Interactions between tumor cells and cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TMEN) significantly influence cancer growth and metastasis. Transforming growth factor-β (TGF-β) is known to be a critical mediator of the CAF phenotype, and osteopontin (OPN) expression in tumors is associated with more aggressive phenotypes and poor patient outcomes. The potential link between these two pathways has not been previously addressed. Utilizing in vitro studies using human mesenchymal stem cells (MSCs) and MDA-MB231 (OPN+) and MCF7 (OPN−) human breast cancer cell lines, we demonstrate that OPN induces integrin-dependent MSC expression of TGF-β1 to mediate adoption of the CAF phenotype. This OPN-TGF-β1 pathway requires the transcription factor, myeloid zinc finger 1 (MZF1). In vivo studies with xenotransplant models in NOD-scid mice showed that OPN expression increases cancer growth and metastasis by mediating MSC-to-CAF transformation in a process that is MZF1- and TGF-β1-dependent. We conclude that tumor-derived OPN engenders MSC-to-CAF transformation in the microenvironment to promote tumor growth and metastasis via the OPN-MZF1-TGF-β1 pathway.

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Background There is growing concern that the quality of inpatient care may differ on weekends versus weekdays. We assessed the “weekend effect” in common urgent general operative procedures. Methods The Healthcare Cost and Utilization Project Florida State Inpatient Database (2007–2010) was queried to identify inpatient stays with urgent or emergent admissions and surgery on the same day. Included were patients undergoing appendectomy, cholecystectomy for acute cholecystitis, and hernia repair for obstructed/gangrenous hernia. Outcomes included duration of stay, inpatient mortality, hospital-adjusted charges, and postoperative complications. Controlling for hospital and patient characteristics and type of surgery, we used multilevel mixed-effects regression modeling to examine associations between patient outcomes and admissions day (weekend vs weekday). Results A total of 80,861 same-day surgeries were identified, of which 19,078 (23.6%) occurred during the weekend. Patients operated on during the weekend had greater charges by $185 (P < .05), rates of wound complications (odds ratio [OR] 1.29, 95% confidence interval [95% CI] 1.05–1.58; P <.05), and urinary tract infection (OR 1.39, 95% CI 1.05–1.85; P < .05). Patients undergoing appendectomy had greater rates of transfusion (OR 1.43, 95% CI 1.09–1.87; P = .01), wound complications (OR 1.32, 95% CI 1.04–1.68; P < .05), urinary tract infection (OR 1.76, 95% CI 1.17–2.67; P < .01), and pneumonia (OR 1.41, 95% CI 1.05–1.88; P < .05). Patients undergoing cholecystectomy had a greater duration of stay (P = .001) and greater charges (P = .003). Conclusion Patients undergoing weekend surgery for common, urgent general operations are at risk for increased postoperative complications, duration of stay, and hospital charges. Because the cause of the “weekend effect” is still unknown, future studies should focus on elucidating the characteristics that may overcome this disparity.

The epithelial to mesenchymal transition (EMT) is implicated in many processes, ranging from tissue and organogenesis to cancer and metastatic spread. Understanding the key regulatory mechanisms and mediators within this process offers the opportunity to develop novel therapeutics with broad clinical applicability. To date, several components of EMT already are targeted using pharmacologic agents in fibrosis and cancer. As our knowledge of EMT continues to grow, the potential for novel therapeutics will also increase. This review focuses on the role of EMT both as a necessary part of development and a key player in disease progression, specifically the similarity in pathways used during both processes as targets for drug development. Also, the key role of the tumor microenvironment with EMT is outlined, focusing on both co-factors and cell types with the ability to modulate the progression of EMT in cancer and metastatic disease. Lastly, we discuss the current status of clinical therapies both in development and those progressed to clinical trial specifically targeting pathologic EMTs including small molecule inhibitors, non-coding RNAs, exogenous co-factors, and adjunctive therapies to current chemotherapeutics.

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Objective We hypothesized that perioperative hospital resources could overcome the “weekend effect” (WE) in patients undergoing emergent/urgent surgeries. Summary Background Data The WE is the observation that surgeon-independent patient outcomes are worse on the weekend compared with weekdays. The WE is often explained by differences in staffing and resources resulting in variation in care between the week and weekend. Methods Emergent/urgent surgeries were identified using the Healthcare Cost and Utilization Project State Inpatient Database (Florida) from 2007 to 2011 and linked to the American Hospital Association (AHA) Annual Survey Database to determine hospital level characteristics. Extended median length of stay (LOS) on the weekend compared with the weekdays (after controlling for hospital, year, and procedure type) was selected as a surrogate for WE. Results Included were 126,666 patients at 166 hospitals. A total of 17 hospitals overcame the WE during the study period. Logistic regression, controlling for patient characteristics, identified full adoption of electronic medical records (OR 4.74), home health program (OR 2.37), pain management program [odds ratio (OR) 1.48)], increased registered nurse-to-bed ratio (OR 1.44), and inpatient physical rehabilitation (OR 1.03) as resources that were predictors for overcoming the WE. The prevalence of these factors in hospitals exhibiting the WE for all 5 years of the study period were compared with those hospitals that overcame the WE (P <0.001). Conclusions Specific hospital resources can overcome the WE seen in urgent general surgery procedures. Improved hospital perioperative infrastructure represents an important target for overcoming disparities in surgical care.

Background: Alcohol (EtOH) exposure has detrimental effects on fracture healing. Results: EtOH inhibits TGF-␤1 protein expression via interference with the transcription factor myeloid zinc finger 1. Conclusion: EtOH-induced deficient fracture healing may be related to reduced TGF-␤1. Significance: Further understanding of the mechanisms responsible for the effects of EtOH are crucial for the development of interventions aimed at averting morbidities related to EtOH consumption.

Osteopontin (OPN) promotes hepatic fibrosis, and developing therapies targeting OPN expression in settings of hepatic injury holds promise. The polyphenol epigallocatechin-3-gallate (EGCG), found in high concentrations in green tea, downregulates OPN expression through OPN mRNA degradation, but the mechanism is unknown. Previous work has shown that microRNAs can decrease OPN mRNA levels, and other studies have shown that EGCG modulates the expression of multiple microRNAs. In our study, we first demonstrated that OPN induces hepatic stellate cells to transform into an activated state. We then identified three microRNAs which target OPN mRNA: miR-181a, miR-10b, and miR-221. In vitro results show that EGCG upregulates all three microRNAs, and all three microRNAs are capable of down regulating OPN mRNA when administered alone. Interestingly, only miR-221 is necessary for EGCG-mediated OPN mRNA degradation and miR-221 inhibition reduces the effects of EGCG on cell function. In vivo experiments show that thioacetamide (TAA)-induced cell cytotoxicity upregulates OPN expression; treatment with EGCG blocks the effects of TAA. Furthermore, chronic treatment of EGCG in vivo upregulates all three microRNAs equally, suggesting that in more chronic treatment all three microRNAs are involved in modulating OPN expression. We conclude that in in vitro and in vivo models of TAA-induced hepatic fibrosis, EGCG inhibits OPN-dependent injury and fibrosis. EGCG works primarily by upregulating miR-221 to accelerate OPN degradation. EGCG may therefore have utility as a protective agent in settings of liver injury.