Histone chaperones are involved in a variety of chromatin transactions. By a proteomics survey, we identified the interaction networks of histone chaperones ASF1, CAF1, HIRA, and NAP1. Here, we analyzed the cooperation of H3/H4 chaperone ASF1 and H2A/H2B chaperone NAP1 with two closely related silencing complexes: LAF and RLAF. NAP1 binds RPD3 and LID-associated factors (RLAF) comprising histone deacetylase RPD3, histone H3K4 demethylase LID/KDM5, SIN3A, PF1, EMSY, and MRG15. ASF1 binds LAF, a similar complex lacking RPD3. ASF1 and NAP1 link, respectively, LAF and RLAF to the DNA-binding Su(H)/Hairless complex, which targets the E(spl) NOTCH-regulated genes. ASF1 facilitates gene-selective removal of the H3K4me3 mark by LAF but has no effect on H3 deacetylation. NAP1 directs high nucleosome density near E(spl) control elements and mediates both H3 deacetylation and H3K4me3 demethylation by RLAF. We conclude that histone chaperones ASF1 and NAP1 differentially modulate local chromatin structure during gene-selective silencing.

Objective To analyse the impact of centralisation of radical cystectomy (RC) provision for bladder cancer in England, on postoperative mortality, length of stay (LoS), complications and re‐intervention rates, from implementation of centralisation from 2003 until 2014. In 2002, UK policymakers introduced the ‘Improving Outcomes Guidance’ (IOG) for urological cancers after a global cancer surgery commission identified substantial shortcomings in provision of care of RCs. One key recommendation was centralisation of RCs to high‐output centres. No study has yet robustly analysed the changes since the introduction of the IOG, to assess a national healthcare system that has mature data on such institutional transformation. Patients and Methods RCs performed for bladder cancer in England between 2003/2004 and 2013/2014 were analysed from Hospital Episode Statistics (HES) data. Outcomes including 30‐day, 90‐day, and 1‐year all‐cause postoperative mortality; median LoS; complication and re‐intervention rates, were calculated. Multivariable statistical analysis was undertaken to describe the relationship between each surgeon and the providers’ annual case volume and mortality. Results In all, 15 292 RCs were identified. The percentage of RCs performed in discordance with the IOG guidelines reduced from 65% to 12.4%, corresponding with an improvement in 30‐day mortality from 2.7% to 1.5% (P = 0.024). Procedures adhering to the IOG guidelines had better 30‐day mortality (2.1% vs 2.9%; P = 0.003) than those that did not, and better 1‐year mortality (21.5% vs 25.6%; P < 0.001), LoS (14 vs 16 days; P < 0.001), and re‐ intervention rates (30.0% vs 33.6%; P < 0.001). Each single extra surgery per centre reduced the odds of death at 30 days by 1.5% (odds ratio [OR] 0.985, 95% confidence interval [CI] 0.977–0.992) and 1% at 1 year (OR 0.990, 95% CI 0.988–0.993), and significantly reduced rates of re‐intervention. Conclusion Centralisation has been implemented across England since the publication of the IOG guidelines in 2002. The improved outcomes shown, including that a single extra procedure per year per centre can significantly reduce mortality and re‐intervention, may serve to offer healthcare planners an evidence base to propose new guidance for further optimisation of surgical provision, and hope for other healthcare systems that such widespread institutional change is achievable and positive.

ObjectiveTo determine whether to use 18 F-fluorodeoxyglucose positron emission tomography (FDG PET) scans in the preoperative staging of bladder cancer (BC). Patients and MethodsIn all, 233 patients with muscle-invasive BC (MIBC) or high-risk non-MIBC being considered for radical cystectomy (RC) between 2005 and 2011 had FDG-PET and computed tomography (CT) of the chest, abdomen and pelvis to assess for pelvic lymph node (LN) involvement or distant metastases. Sensitivity and specificity for detecting pelvic LN involvement was determined by comparing the results of the scans to the histopathology reports in patients undergoing RC. These parameters for distant metastases were determined from biopsy results or follow-up imaging. In patients who did not undergo RC, follow-up imaging was used to evaluate the sensitivity and specificity. Patients were excluded from analysis if they either had neoadjuvant chemotherapy or had <10 LNs removed at lymphadenectomy. ResultsThe PET scan was able to detect metastatic disease outside of the pelvis with a sensitivity of 54% compared with 41% for the staging CT (N = 207). Both scans had similar specificities of 97% and 98%. There were 13 PET avid lesions not visualised on the corresponding staging CT scans. These proved to be metastatic BC (six patients), a synchronous primary colonic cancer (one), colonic adenomas (one), basal cell tumour of the parotid gland (one) and inflammatory lesions (four). The sensitivity and specificity of the CT scans for pelvic LN involvement was 45% and 98%, respectively (N = 93). Using a combination of the PET and CT scan, the sensitivity for detecting metastatic disease in LNs increased to 69% with a 3% reduction in specificity to 95%. ConclusionsPET when used in conjunction with a standard CT scan provides a small improvement in preoperative staging of BC. However, this advantage is not significant enough to justify the additional cost. Hence we recommend use of dual imaging only in highly selected patients.

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