Epigenetic reprogramming at estrogen-receptor binding sites alters 3D chromatin landscape in endocrine-resistant breast cancer

Endocrine therapy resistance frequently develops in estrogen receptor positive (ER+) breast cancer, but the underlying molecular mechanisms are largely unknown. Here, we show that 3-dimensional (3D) chromatin interactions both within and between topologically associating domains (TADs) frequently change in ER+ endocrine-resistant breast cancer cells and that the differential interactions are enriched for resistance-associated genetic variants at CTCF-bound anchors. Ectopic chromatin interactions are preferentially enriched at active enhancers and promoters and ER binding sites, and are associated with altered expression of ER-regulated genes, consistent with dynamic remodelling of ER pathways accompanying the development of endocrine resistance. We observe that loss of 3D chromatin interactions often occurs coincidently with hypermethylation and loss of ER binding. Alterations in active A and inactive B chromosomal compartments are also associated with decreased ER binding and atypical interactions and gene expression. Together, our results suggest that 3D epigenome remodelling is a key mechanism underlying endocrine resistance in ER+ breast cancer

Comparison of colistin monotherapy and non-colistin combinations in the treatment of multi-drug resistant Acinetobacter spp. bloodstream infections: a multicenter retrospective analysis.

OBJECTIVES: To compare the efficacy of colistin (COL) monotherapy versus non-COL based combinations in the treatment of bloodstream infections (BSIs) due to multidrug resistant Acinetobacter spp.(MDR-A). MATERIALS AND METHODS: Retrospective data of 107 MDR-A BSI cases from 27 tertiary centers in Turkey were included. PRIMARY END-POINT: 14-day mortality. SECONDARY END-POINTS: Microbial eradication and clinical improvement. RESULTS: Thirty-six patients in the COL monotherapy (CM) group and 71 in the non-COL based combinations (NCC) group were included in the study. Mean age was 59.98 ± 20 years (range: 18-89) and 50.5% were male. Median duration of follow-up was 40 days (range: 9-297). The 14-day survival rates were 52.8% in CM and 47.23% in NCC group (P = 0.36). Microbiological eradication was achieved in 69% of CM and 83% of NCC group (P = 0.13). Treatment failure was detected in 22.9% of cases in both CM and NCC groups. Univariate analysis revealed that mean age (P = 0.001), Charlson comorbidity index (P = 0.03), duration of hospital stay before MDR-A BSI (P = 0.04), Pitt bacteremia score (P = 0.043) and Acute Physiology and Chronic Health Evaluation II score (P = 0.05) were significant in terms of 14-day mortality. Advanced age (P = 0.01) and duration of hospital stay before MDR-A BSI (P = 0.04) were independently associated with 14-day mortality in multivariate analysis. CONCLUSION: No significant difference was detected between CM and non-COL based combinations in the treatment of MDR-A BSIs in terms of efficacy and 14-day mortality

EFFICACY OF COLISTIN AND NON-COLISTIN MONOTHERAPIES IN MULTI-DRUG

Objective: This retrospective study aimed to investigate the efficacies of colistin and non-colistin monotherapies in multi-drug resistant Acinetobacter baumannii bacteremia (MDR-AB).Materials and methods: Cases with MDR-AB from 27 tertiary-referral hospitals between January 2009 and December 2012 were included. Patients' data that were on either colistin monotherapy (CM) or non-colistin monotherapy (NCM) were compared. Mortality on Day 14 was the primary endpoint, whereas microbiological eradication and clinical outcome were the secondary ones.Results: Eighty-four cases were included in the study with 36 being in the CM group and 48 in the NCM group. Thirty-eight (452%) cases were male and the mean age was 602 years. The mean durations of pre-MDR-AB hospital stay and intensive care unit stay were 25.8 days and 20.9 days, respectively. All of the cases had fever (>38 degrees C). The mean Pitt bacteremia score (PBS) of the patients was calculated as 6.8, APACHE 2 score as 18.9 and the Charlson co-morbidity index (CCI) as 3.7 (CM: 3.6 vs. NCM: 3.9). Twenty (55.6%) cases in the CM group and 26 cases in the NCM group (542%) (p=0.81) died; 9 cases in the CM group (25%) and 16 cases in the NCM group (33 3%) had treatment failure (P=0.55). Bacteriological eradication was achieved in 20 (55.6%) cases in the CM group and in 36 cases (75%) in the NCM group (P=0.061).Conclusions: No significant difference could be identified between the colistin monotherapy and non-colistin monotherapy options in MDR-AB cases with respect to the results of efficacy and 14-day mortality