Chemotherapy resistance frequently drives tumour progression. However, the underlying molecular mechanisms are poorly characterized. Epithelial-to-mesenchymal transition (EMT) has been shown to correlate with therapy resistance, but the functional link and signalling pathways remain to be elucidated. We report here that miR-30c, a human breast tumour prognostic marker, plays a pivotal role in chemo-resistance by a direct targeting of TWF1, which encodes an actin-binding protein and promotes EMT. An IL-6 family member, IL-11 was identified as a secondary target of TWF1 in the miR-30c signalling pathway. Expression of miR-30c inversely correlated with TWF1 and IL-11 levels in primary breast tumours and low IL-11 correlated with relapse-free survival in breast cancer patients. Our study demonstrates that miR-30c is transcriptionally regulated by GATA3 in breast tumours. Identification of a novel miRNA-mediated pathway that regulates chemo-resistance in breast cancer will facilitate the development of novel therapeutic strategies.

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Objective Rapid response team (RRT) activation criteria were created using expert opinion and have demonstrated variable accuracy in previous studies. We developed a cardiac arrest risk triage (CART) score to predict cardiac arrest (CA) and compared it to the Modified Early Warning Score (MEWS), a commonly cited RRT activation criterion. Design A retrospective cohort study. Setting An academic medical center in the United States. Patients All patients hospitalized from November 2008 to January 2011 who had documented ward vital signs were included in the study. These patients were divided into three cohorts: patients who suffered a CA on the wards, patients who had a ward to intensive care unit (ICU) transfer, and patients who had neither of these outcomes (controls). Interventions None. Measurements and Main Results Ward vital signs from admission until discharge, ICU transfer, or ward CA were extracted from the medical record. Multivariate logistic regression was used to predict CA, and the CART score was calculated using the regression coefficients. The model was validated by comparing its accuracy for detecting ICU transfer to the MEWS. Each patient’s maximum score prior to CA, ICU transfer, or discharge was used to compare the areas under the receiver operating characteristic curves (AUC) between the two models. Eighty-eight CA patients, 2820 ICU transfers, and 44519 controls were included in the study. The CART score more accurately predicted CA than the MEWS (AUC 0.84 vs. 0.76;P=0.001). At a specificity of 89.9%, the CART score had a sensitivity of 53.4% compared to 47.7% for the MEWS. The CART score also predicted ICU transfer better than the MEWS (AUC 0.71 vs. 0.67;P<0.001). Conclusions The CART score is simpler and more accurately detected CA and ICU transfer than the MEWS. Implementation of this tool may decrease RRT resource utilization and provide a better opportunity to improve patient outcomes than the MEWS.

OBJECTIVE To estimate whether metformin use by ovarian cancer patients with type II diabetes was associated with improved survival. METHODS We reviewed the effect of diabetes and diabetes medications on ovarian cancer treatment and outcomes in a single-institution retrospective cohort. Inclusion criteria were International Federation of Gynecology and Obstetrics (FIGO) stage I–IV epithelial ovarian, fallopian or peritoneal cancer. Exclusion criteria were noninvasive pathology or non-epithelial malignancies. The primary exposures analyzed were history of type II diabetes and diabetes medications. The primary outcomes were progression-free and overall ovarian cancer survival. RESULTS Of the 341 ovarian cancer patients included in the study, 297 did not have diabetes, 28 were type II diabetic patients who did not take metformin, and 16 were type II diabetic patients who used metformin. The progression-free survival at five years was 51% for diabetic patients who used metformin compared to 23% for the nondiabetic patients and 8% for the diabetic patients who did not use metformin (P=.03). The overall survival at 5 years was 63%, 37%, and 23% for the diabetic patients who used metformin, the nondiabetic patients, and the diabetic patients who did not use metformin, respectively (P=.03). The patients with diabetes received the same treatment for ovarian cancer as the patients without diabetes. The association of metformin use and increased progression-free survival, but not overall survival, remained significant after controlling for standard clinico-pathologic parameters. CONCLUSION In this ovarian cancer cohort, the patients with type II diabetes who used metformin had longer progression-free survival, despite receiving similar treatment for ovarian cancer.

