncated target proteins, or skipping of the edited exon leading to protein isoforms with internal sequence deletions. Detailed analysis of three truncated targets, BRD4, DNMT1 and NGLY1, revealed partial preservation of protein function. Our results imply that systematic characterization of residual protein expression or function in CRISPR-Cas9 generated KO lines is necessary for phenotype interpretation.

Oncolytic viruses induce local tumor destruction and inflammation. Whether virotherapy can also overcome immunosuppression in noninfected tumor areas is under debate. To address this question, we have explored immunologic effects of oncolytic herpes simplex viruses (oHSVs) in a genetically engineered mouse model of isocitrate dehydrogenase (IDH) wild-type glioblastoma, the most common and most malignant primary brain tumor in adults. Our model recapitulates the genomics, the diffuse infiltrative growth pattern, and the extensive macrophage-dominant immunosuppression of human glioblastoma. Infection with an oHSV that was armed with a UL16-binding protein 3 (ULBP3) expression cassette inhibited distant tumor growth in the absence of viral spreading (abscopal effect) and yielded accumulation of activated macrophages and T cells. There was also abscopal synergism of oHSV(ULBP3) with anti–programmed cell death 1 (anti–PD-1) against distant, uninfected tumor areas; albeit consistent with clinical trials in patients with glioblastoma, monotherapy with anti–PD-1 was ineffective in our model. Arming oHSV with ULBP3 led to upregulation of antigen processing and presentation gene sets in myeloid cells. The cognate ULBP3 receptor NKG2D, however, is not present on myeloid cells, suggesting a noncanonical mechanism of action of ULBP3. Overall, the myeloid-dominant, anti–PD-1–sensitive abscopal effect of oHSV(ULBP3) warrants further investigation in patients with IDH wild-type glioblastoma.

We report the discovery of a galaxy overdensity around a Compton-thick Fanaroff-Riley type II (FRII) radio galaxy at z=1.7 in the deep multiband survey around the z=6.3 QSO SDSS J1030+0524. Based on a 6hr VLT/MUSE and on a 4hr LBT/LUCI observation, we identify at least eight galaxy members in this structure with spectroscopic redshift z=1.687-1.699, including the FRII galaxy at z=1.699. Most of the identified overdensity members are blue, compact galaxies that are actively forming stars at rates of $\sim$8-60 $M_{\odot}$ yr$^{-1}$. Based on a 500ks Chandra ACIS-I observation we found that the FRII nucleus hosts a luminous QSO ($L_{2-10keV}=1.3\times10^{44}$ erg s$^{-1}$, intrinsic and rest-frame) that is obscured by Compton-thick absorption ($N_H=1.5\pm0.6\times 10^{24}$ cm$^{-2}$). Our Chandra observation, the deepest so far for a distant FRII within a galaxy overdensity, revealed significant diffuse X-ray emission within the region covered by the overdensity. In particular, X-ray emission extending for $\sim$240 kpc is found around the Eastern lobe of the FRII. Four out of the six MUSE star forming galaxies in the overdensity are distributed in an arc-like shape at the edge of this diffuse X-ray emission. The probability of observing by chance four out of the six $z=1.7$ sources at the edge of the diffuse emission is negligible. In addition, these four galaxies have the highest specific star formation rates of the MUSE galaxies in the overdensity and lie above the main sequence of field galaxies of equal stellar mass at z=1.7. We propose that the diffuse X-rays originate from an expanding bubble of gas that is shock-heated by the FRII jet, and that star formation is promoted by the compression of the cold interstellar medium of the galaxies around the bubble, which may be remarkable evidence of positive AGN feedback on cosmological scales. [shortened version], 17 pages, 13 figures. Accepted for publication in A&A