Extracellular vesicles produced in B cells deliver tumor suppressor miR-335 to breast cancer cells disrupting oncogenic programming in vitro and in vivo.

The successful implementation of miRNA (miR) therapies in humans will ultimately rely on the use of vehicles with improved cellular delivery capability. Here we tested a new system that leverages extracellular vesicles (EVs) laden with a tumor suppressor miRNA (miR-335) produced in B cells by plasmid DNA induction (iEVs). We demonstrate that iEVs-335 efficiently and durably restored the endogenous miR-335 pool in human triple negative breast cancer cells, downregulated the expression of the miR-335 target gene SOX4 transcription factor, and markedly inhibited tumor growth in vivo. Remarkably, iEVs-335 mediated transcriptional effects that persisted in tumors after 60 days post orthotopic implantation. Genome-wide RNASeq analysis of cancer cells treated in vitro with iEVs-335 showed the regulation of a discrete number of genes only, without broad transcriptome perturbations. This new technology may be ideally suited for therapies aimed to restore tumor suppressor miRNAs in cancer cells, disrupting the oncogenic program established after escape from miRNA control

The influence of ATC message length and timing on pilot communication

Pilot-controller communication is critical to safe and efficient flight. It is often a challenging component of piloting, which is reflected in the number of incidents and accidents involving miscommunication. Our previous field study identified communication problems that disrupt routine communication between pilots and controllers. The present part-task simulation study followed up the field results with a more controlled investigation of communication problems. Pilots flew a simulation in which they were frequently vectored by Air Traffic Control (ATC), requiring intensive communication with the controller. While flying, pilots also performed a secondary visual monitoring task. We examined the influence of message length (one message with four commands vs. two messages with two commands each) and noncommunication workload on communication accuracy and length. Longer ATC messages appeared to overload pilot working memory, resulting in more incorrect or partial readbacks, as well as more requests to repeat the message. The timing between the two short messages also influenced communication. The second message interfered with memory for or response to the first short message when it was delivered too soon after the first message. Performing the secondary monitoring task did not influence communication. Instead, communication reduced monitoring accuracy

Oral versus intravenous clarithromycin in moderate to severe community-acquired pneumonia:an observational study

Objectives: British Thoracic Society guidelines recommend clarithromycin in addition to beta-lactam antibiotics for patients with community-acquired pneumonia and CURB-65 score 2-5. Intravenous therapy is commonly used but there are few data on whether oral therapy is equally effective.Methods: This observational study used propensity matching to compare two groups of patients with moderate to severe community-acquired pneumonia (CURB-65 score 2-5) treated with oral (n = 226) or intravenous (n = 226) clarithromycin on admission. Outcomes were 30-day mortality, intensive care unit admission, time to clinical stability, and length of hospital stay.Results: There was no significant difference in 30-day mortality (16.8% for intravenous [IV] group vs. 14.6% for oral group, hazard ratio for IV group 1.11 95% CI 0.70-1.78), ICU admission (10.6% in both groups) or complications (10.6% for IV group and 9.3% for oral group) between the groups. The time to clinical stability in both cohorts was a median of 5 days (interquartile range 3-7 days, p = 0.3). The median length of hospital stay was 8 days in the IV group (interquartile range 4-14 days) and 7 days in the oral group (interquartile range 4-13 days), p = 0.5. No other differences were observed between oral and IV groups.Conclusion: Where the oral route is not compromised, oral macrolides appear to be equivalent to IV in treating moderate to severe CAP.</p

Prostate cancer cells undergoing ER stress in vitro and in vivo activate transcription of pro-inflammatory cytokines

Navin R Mahadevan, Antonio Fernandez, Jeffrey J Rodvold, Gonzalo Almanza, Maurizio ZanettiThe Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California, San Diego, USABackground: Several micro-environmental and cell-intrinsic stimuli cause tumor cells to undergo endoplasmic reticulum (ER) stress in vivo. The occurrence of an ER stress response has been associated with tumor progression and angiogenesis. Recently, we found that pharmacological induction of ER stress in B lymphoma cells upregulates the transcription of several pro-inflammatory cytokines.Results: Here, we show that transgenic adenocarcinoma of the mouse prostate (TRAMP) C1 murine prostate cancer cells induced to undergo ER stress in vitro activate the transcription of interleukin 6 (IL-6), interleukin 23p19 (IL-23p19), and tumor necrosis factor a (TNF-a). Furthermore we show that TRAMP C1 tumors growing in vivo spontaneously experience ER stress and that transcription of IL-6, IL-23p19, and TNF-a correlates with the in vivo ER stress response.Conclusions: These results suggest that an ER stress response in prostate cancer cells activates a program of pro-inflammatory cytokine transcription. A possible implication of this finding is that cancer cells may use the ER stress response to modify their microenvironment.Keywords: unfolded protein response, tumorigenesis, inflammatio

Multidrug-Resistant Acinetobacter baumannii Osteomyelitis from Iraq

Multidrug-Resistant Acinetobacter baumannii Osteomyelitis from Ira

From the periphery to the brain: Lipocalin-2, a friend or foe?

