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Development of chemoresistance is a persistent problem during cancer treatment. Long non-coding RNAs (LncRNAs) are currently emerging as an integral functional component of the human genome and as critical regulators of cancer development and progression. In the present study, we investigated the role and molecular mechanism of H19 lncRNA in chemoresistance development by using doxorubicin (Dox) resistance in breast cancer cells as a model system. H19 lncRNA expression was significantly increased in anthracycline-treated and Dox-resistant MCF-7 breast cancer cells. This H19 overexpression was contributed to cancer cell resistance to anthracyclines and paclitaxel as knockdown of H19 lncRNA by a specific H19 shRNA in Dox-resistant cells significantly improved the cell sensitivity to anthracyclines and paclitaxel. Furthermore, gene expression profiling analysis revealed that a total of 192 genes were associated with H19-mediated Dox resistance. These genes were enriched in multiple KEGG pathways that are related to chemoresistance. Using genetic and pharmacological approaches, we demonstrated that MDR1 and MRP4 were major effectors of H19-regulated Dox resistance in breast cancer cells as MDR1 and MRP4 expression was markedly elevated in Dox-resistant cells while dramatically reduced when H19 was knocked down. Moreover, we found that CUL4A, an ubiquitin ligase component, was a critical factor bridging H19 lncRNA to MDR1 expression, and a high tumor CUL4A expression was associated with low survival in breast cancer patients treated with chemotherapy. These data suggest that H19 lncRNA plays a leading role in breast cancer chemoresistance, mediated mainly through a H19-CUL4A-ABCB1/MDR1 pathway.
chemoresistance, lncRNA H19, CUL4A, ABCB1, breast cancer
LncRNA H19 is a major mediator of doxorubicin chemoresistance in breast cancer cells through a cullin4A-MDR1 pathway
Qiong-Ni Zhu,1 Guo Wang,1 Ying Guo,1 Yan Peng,1 Rui Zhang,1 Jun-Li Deng,1 Zhi-Xing Li,1 and Yuan-Shan Zhu1,2
2017 Nov 3;
Rationale: Although gastrostomy tubes have shown to be of limited benefit in patients with advanced dementia, they continue to be used to deliver nutritional support in critically ill patients. The epidemiology and short-term outcomes are unclear.
Objectives: To quantify national practice patterns and short-term outcomes of gastrostomy tube placement among the critically ill over the last two decades in the United States.
Methods: Using the U.S. Agency for Healthcare and Research Quality’s Healthcare Cost and Utilization Project’s National Inpatient Sample, we evaluated trends in annual population-standardized rates of gastrostomy tube placement among critically ill adults from 1994 to 2014; we also quantified trends in length of stay, in-hospital mortality, and discharge location. We conducted sensitivity analyses among mechanically ventilated patients, survivors, and decedents of critical illness, and in a critically ill population excluding patients with dementia.
Results: From 1994 to 2014, population-based rates of gastrostomy tube use in critically ill patients increased from 11.9 to 28.8 gastrostomies per 100,000 U.S. adults (peak in incidence in 2010), an increase of 142% (31,392-91,990 gastrostomy tubes in critically ill patients; P < 0.001). Patients receiving gastrostomy tubes during critical illness occupied a growing proportion of all gastrostomy tube placements, accounting for 19.6% of all gastrostomy tubes placed in 1994 and 50.8% in 2014. The rate of gastrostomies in critically ill patients remained roughly stable, from 2.5% of critically ill patients in 1994 to a peak of 3.7% in 2002 before declining again to 2.4% in 2014. Hospital length of stay and in-hospital mortality decreased among gastrostomy tube recipients (28.7 d to 20.5 d, P < 0.001; 25.9-11.3%, P < 0.001; respectively), whereas discharges to long-term facilities increased significantly (49.6-70.6%; P < 0.001). Sensitivity analyses among mechanically ventilated patients revealed similar increases in population-based estimates of gastrostomy tube placement. Conclusions: The incidence of gastrostomy tube placement among critically ill patients more than doubled between 1994 and 2014, with most patients being discharged to long-term care facilities. Critically ill patients are now the primary utilizer of gastrostomy tubes placed in the United States. Additional research is needed to better characterize the long-term risk and benefits of gastrostomy tube use in critically ill patients.
gastrostomy, critical illness, patient care planning
Gastrostomy Tube Use in the Critically Ill, 1994-2014
Anica C. Law,corresponding author1,2 Jennifer P. Stevens,1,2 and Allan J. Walkey3,4,5,*
To describe the epidemiology of EOS including blood culture utilisation, across a large and geographically diverse Australian health district.
Sepsis in the first three days of life remains a leading cause of death and morbidity. In high-income countries, group B Streptococcus (GBS) and Escherichia coli (E. coli) have dominated as causes of EOS for five decades.
An 11-year retrospective cohort study to determine the epidemiology of EOS. Incidence rates were calculated per 1000 live births. Logistic regression with linear temporal trend and covariates for potential effect modifiers were employed. Blood culture utilisation was determined by examining the rate of babies undergoing blood culture within 72 hours of birth.
Among 93,584 live born babies, 65 had confirmed EOS (0.69/1000 live births); 22 term, 43 preterm. Across the 4 largest birth units, the proportion of babies having blood culture within 72 hours of birth varied from 1.9-5.1% for term and 21-35% for preterm babies. The annual change in the EOS rate was significant, OR 0.91 (95% CI, 0.84 to 0.99, p = 0.03). Group B Streptococcus was the most common cause of EOS in term neonates at 0.35/1000 live births (95% CI, 0.07-0.63) in 2006 and 0.1/1000 live births (95% CI, 0-0.2) in 2016. Escherichia coli was the most common cause in preterm babies at 3.4/1000 (95% CI, 0.11-6.76) in 2006 reducing significantly to 1.35/1000 live births (95% CI, -0.07-2.78) by 2016.
Escherichia coli and GBS were the most common causes of EOS in preterm and term babies respectively. Rates of all cause term and preterm EOS declined significantly as did preterm sepsis due to E. coli. While rate of sepsis due to early-onset GBS declined, this did not reach significance. Given the high proportion of preterm babies undergoing blood culture, it is unlikely that any EOS events were missed.
Epidemiology of neonatal early-onset sepsis in a geographically diverse Australian health district 2006-2016
Kathryn Braye, Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Validation, Visualization, Writing - original draft, Writing - review & editing,#1,2,* Maralyn Foureur, Methodology, Supervision, Validation, Writing - review & editing,#1,2,3 Koert de Waal, Supervision, Validation, Writing - review & editing,4,5,‡ Mark Jones, Data curation, Formal analysis, Methodology, Writing - review & editing,6,‡ Elise Putt, Data curation, Investigation, Validation, Visualization, Writing - review & editing,#2 and John Ferguson, Conceptualization, Data curation, Investigation, Methodology, Supervision, Validation, Writing - review & editing#2,5,7 Christine E. East, Editor