Pan-cancer analysis of transcriptional metabolic dysregulation using The Cancer Genome Atlas.

Understanding metabolic dysregulation in different disease settings is vital for the safe and effective incorporation of metabolism-targeted therapeutics in the clinic. Here, using transcriptomic data for 10,704 tumor and normal samples from The Cancer Genome Atlas, across 26 disease sites, we present a novel bioinformatics pipeline that distinguishes tumor from normal tissues, based on differential gene expression for 114 metabolic pathways. We confirm pathway dysregulation in separate patient populations, demonstrating the robustness of our approach. Bootstrapping simulations were then applied to assess the biological significance of these alterations. We provide distinct examples of the types of analysis that can be accomplished with this tool to understand cancer specific metabolic dysregulation, highlighting novel pathways of interest, and patterns of metabolic flux, in both common and rare disease sites. Further, we show that Master Metabolic Transcriptional Regulators explain why metabolic differences exist, can segregate patient populations, and predict responders to different metabolism-targeted therapeutics.

IPI59: An Actionable Biomarker to Improve Treatment Response in Serous Ovarian Carcinoma Patients.

Despite improvements in operative management and therapies, overall survival rates in advanced ovarian cancer have remained largely unchanged over the past three decades. Although it is possible to identify high-risk patients following surgery, the knowledge does not provide information about the genomic aberrations conferring risk, or the implications for treatment. To address these challenges, we developed an integrative pathway-index model and applied it to messenger RNA expression from 458 patients with serous ovarian carcinoma from the Cancer Genome Atlas project. The biomarker derived from this approach, IPI59, contains 59 genes from six pathways. As we demonstrate using independent datasets from six studies, IPI59 is strongly associated with overall and progression-free survival, and also identifies high-risk patients who may benefit from enhanced adjuvant therapy.

Emergency department thoracotomy for pericardiac tamponade.

A 31-year-old man with a penetrating chest injury presented acutely with pulseless electrical activity, as a result of a ventricular laceration causing pericardial tamponade. Emergency department thoracotomy was performed to release the tamponade and he was operated on immediately to repair the laceration. He subsequently survived and was discharged to a community hospital for rehabilitation. We present this case of penetrating cardiac injury in which the patient arrived in extremis and for which emergency department thoracotomy was performed, and we discuss the role of emergency thoracotomy, its indications and outcome indicators.

Adenosine and its receptor agonists regulate nitric oxide production and RAW 264.7 macrophages via both receptor binding and its downstream metabolites-inosine.

Adenosine and its receptor agonists enhanced the production of nitric oxide (NO) in lipopolysaccharide (LPS)-treated RAW 264.7 cells. The enhancement of LPS-induced NO production by adenosine, as represented by the amount of its oxidation products, nitrite and nitrate, was inhibited by adenosine uptake inhibitors, such as dipyridamole, S(4-nitrobenzyl)-6-thioinosine (NBTI) and S(4-nitrobenzyl)-6-thioguanosine (NBTG). These indicate that the uptake of adenosine by macrophages is a prerequisite for the enhancement effects observed. A downstream metabolite of adenosine, inosine, also potentiated the LPS-induced NO production in a dose-dependent manner while its enhancement effect was also inhibited by dipyridamole. However, the degree of enhancement by inosine on NO production and nitric oxide synthase (NOS) activity in LPS-treated RAW 264.7 was weaker than the effect of adenosine. Furthermore, adenosine agonists also enhanced the NO production in a dose-dependent manner, but were not specific for A1, A2 nor A3 adenosine receptor. Adenosine uptake inhibitors had no effects on the enhancement activity of the adenosine receptor agonists. Thus, extracellular receptor/s may also play an important role in the observed enhancement responses. The results of this study indicate that the enhancement effects of adenosine on NO production in macrophages could be mediated by the extracellular adenosine receptors as well as the downstream metabolites of adenosine.

Lead concentrations in breast milk of Malaysian urban and rural mothers.

This study was conducted to determine lead concentrations in breast milk among urban and rural mothers in Malaysia, and to determine if lead absorption among urban maternal populations in Malaysia poses a potential health hazard to infants through breastfeeding. Milk samples, which were collected from 89 urban and 91 rural mothers, were analyzed by flameless atomic absorption spectrophotometry. The mean lead level in urban samples was 0.0253 microgram/ml, which was significantly higher than that of the rural samples (0.0211 microgram/ml). The estimated daily lead intake of breast-fed infants in Malaysia was well below proposed tolerable levels. There also appeared to be no specific pattern in the milk lead levels at different periods of lactation. The significance of the higher milk lead concentrations in urban mothers is also discussed.