Distinct signals and immune cells drive liver pathology and glomerulonephritis in ABIN1[D485N] mice

We report that TLR7, IL-6, and the adaptive immune system are essential for autoimmunity and glomerulonephritis but not for liver pathology in mice expressing the ubiquitin-binding-defective ABIN1[D485N] mutant. The blood and organs of ABIN1[D485N] mice have exceptionally high numbers of patrolling monocytes (pMo), which develop independently of IL-6 and the adaptive immune system. They are detectable in the blood months before autoimmunity and organ pathology are seen and may have diagnostic potential. The splenic pMo, inflammatory monocytes (iMo), and neutrophils of ABIN1[D485N] mice expressed high levels of mRNAs encoding proteins released during NETosis, which together with the high numbers of monocyte-derived dendritic cells (MoDCs) may drive the liver pathology in ABIN1[D485N] mice, and contribute to the pathology of other organs. The splenic iMo of ABIN1[D485N] mice displayed high expression of mRNAs encoding proteins controlling cell division and were actively dividing; this may underlie the increased pMo and MoDC numbers, which are derived from iMo. An orally active IRAK4 inhibitor suppressed all facets of the disease phenotype and prevented the increase in pMo numbers

Pelvic bone anatomy vs implanted gold seed marker registration for image-guided intensity modulated radiotherapy for prostate carcinoma: Comparative analysis of inter-fraction motion and toxicities

Objectives: We compared the prostate motion variability and toxicities between patients treated with gold marker registration based IG-IMRT (IG-IMRT-M) and bony landmark registration based IG-IMRT (IG-IMRT-B). Methods: T1c-T3b (node negative), intermediate and high risk (non-metastatic) adenocarcinoma of prostate, age ≥18 years, Karnofsky Performance Status of ≥70 were included in this retrospective study. The prostate motion variability, acute and late radiation toxicities between the two treatment arms (IG-IMRT-M versus IG-IMRT-B) were compared. Results: Total of 35 patients (17 for IG-IMRT-M and 18 for IG-IMRT-B) were treated with a median radiotherapy dose of 76 Gray. The prostate variability observed with and without markers in millimeter was 4.1 ± 2.3 vs 3.7 ± 2.1 [Antero-Posterior (A-P); p = 0.001], 2.3 ± 1.5 vs 2.1 ± 1.2 [Superior-Inferior (S-I); p = 0.095] and 1.1 ± 1.7 vs 0.4 ± 1.4 [Left-Right (L-R); p = 0.003]. There was higher acute toxicity in IG-IMRT-B arm compared to IG-IMRT-M arm in terms of grade ≥2 diarrhea [50% vs 11% OR = 7.5 (1.3–42.7); p = 0.02] and grade ≥2 proctitis [38% vs 5.8%, OR = 10.1 (1.09–94.1); p = 0.04]. At a median follow up of 36 months, the late genitourinary toxicities grade ≥2 [27% vs 0%; p = 0.04] were higher in the IG-IMRT-B arm compared to IG-IMRT-M arm. Conclusions: IG-IMRT-M detects higher prostate motion variability as compared to IG-IMRT-B, inferring a significant prostate motion inside fixed pelvic bony cavity. The addition of marker based image guidance results in higher precision of prostate localization and lesser acute and late toxicities

Suppression of interferon β gene transcription by inhibitors of bromodomain and extra-terminal (BET) family members

PLK (Polo-like kinase) inhibitors, such as BI-2536, have been reported to suppress IFNB (encoding IFNβ, interferon β) gene transcription induced by ligands that activate TLR3 (Toll-like receptor 3) and TLR4. In the present study, we found that BI-2536 is likely to exert this effect by preventing the interaction of the transcription factors IRF3 (interferon-regulatory factor 3) and c-Jun with the IFNB promoter, but without affecting the TBK1 {TANK [TRAF (tumour-necrosis-factor-receptor-associated factor)-associated nuclear factor κB activator]-binding kinase 1}-catalysed phosphorylation of IRF3 at Ser396, the dimerization and nuclear translocation of IRF3 or the phosphorylation of c-Jun and ATF2 (activating transcription factor 2). Although BI-2536 inhibits few other kinases tested, it interacts with BET (bromodomain and extra-terminal) family members and displaces them from acetylated lysine residues on histones. We found that BET inhibitors that do not inhibit PLKs phenocopied the effect of BI-2536 on IFNB gene transcription. Similarly, BET inhibitors blocked the interaction of IRF5 with the IFNB promoter and the secretion of IFNβ induced by TLR7 or TLR9 ligands in the human plasmacytoid dendritic cell line GEN2.2, but without affecting the nuclear translocation of IRF5. We found that the BET family member BRD4 (bromodomain-containing protein 4) was associated with the IFNB promoter and that this interaction was enhanced by TLR3- or TLR4-ligation and prevented by BI-2536 and other BET inhibitors. Our results establish that BET family members are essential for TLR-stimulated IFNB gene transcription by permitting transcription factors to interact with the IFNB promoter. They also show that the interaction of the IFNB promoter with BRD4 is regulated by TLR ligation and that BI-2536 is likely to suppress IFNB gene transcription by targeting BET family members