No abstract

Murine B cells express and respond to TLR1, TLR2, TLR4, TLR6, TLR7/8, and TLR9 ligands (6-8), resulting in NF-B activation through MyD88 or TRIF (TIR domain-containing adapter inducing beta interferon)-dependent pathways (9). NF-B activates genes involved in cytokine synthesis, antibody secretion, and cell proliferation (10). The NF-B family includes p105, which is processed into p50 (encoded by Nfkb1), p100 that is processed into p52 (encoded by Nfkb2), RelA (p65), Rel (c-Rel), and RelB, which all interact with DNA as hetero-or homodimers (11). Full TLR signaling in B cells may require major histocompatibility complex class II (MHC-II) interaction with Bruton's tyrosine kinase (Btk) and CD40 (12). However, many aspects of gene regulation involving TLR expression and signal transduction in B cells remain unclear.PU.1 and Spi-B are E26 transformation-specific (ETS) family transcription factors encoded by Sfpi1 and Spib, respectively, and are important in B cell development and function (13). PU.1 is expressed in most hematopoietic cell types, directly regulating many genes involved in cellular communication (14). Spi-B is expressed in B cells, in plasmacytoid dendritic cells, and, at lower levels, in T cells (15). PU.1 and Spi-B share 67% amino acid homology in their DNA binding domain and can bind an identical consensus sequence containing the core motif 5=-GGAA-3= (16-18). Both transcription factors are expressed in B cells, regulate common target genes, and are functionally redundant (19,20 In this study, it was determined whether PU.1 and Spi-B regulate innate immune responses in B cells. Impairment in TLR-mediated proliferation in PUB B cells was observed. Gene and protein expression analysis, luciferase reporter assays, and chromatin im- Citation Li SKH, Abbas AK, Solomon LA, Groux GMN, DeKoter RP. 2015. Nfkb1 activation by the E26 transformation-specific transcription factors PU.1 and Spi-B promotes Toll-like receptor-mediated splenic B cell proliferation.

Objectives: Aromatase inhibitor induced bone loss (AIBL) is a recognised adverse event with resultant increase in fracture risk. We aimed to determine the real-world impact of the 2017 consensus guidelines on AIBL and it is effective in fracture prevention. Methods: Over a 7-year study period, 1001 women prescribed AI were split in two groups. First group were offered bone active treatment based on NOS 2009 guidelines whereas the second group followed the 2017 consensus guidelines. Results: 1001 women were included. First group: 361 women had a baseline DEXA with 143 (40%) women had a normal DEXA, 174 (48%) had osteopenia and 44 (12%) had osteoporosis. Of the women with osteopenia, 44 (25%) women were offered treatment and 22 (13%) women had a fracture. Second group: 640 women had a baseline DEXA with 216 (33%) women were normal, 322(50%) had osteopenia and 107 (17%) had osteoporosis. Of the women with osteopenia, 127 (39%) women were offered treatment and 8 (2.5%) women had a fracture. Conclusions: Our study provides real world evidence of the success of 2017 consensus statement in lowering fracture risk. A significant reduction in fractures pre (13%) and post guidelines change (2.5%) was demonstrated (absolute risk reduction of 10.5%) which has implications for healthcare systems worldwide as we have demonstrated this approach can reduce morbidity.