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\"As the world's deadliest mom forces Robin to make the ultimate choice between his past and future, Superboy finds himself caught in middle in this volume of Super Sons! In this exciting concluding chapter, Talia al Ghul returns for her son Damian, whom she trained from birth to be an assassin. With the evil in Robin's past finally revealed to Superboy, it might be too much for the Sons' partnership to survive...especially when the boys find out her next victim is one of the most important people in their lives!\"-- Provided by publisher.

Background: The DNA-repair gene DNA-dependent kinase catalytic subunit (DNA-PKcs) favours or inhibits carcinogenesis, depending on the cancer type. Its role in human hepatocellular carcinoma (HCC) is unknown. Methods: DNA-dependent protein kinase catalytic subuni, H2A histone family member X (H2AFX) and heat shock transcription factor-1 (HSF1) levels were assessed by immunohistochemistry and/or immunoblotting and qRT–PCR in a collection of human HCC. Rates of proliferation, apoptosis, microvessel density and genomic instability were also determined. Heat shock factor-1 cDNA or DNA-PKcs-specific siRNA were used to explore the role of both genes in HCC. Activator protein 1 (AP-1) binding to DNA-PKcs promoter was evaluated by chromatin immunoprecipitation. Kaplan–Meier curves and multivariate Cox model were used to study the impact on clinical outcome. Results: Total and phosphorylated DNA-PKcs and H2AFX were upregulated in HCC. Activated DNA-PKcs positively correlated with HCC proliferation, genomic instability and microvessel density, and negatively with apoptosis and patient’s survival. Proliferation decline and massive apoptosis followed DNA-PKcs silencing in HCC cell lines. Total and phosphorylated HSF1 protein, mRNA and activity were upregulated in HCC. Mechanistically, we demonstrated that HSF1 induces DNA-PKcs upregulation through the activation of the MAPK/JNK/AP-1 axis. Conclusion: DNA-dependent protein kinase catalytic subunit transduces HSF1 effects in HCC cells, and might represent a novel target and prognostic factor in human HCC.

Background and aim:Previous studies indicate unrestrained cell cycle progression in liver lesions from hepatocarcinogenesis-susceptible Fisher 344 (F344) rats and a block of G1–S transition in corresponding lesions from resistant Brown Norway (BN) rats. Here, the role of the Forkhead box M1B (FOXM1) gene during hepatocarcinogenesis in both rat models and human hepatocellular carcinoma (HCC) was assessed.Methods and results:Levels of FOXM1 and its targets were determined by immunoprecipitation and real-time PCR analyses in rat and human samples. FOXM1 function was investigated by either FOXM1 silencing or overexpression in human HCC cell lines. Activation of FOXM1 and its targets (Aurora Kinose A, Cdc2, cyclin B1, Nek2) occurred earlier and was most pronounced in liver lesions from F344 than BN rats, leading to the highest number of Cdc2–cyclin B1 complexes (implying the highest G2–M transition) in F344 rats. In human HCC, the level of FOXM1 progressively increased from surrounding non-tumorous livers to HCC, reaching the highest levels in tumours with poorer prognosis (as defined by patients’ length of survival). Furthermore, expression levels of FOXM1 directly correlated with the proliferation index, genomic instability rate and microvessel density, and inversely with apoptosis. FOXM1 upregulation was due to extracellular signal-regulated kinase (ERK) and glioblastoma-associated oncogene 1 (GLI1) combined activity, and its overexpression resulted in increased proliferation and angiogenesis and reduced apoptosis in human HCC cell lines. Conversely, FOXM1 suppression led to decreased ERK activity, reduced proliferation and angiogenesis, and massive apoptosis of human HCC cell lines.Conclusions:FOXM1 upregulation is associated with the acquisition of a susceptible phenotype in rats and influences human HCC development and prognosis.

