Summary Metastasis is a major clinical challenge for cancer treatment. Emerging evidence suggests that epigenetic aberrations contribute significantly to tumor formation and progression. However, the drivers and roles of such epigenetic changes in tumor metastasis are still poorly understood. Using bioinformatic analysis of human breast cancer gene expression datasets, we identified histone demethylase RBP2 as a putative mediator of metastatic progression. By using both human breast cancer cells and genetically engineered mice, we demonstrated that RBP2 is critical for breast cancer metastasis to the lung in multiple in vivo models. Mechanistically, RBP2 promotes metastasis as a pleiotropic positive regulator of many metastasis genes. In addition, RBP2 loss suppresses tumor formation in the MMTV-neu transgenic mice. These results suggest that therapeutically targeting RBP2 is a potential strategy to inhibit tumor progression and metastasis.

Basal transcription of human mitochondrial DNA (mtDNA) in vitro requires the single-subunit, bacteriophage-related RNA polymerase, POLRMT, and transcription factor h-mtTFB2. This two-component system is activated differentially at mtDNA promoters by human mitochondrial transcription factor A (h-mtTFA). Mitochondrial ribosomal protein L7/L12 (MRPL12) binds directly to POLRMT, but whether it does so in the context of the ribosome or as a "free" protein in the matrix is unknown. Furthermore, existing evidence that MRPL12 activates mitochondrial transcription derives from overexpression studies in cultured cells and transcription experiments using crude mitochondrial lysates, precluding direct effects of MRPL12 on transcription to be assigned. Here, we report that depletion of MRPL12 from HeLa cells by shRNA results in decreased steady-state levels of mitochondrial transcripts, which are not accounted for by changes in RNA stability. We also show that a significant "free" pool of MRPL12 exists in human mitochondria not associated with ribosomes. "Free" MRPL12 binds selectively to POLRMT in vivo in a complex distinct from those containing h-mtTFB2. Finally, using a fully recombinant mitochondrial transcription system, we demonstrate that MRPL12 stimulates promoter-dependent and promoter-independent transcription directly in vitro. Based on these results, we propose that, when not associated with ribosomes, MRPL12 has a second function in transcription, perhaps acting to facilitate the transition from initiation to elongation. We speculate that this is one mechanism to coordinate mitochondrial ribosome biogenesis and transcription in human mitochondria, where transcription of rRNAs from the mtDNA presumably needs to be adjusted in accordance with the rate of import and assembly of the nucleus-encoded MRPs into ribosomes.TFAM | TFB2M | translation | oxidative phosphorylation | gene expression

Preclinical evidence has demonstrated anti-tumorigenic effects of metformin. The effects of metformin following pancreatic cancer, however, remain undefined. We sought to assess the association between metformin use and survival using a large, nationally representative sample of patients undergoing surgery for pancreatic cancer. Patients undergoing a pancreatic resection between January 01, 2010, and December 31, 2012, were identified using the Truven Health MarketScan database. Clinical data, including history of metformin use, as well as operative details and information on long-term outcomes were collected. Multivariable Cox proportional hazards regression analysis was performed to assess the effect of metformin use on overall survival (OS). A total of 3393 patients were identified. The mean age of patients was 54.2 years (SD = 9.1 years). Roughly one half of patients were female (n = 1735, 51.1 %); 49.1 % (n = 1665) presented with a Charlson comorbidity index of 3 or greater (CCI ≥3); and 19.6 % (n = 664) had diabetes. At the time of surgery, 60.0 % (n = 2034) of patients underwent a pancreaticoduodenectomy, 35.7 % (n = 1212) a partial/distal pancreatectomy, while 4.3 % (n = 147) had a total pancreatectomy. On pathology, 1057 (31.2 %) had lymph node metastasis. Metformin use was identified in 456 patients (13.4 %) and was more commonly administered among patients without locally advanced disease (14.3 vs. 11.6 %, p = 0.038). While OS was comparable between patients within the first year of surgery (OS at 1 year 65.4 % [95 % confidence interval (CI) 63.4-67.3 %] vs. 69.2 % [95 % CI 64.2-73.4 %]), patients who received metformin demonstrated an improved OS beginning at 18 months following surgery. On multivariable analysis adjusting for patient and clinicopathologic characteristics, metformin use was independently associated with a decreased risk of mortality (hazard ratio [HR] = 0.79, 95 % CI 0.67-0.93, p = 0.005). Metformin use was associated with an improved overall survival among patients undergoing pancreatic surgery for pancreatic cancer. Further work is necessary to better understand its role in modifying cancer-specific and overall health outcomes.

BACKGROUND: All-cause readmission rates in patients undergoing ileostomy formation are as high as 20–30%. Dehydration is a leading cause. No predictive model for dehydration readmission has been described. OBJECTIVE: To develop and validate the Dehydration Readmission after Ileostomy Prediction (DRIP) scoring system to predict risk of readmission for dehydration after ileostomy formation. DESIGN: Patients who underwent ileostomy formation were identified using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) dataset (2012–2015). Predictors for dehydration were identified using multivariable logistic regression analysis and translated into point scoring system based on corresponding β coefficients using 2012–2014 data (derivation). Model discrimination was assessed with receiver operating characteristic curves using 2015 data (validation). SETTINGS: This study used the ACS-NSQIP. PATIENTS: A total of 8064 patients (derivation) and 3467 patients (validation) were included from the ACS-NSQIP. MAIN OUTCOME MEASURES: Dehydration readmission within 30 days of operation RESULTS: A total of 8064 patients were in the derivation sample, with 2.9% (20.1% overall) readmitted for dehydration. Twenty-five variables were queried, and seven predictors were identified with points assigned: ASA Class III (4 points), female gender (5 points), ileal pouch anal anastomosis (4 points), age ≥65 years (5 points), shortened length of stay (5 points), ASA Class I-II with inflammatory bowel disease (7 points), and hypertension (9 points). A 39-point, 5-tier risk category scoring system was developed. The model performed well in derivation (AUC=0.71) and validation (AUC=0.74) samples and passed the Hosmer-Lemeshow goodness-of-fit test. LIMITATIONS: Limitations of this study pertained to those of the ACS-NSQIP including: lack of generalizability, lack of ileostomy-specific variables, and inability to capture multiple readmission ICD-9/10 codes. CONCLUSIONS: The DRIP score is a validated scoring system that identifies patients at risk for dehydration readmission after ileostomy formation. It is a specific approach to optimize patient factors, implement interventions, and prevent readmissions. See Video Abstract at http://links.lww.com/DCR/Axxx.