Lipocalin-2 (LCN2) is an acute-phase protein that, by binding to iron-loaded siderophores, acts as a potent bacteriostatic agent in the iron-depletion strategy of the immune system to control pathogens. The recent identification of a mammalian siderophore also suggests a physiological role for LCN2 in iron homeostasis, specifically in iron delivery to cells via a transferrin-independent mechanism. LCN2 participates, as well, in a variety of cellular processes, including cell proliferation, cell differentiation and apoptosis, and has been mostly found up-regulated in various tissues and under inflammatory states, being its expression regulated by several inducers. In the central nervous system less is known about the processes involving LCN2, namely by which cells it is produced/secreted, and its impact on cell proliferation and death, or in neuronal plasticity and behaviour. Importantly, LCN2 recently emerged as a potential clinical biomarker in multiple sclerosis and in ageing-related cognitive decline. Still, there are conflicting views on the role of LCN2 in pathophysiological processes, with some studies pointing to its neurodeleterious effects, while others indicate neuroprotection. Herein, these various perspectives are reviewed and a comprehensive and cohesive view of the general function of LCN2, particularly in the brain, is provided.Ana Catarina Ferreira and Sandro Da Mesquita are recipients of PhD fellowships by the Fundação para a Ciência e Tecnologia (FCT, Portugal)/FEDER. Fernanda Marques is an assistant researcher IF/ 00231/2013 of the Fundação para a Ciência e Tecnologia (FCT, Portugal). This work was supported by Fundação para a Ciência e Tecnologia (FCT) and COMPETE through the project: EXPL/NEUOSD/2196/2013 (to Marques F). The authors thank Nadine Santos for the helpful comments on the manuscript

Comparison of Hospital Charge Prediction Models for Colorectal Cancer Patients: Neural Network vs. Decision Tree Models

Analysis and prediction of the care charges related to colorectal cancer in Korea are important for the allocation of medical resources and the establishment of medical policies because the incidence and the hospital charges for colorectal cancer are rapidly increasing. But the previous studies based on statistical analysis to predictthe hospital charges for patients did not show satisfactory results. Recently, data mining emerges as a new technique to extract knowledge from the huge and diverse medical data. Thus, we built models using data mining techniques to predict hospital charge for the patients. A total of 1,022 admission records with 154 variables of 492 patients were used to build prediction models who had been treated from 1999 to 2002 in the Kyung Hee University Hospital. We built an artificial neural network (ANN) model and a classification and regression tree (CART) model, and compared their prediction accuracy. Linear correlation coefficients were high in both models and the mean absolute errors were similar. But ANN models showed a better linear correlation than CART model (0.813 vs. 0.713 for the hospital charge paid by insurance and 0.746 vs. 0.720 for the hospital charge paid by patients). We suggest that ANN model has a better performance to predict charges of colorectal cancer patients

IRE1α and IGF signaling predict resistance to an endoplasmic reticulum stress-inducing drug in glioblastoma cells.

To date current therapies of glioblastoma multiforme (GBM) are largely ineffective. The induction of apoptosis by an unresolvable unfolded protein response (UPR) represents a potential new therapeutic strategy. Here we tested 12ADT, a sarcoendoplasmic reticulum Ca2+ ATPase (SERCA) inhibitor, on a panel of unselected patient-derived neurosphere-forming cells and found that GBM cells can be distinguished into "responder" and "non-responder". By RNASeq analysis we found that the non-responder phenotype is significantly linked with the expression of UPR genes, and in particular ERN1 (IRE1) and ATF4. We also identified two additional genes selectively overexpressed among non-responders, IGFBP3 and IGFBP5. CRISPR-mediated deletion of the ERN1, IGFBP3, IGFBP5 signature genes in the U251 human GBM cell line increased responsiveness to 12ADT. Remarkably,&nbsp;&gt;65% of GBM cases in The Cancer Genome Atlas express the non-responder (ERN1, IGFBP3, IGFBP5) gene signature. Thus, elevated levels of IRE1α and IGFBPs predict a poor response to drugs inducing unresolvable UPR and possibly other forms of chemotherapy helping in a better stratification GBM patients