BackgroundAutoreactive proteinase 3 (PR3+) B cells have recently been phenotypically and functionally characterized, and the presence of defective central antigen-independent and peripheral antigen-dependent checkpoints in patients with ANCA-associated vasculitis (AAV) has been shown. This work aimed to investigate the central tolerance-checkpoint controlling immature PR3+ B cells in the bone marrow (BM), before their migration into the periphery as transitional B cells.ObjectivesWe investigated the presence and the specific phenotypic features of PR3+ B cells in BM mononuclear cells (BMMC) of non-vasculitis controls (No-AAV), comparing them to paired peripheral blood mononuclear cells (PBMC) of No-AAV and PBMC of PR3-AAV patients, and the central tolerance-checkpoint for PR3+ B cells.MethodsWe used a customized flow-cytometry assay, using PR3 as ligand to target autoreactive PR3+ B cells (PR3+B cells). Adult PR3-ANCA positive AAV (PR3-AAV) patients with a clinical diagnosis of granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) were selected among consecutive subjects with AAV seen in our Rheumatology Unit. Subjects without vasculitis (No AAV) were selected among consecutive subjects undergoing bone marrow aspirate to exclude hematologic conditions of myeloid origin and eventually resulted healthy or in long-term complete remission during follow-up of myeloid neoplasms. PMBC from AAV patients and paired samples of BMMC and PBMC from No AAV were collected and analyzed.ResultsThe proportion of PR3+ B cells within BMMC (median [IQR25-75%]; 1.98%[1.77-2.75]) was higher than within PBMC of No-AAV (0.9%[0.63-1.44], p<0.01 by paired comparison) and similar to their proportion within PBMC of PR3-AAV patients (1.82%[1.66-3.21]; p>0.05). When focusing on immature/transitional CD24++CD38++B cells only in No-AAV, we observed distinct phenotypes within BMMC versus PBMC (i.e. higher proportion of CD27-CD10+ and lower expression of CD21, IgD, IgM within BMMC versus PBMC), representing two separate developmental steps of B cell maturation. Within CD24++CD38++ B cells, BMMC contained the greatest proportion of PR3+ B cells as compared to PBMC (3.35%[1.99-4.92] versus 1.23%[0.62-1.55], p<0.01). We observed a significant decline of the PR3+ fraction from T1-like/immature subset (IgD-IgM+; 2.80%[1.23-4.02]) to T2-like/early transitional subset (IgD+IgM+; 1.76%[0.96-2.68], p<0.01) in BMMC, while no significant reduction was observed between the latter subset and the transitional compartment of PBMC (1.26%[0.62-1.56], p>0.05).ConclusionTo prevent PR3-related autoimmunity, autoreactive PR3+ B cells pass a stringent selection in the BM, and their removal by central tolerance-checkpoint activity occurs mainly between T1-like/immature to T2-like/early transitional B cells of BMMC.References[1]Cornec D. Identification and phenotyping of circulating autoreactive proteinase 3-specific B cells in patients with PR3-ANCA associated vasculitis and healthy controls. J of Autoimmunity, 2017.[2]Berti A. Circulating autoreactive proteinase 3+ B cells and tolerance checkpoints in ANCA-associated vasculitis. JCI Insight, 2021.Acknowledgements:NIL.Disclosure of InterestsAlvise Berti Speakers bureau: GSK, Michele Tomasi: None declared, Isabella Pesce: None declared, Enrico Lista: None declared, Anna Guella: None declared, Giuseppe Paolazzi: None declared, Roberto Bortolotti: None declared, Guido Grandi: None declared, Sophie Hillion: None declared, Ulrich Specks: None declared, Divi Cornec: None declared.

Very little is known about the influence of environmental radiation on living matter. In principle, important information can be acquired by analysing possible differences between parallel biological systems, one in a reference-radiation environment (RRE) and the other in a low-radiation environment (LRE). We took advantage of the unique opportunity represented by the cell culture facilities at the Gran Sasso National Laboratories of the Istituto Nazionale di Fisica Nucleare, where environment dose rate reduction factors in the underground (LRE), with respect to the external laboratory (RRE), are as follows: 10 3 for neutrons, 10 7 for directly ionizing cosmic rays and 10 for total γ-rays. Chinese hamster V79 cells were cultured for 10 months in both RRE and LRE. At the end of this period, all the cultures were kept in RRE for another 6 months. Changes in the activities of antioxidant enzymes (superoxide dismutase, SOD; catalase, CAT; glutathione peroxidase, GPX) and spontaneous mutation frequency at the hypoxanthine–guanine phosphoribosyl transferase ( hprt) locus were investigated. The results obtained suggest that environmental radiation might act as a trigger of defence mechanisms in V79 cells, specifically those in reference conditions, showing a higher degree of defence against endogenous damage as compared to cells grown in a very low-radiation environment. Our findings corroborate the hypothesis that environmental radiation contributes to the development of defence mechanisms in today living organisms/systems.

