Supplementary Figure LegendsSupplementary Figure Legends Supplementary Figure 1. Paclitaxel reduces growth of aggressive breast cells. Panels A and B. UFH-001, MDA-MB-231 LM2, T47D, or MCF10 A cells were exposed to specific concentrations of Paclitaxel for 24 h (Panel A) or 48 (Panel B). The MTT assay was then used to assess viability/cell growth. Data are reported as percent of control: avg ± S.E.M., n = 3. Panel C. LDH activity was measured in the medium of cells treated with specific concentrations of Paclitaxel for 32 h followed by exposure to 70 µM BCP or vehicle for 16 h. Data are reported as the avg ± S.E.M., n=3. Panel D. Under the same conditions as in Panel C, the MTT assay was performed at 48 to assess viability/cell growth. Data are presented at OD at 570: avg ± S.E.M., n = 3. Supplementary Figure 2. Cytotoxicity of BCP is not affected by hypoxia. Cells were exposed to normoxic or hypoxic condition in the presence of increasing concentrations of BCP. LDH release was measured after 16 h. Data shown represent the average of at least 3 biological replicates ± S.E.M.
Objective Capnography is indicated as a guide to assess and monitor both endotracheal intubation and cardiopulmonary resuscitation (CPR). Our primary objective was to determine the effect of the 2010 American Heart Association (AHA) guidelines on the frequency of capnography use during critical events in children in the emergency department (ED). Our secondary objective was to examine associations between patient characteristics and capnography use among these patients. Methods A retrospective chart review was performed on children aged 0 to 21 years who were intubated or received CPR in 2 academic children's hospital EDs between January 2009 and December 2012. Age, sex, time of arrival, medical or traumatic cause, length of CPR, return of spontaneous circulation (ROSC), documented use of capnography and colorimetry, capnography values, and adverse events were recorded. Results Two hundred ninety-two patients were identified and analyzed. Intubation occurred in 95% of cases and CPR in 30% of cases. Capnography was documented in only 38% of intubated patients and 13% of patients requiring CPR. There was an overall decrease in capnography use after publication of the 2010 AHA recommendations (P = 0.05). Capnography use was associated with a longer duration of CPR and return of spontaneous circulation. Conclusions Despite the 2010 AHA recommendations, a minority of critically ill children are being monitored with capnography and an unexpected decrease in documented use occurred among our sample. Further education and implementation of capnography should take place to improve the use of this monitoring device for critically ill pediatric patients in the ED.
β-caryophyllene (BCP) exhibits anti-proliferative properties in cancer cells. Here, we examine the hypothesis that BCP induces membrane remodeling. Our data show that high concentrations of BCP increase membrane permeability of human breast cells (hBrC) causing detachment and cell death. At a sub-lethal concentration of BCP, we show that BCP induces a striking upregulation of genes involved in cholesterol biosynthesis, including the gene that encodes for HMGCoA reductase (HMGCR), the ratedetermining step in cholesterol biosynthesis. In addition, stearoyl-CoA desaturase (SCD) is also upregulated which would lead to the enhanced formation of monounsaturated fatty acids, specifically oleate and palmitoleate from stearoyl CoA and palmitoyl CoA, respectively. These fatty acids are major components of membrane phospholipids and cholesterol esters. Together, these data suggest that cells respond to BCP by increasing the synthesis of components found in membranes. These responses could be viewed as a repair mechanism and/or as a mechanism to mount resistance to the cytotoxic effect of BCP. Blocking HMGCR activity enhances the cytotoxicity of BCP, suggesting that BCP may provide an additional therapeutic tool in controlling breast cancer cell growth.
RESULTS: 1. Early pre-cancerous lesions in the macroscopically normal kidney from VHL patients mainly express HIF1 and this correlates with the presence of the pro-apototic protein BNip3. 2. More advanced lesions express both HIF1 and HIF2 and this correlates with the presence of the key cell cycle regulatory protein Cyclin D1. 3. In sporadic CCRCs areas of tumour are seen with strong expression of HIF2 and apparent 'loss' of HIF1 expression. Serial adjacent sections show that those areas with sole expression of HIF2 have markedly increased expression of VEGF, Cyclin D1 and increased cell proliferation. 4. Cell culture experiments indicate that BNip3 is a target for HIF1 and Cyclin D1 for HIF2. 5. Metastatic deposits from CCRC primaries display strong expression of HIF2.CONCLUSIONS: HIF1 and HIF2 appear to have different roles in CCRC tumorigenesis. We hypothesize that lesions demonstrating activation of HIF1 will not progress unless there is also activation of HIF2. The transition from expression of HIF1 alone, to dual expression, and then un-opposed HIF2 expression may explain the switch from slow growth to aggressive metastastic behaviour in renal cancer.
The search for therapeutic anti-cancer drugs has spanned both synthetic and natural products approaches, and notable success has been achieved from unique chemistries produced by plants. Early studies in E.coli showed that cyclic hydrocarbons, including terpenes, interact directly with biological membranes. Accumulation of hydrocarbons results in membrane swelling and increased membrane fluidity, both signs of cell stress. At biological temperatures, membrane fluidity is controlled by the saturation state of the acyl chains of fatty acids (primarily in phospholipids) and cholesterol content. Changes in either of these parameters leads to membrane remodeling which can affect membrane function. Terpenes are, themselves, precursors to complex sterols across all kingdoms of life. Beta-caryophylene (BCP), a bicyclic sesquiterpene, induces cell death across a variety of cancer cell types, although the mechanism(s) by which this occurs is not completely known. Our data show that BCP induces membrane permeability in breast cancer lines representing both ER-positive and triple negative phenotypes (TNBC), as measured by lactate dehydrogenase release from cells. We sought to understand this phenomenon by looking at changes in the transcriptome of treated cells compared to controls. We chose to examine cells exposed to hypoxia, rationalizing that this condition, in vivo, creates an aggressive phenotype, is associated with TNBC and drug-resistant (recurrent) breast cancers, and is an independent prognosticator for poor patient outcome. We isolated high quality RNA (RIN>9) at the University of Florida. The Genomics Core at the University of Louisville prepared libraries and performed the sequencing run (Illumina NextSeq 500). This generated over 144 million 75bp reads that aligned to the human genome (96.3% alignment rate), or approximately 24 million reads per sample. As a first approach in data analysis, we selected differential expression based on the FDR adjusted p-values (q-values) <0.05 (as determined by CuffDiff), and analyzed this gene set for pathway involvement using the reactome data base. Reactome also assesses FDR values for pathway analysis, and we selected pathway FDR <0.05 providing the highest level of specificity. This search modality revealed an orchestrated up-regulation of lipid metabolism, including that of cholesterol biosynthesis. This is consistent with BCP-induced membrane remodeling. We have validated these results, not by PCR, but through protein expression and metabolic assays. Because these events occur at concentrations that are sub-cytotoxic, this potentially reveals a new mechanism underlying the development of drug resistance. Citation Format: Mam Y. Mboge, Adam P. Bullock, Riley O'Dennell, John V. Matthias, Julie A. Davila, Christopher J. Frost, Susan C. Frost. Beta-caryophyllene regulates lipid biosynthesis in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1436.
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