Objective Over 200,000 in-hospital cardiac arrests (CAs) occur in the U.S. each year and many of these events may be preventable. Current vital sign-based risk scores for ward patients have demonstrated limited accuracy, which leads to missed opportunities to identify those patients most likely to suffer CA and inefficient resource utilization. We derived and validated a prediction model for CA while treating intensive care unit (ICU) transfer as a competing risk using electronic health record (EHR) data. Design A retrospective cohort study. Setting An academic medical center in the United States with approximately 500 inpatient beds. Patients Adult patients hospitalized from November 2008 until August 2011 who had documented ward vital signs. Interventions None. Measurements and Main Results Vital sign, demographic, location, and laboratory data were extracted from the EHR and investigated as potential predictor variables. A person-time multinomial logistic regression model was used to simultaneously predict CA and ICU transfer. The prediction model was compared to the VitalPAC™ Early Warning Score (ViEWS) using the area under the receiver operating characteristic curve (AUC) and was validated using three-fold cross validation. A total of 56,649 controls, 109 CA patients, and 2,543 ICU transfers were included. The derived model more accurately detected CA (AUC 0.88 vs. 0.78; P<0.001) and ICU transfer (AUC 0.77 vs. 0.73; P<0.001) than the ViEWS, and accuracy was similar with cross-validation. At a specificity of 93%, our model had a higher sensitivity than the ViEWS for CA patients (65% vs. 41%). Conclusions We developed and validated a prediction tool for ward patients that can simultaneously predict the risk of CA and ICU transfer. Our model was more accurate than the ViEWS and could be implemented in the EHR to alert caregivers with real-time information regarding patient deterioration.

This study was performed to investigate the association between FSH receptor (FSHR) gene polymorphism at position 680 and the outcomes of controlled ovarian hyperstimulation (COH) for in vitro fertilization and embryo transfer (IVF-ET) in Korean women. Two hundred and sixty-three patients under 40 years of age who underwent IVF-ET procedures were included in this study. Patients with polycystic ovary syndrome, endometriosis, or a previous history of ovarian surgery were excluded. Following extraction of genomic DNA, the FSHR polymorphism at position 680 was determined by polymerase chain reaction and restriction fragment length polymorphism analysis. The FSHR genotype distribution was 41.8% for Asn/ Asn, 45.6% for Asn/Ser, and 12.5% for Ser/Ser FSHR genotype groups. Although there was no difference among the three genotype groups in terms of the age and infertility diagnosis of study subjects, the basal levels of FSH (day 3) were significantly different [5.7 ± 0.3 IU/l (mean±SEM), 6.0 ± 0.3 IU/l, and 8.2 ± 0.9 IU/l for Asn/Asn, Asn/Ser, and Ser/Ser groups, respectively. The Ser/Ser group tended to require a higher dose of gonadotropins for COH, and tended to show lower serum estradiol levels at the time of hCG administration than the other two groups, though these differences did not reach statistical significance. The numbers of oocytes retrieved tended to be different for the three groups (9.6 ± 0.6, 10.2 ± 0.6, and 7.9 ± 0.8 for Asn/Asn, Asn/Ser, and Ser/Ser groups, respectively). Clinical pregnancy rate was significantly higher in Asn/Asn, compared to the others (45.7 vs. 30.5%, P=0.013). The homozygous Ser/Ser genotype of FSHR polymorphism at position 680 may be associated with a reduced ovarian response to COH for IVF-ET, while Asn/Asn genotypes showed a higher pregnancy rate.

The beneficial paracrine roles of mesenchymal stem cells (MSCs) in tissue repair have potential in therapeutic strategies against various diseases. However, the key therapeutic factors secreted from MSCs and their exact molecular mechanisms of action remain unclear. In this study, the cell-free secretome of umbilical cord-derived MSCs showed significant anti-fibrotic activity in the mouse models of liver fibrosis. The involved action mechanism was the regulation of hepatic stellate cell activation by direct inhibition of the TGF/Smad-signaling. Antagonizing the milk fat globule-EGF factor 8 (MFGE8) activity blocked the anti-fibrotic effects of the MSC secretome in vitro and in vivo. Moreover, MFGE8 was secreted by MSCs from the umbilical cord as well as other tissues, including teeth and bone marrow. Administration of recombinant MFGE8 protein alone had a significant anti-fibrotic effect in two different models of liver fibrosis. Additionally, MFGE8 downregulated TGF type I receptor expression by binding to v3 integrin on HSCs. These findings revealed the potential role of MFGE8 in modulating TGF-signaling. Thus, MFGE8 could serve as a novel therapeutic agent for liver fibrosis. [BMB Reports 2017; 50(2): 58-59]