The large-scale polarization explorer (LSPE) is a cosmology program for the measurement of large-scale curl-like features (B-modes) in the polarization of the cosmic microwave background. Its goal is to constrain the background of inflationary gravity waves traveling through the universe at the time of matter-radiation decoupling. The two instruments of LSPE are meant to synergically operate by covering a large portion of the northern microwave sky. LSPE/STRIP is a coherent array of receivers planned to be operated from the Teide Observatory in Tenerife, for the control and characterization of the low-frequency polarized signals of galactic origin; LSPE/SWIPE is a balloon-borne bolometric polarimeter based on 330 large throughput multi-moded detectors, designed to measure the CMB polarization at 150 GHz and to monitor the polarized emission by galactic dust above 200 GHz. The combined performance and the expected level of systematics mitigation will allow LSPE to constrain primordial B-modes down to a tensor/scalar ratio of 10 - 2 . We here report the status of the STRIP pre-commissioning phase and the progress in the characterization of the key subsystems of the SWIPE payload (namely the cryogenic polarization modulation unit and the multi-moded TES pixels) prior to receiver integration.

The Q & U Bolometric Interferometer for Cosmology (QUBIC) is a cosmology experiment that aims to measure the B-mode polarization of the cosmic microwave background (CMB). Measurements of the primordial B-mode pattern of the CMB polarization are in fact among the most exciting goals in cosmology as it would allow testing of the inflationary paradigm. Many experiments are attempting to measure the B-modes, from the ground and the stratosphere, using imaging Stokes polarimeters. The QUBIC collaboration developed an innovative concept to measure CMB polarization using bolometric interferometry. This approach mixes the high sensitivity of bolometric detectors with the accurate control of systematics due to the interferometric layout of the instrument. We present the calibration results for the Technological Demonstrator, before its commissioning in the Argentinian observing site and preparation for first light.

QUBIC is a ground-based experiment aiming to measure the B-mode polarization of the cosmic microwave background. The developed instrument is an innovative two-frequency band bolometric interferometer that will operate at 300 mK with NbSi TES arrays. In this paper, we describe the fabrication process of the detectors.

Q & U Bolometric Interferometer for Cosmology (QUBIC) is an international ground-based experiment dedicated in the measurement of the polarized fluctuations of the Cosmic Microwave Background. It is based on bolometric interferometry, an original detection technique which combines the immunity to systematic effects of an interferometer with the sensitivity of low-temperature incoherent detectors. QUBIC will be deployed in Argentina, at the Alto Chorrillos mountain site near San Antonio de los Cobres, in the Salta Province. The QUBIC detection chain consists in 2048 NbSi transition edge sensors (TESs) cooled to 350 mK.The voltage-biased TESs are read out with time domain multiplexing based on Superconducting QUantum Interference Devices at 1 K and a novel SiGe application-specific integrated circuit at 60 K allowing to reach an unprecedented multiplexing factor equal to 128. The QUBIC experiment is currently being characterized in the laboratory with a reduced number of detectors before upgrading to the full instrument. I will present the last results of this characterization phase with a focus on the detectors and readout system.

The Q & U Bolometric Interferometer for Cosmology, QUBIC, is an innovative experiment designed to measure the polarization of the cosmic microwave background and in particular the signature left therein by the inflationary expansion of the Universe. The expected signal is extremely faint; thus, extreme sensitivity and systematic control are necessary in order to attempt this measurement. QUBIC addresses these requirements using an innovative approach combining the sensitivity of transition-edge sensor cryogenic bolometers, with the deep control of systematics characteristic of interferometers. This makes QUBIC unique with respect to others' classical imagers experiments devoted to the CMB polarization. In this contribution, we report a description of the QUBIC instrument including recent achievements and the demonstration of the bolometric interferometry performed in laboratory. QUBIC will be deployed at the observation site in Alto Chorrillos, in Argentina, at the end of 2019.