Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer.

Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest, possibly because of dynamic changes in cellular signaling that drive resistance and limit drug efficacy. Using a quantitative chemoproteomics approach, we mapped kinome dynamics in response to inhibitors of this pathway and identified signaling changes that correlate with drug sensitivity. Maintenance of AURKA after drug treatment was associated with resistance in breast cancer models. Incomplete inhibition of AURKA was a common source of therapy failure, and combinations of PI3K, AKT or mTOR inhibitors with the AURKA inhibitor MLN8237 were highly synergistic and durably suppressed mTOR signaling, resulting in apoptosis and tumor regression in vivo. This signaling map identifies survival factors whose presence limits the efficacy of targeted therapies and reveals new drug combinations that may unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer

An intracellular pH gradient in the anammox bacterium Kuenenia stuttgartiensis as evaluated by 31P NMR

The cytoplasm of anaerobic ammonium oxidizing (anammox) bacteria consists of three compartments separated by membranes. It has been suggested that a proton motive force may be generated over the membrane of the innermost compartment, the “anammoxosome”. 31P nuclear magnetic resonance (NMR) spectroscopy was employed to investigate intracellular pH differences in the anammox bacterium Kuenenia stuttgartiensis. With in vivo NMR, spectra were recorded of active, highly concentrated suspensions of K. stuttgartiensis in a wide-bore NMR tube. At different external pH values, two stable and distinct phosphate peaks were apparent in the recorded spectra. These peaks were equivalent with pH values of 7.3 and 6.3 and suggested the presence of a proton motive force over an intracytoplasmic membrane in K. stuttgartiensis. This study provides for the second time—after discovery of acidocalcisome-like compartments in Agrobacterium tumefaciens—evidence for an intracytoplasmic pH gradient in a chemotrophic prokaryotic cell

Variations in corticosteroid/anesthetic injections for painful shoulder conditions: comparisons among orthopaedic surgeons, rheumatologists, and physical medicine and primary-care physicians

<p>Abstract</p> <p>Background</p> <p>Variations in corticosteroid/anesthetic doses for injecting shoulder conditions were examined among orthopaedic surgeons, rheumatologists, and primary-care sports medicine (PCSMs) and physical medicine and rehabilitation (PMRs) physicians to provide data needed for documenting inter-group differences for establishing uniform injection guidelines.</p> <p>Methods</p> <p>264 surveys, sent to these physicians in our tri-state area of the western United States, addressed corticosteroid/anesthetic doses and types used for subacromial impingement, degenerative glenohumeral and acromioclavicular arthritis, biceps tendinitis, and peri-scapular trigger points. They were asked about preferences regarding: 1) fluorinated vs. non-fluorinated corticosteroids, 2) acetate vs. phosphate types, 3) patient age, and 4) adjustments for special considerations including young athletes and diabetics.</p> <p>Results</p> <p>169 (64% response rate, RR) surveys were returned: 105/163 orthopaedic surgeons (64%RR), 44/77 PCSMs/PMRs (57%RR), 20/24 rheumatologists (83%RR). Although corticosteroid doses do not differ significantly between specialties (p > 0.3), anesthetic volumes show broad variations, with surgeons using larger volumes. Although 29% of PCSMs/PMRs, 44% rheumatologists, and 41% surgeons exceed "recommended" doses for the acromioclavicular joint, >98% were within recommendations for the subacromial bursa and glenohumeral joint. Depo-Medrol^®(methylprednisolone acetate) and Kenalog^®(triamcinolone acetonide) are most commonly used. More rheumatologists (80%) were aware that there are acetate and phosphate types of corticosteroids as compared to PCSMs/PMRs (76%) and orthopaedists (60%). However, relatively fewer rheumatologists (25%) than PCSMs/PMRs (32%) or orthopaedists (32%) knew that phosphate types are more soluble. Fluorinated corticosteroids, which can be deleterious to soft tissues, were used with these frequencies for the biceps sheath: 17% rheumatologists, 8% PCSMs/PMRs, 37% orthopaedists. Nearly 85% use the same non-fluorinated corticosteroid for all injections; <10% make adjustments for diabetic patients.</p> <p>Conclusion</p> <p>Variations between specialists in anesthetic doses suggest that surgeons (who use significantly larger volumes) emphasize determining the percentage of pain attributable to the injected region. Alternatively, this might reflect a more profound knowledge that non-surgeons specialists have of the potentially adverse cardiovascular effects of these agents. Variations between these specialists in corticosteroid/anesthetic doses and/or types, and their use in some special situations (e.g., diabetics), bespeak the need for additional investigations aimed at establishing uniform injection guidelines, and for identifying knowledge deficiencies that warrant advanced education.</p

High prevalence of fecal carriage of extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae in a pediatric unit in Madagascar

<p>Abstract</p> <p>Background</p> <p>Extended-spectrum β-lactamase (ESBL)-producing <it>Enterobacteriaceae </it>have spread worldwide but there are few reports on carriage in hospitals in low-income countries. ESBL-producing <it>Enterobacteriaceae </it>(ESBL-PE) have been increasingly isolated from nosocomial infections in Antananarivo, Madagascar.</p> <p>Methods</p> <p>we conducted a prevalence survey in a pediatric unit from March to April 2008 Patient rectal swabs were sampled on the first and the last day of hospitalization. Medical staff and environment were also sampled. Rectal and environmental swabs were immediately plated onto Drigalski agar supplemented with 3 mg/liter of ceftriaxon.</p> <p>Results</p> <p>Fecal carriage was detected in 21.2% of 244 infants on admission and 57.1% of 154 on discharge, after more than 48 hours of hospitalization (p < 0.001). The species most frequently detected on admission were <it>Escherichia coli and Klebsiella pneumoniae </it>(36.9%), whereas, on discharge, <it>K. pneumoniae </it>was the species most frequently detected (52.7%). ESBL-associated resistances were related to trimethoprim-sulfamethoxazole (91.3%), gentamicin (76.1%), ciprofloxacin (50.0%), but not to amikacin and imipenem. The increased prevalence of carriage during hospitalization was related to standard antimicrobial therapy.</p> <p>Conclusion</p> <p>The significant emergence of multidrug-resistant enteric pathogens in Malagasy hospitals poses a serious health threat requiring the implementation of surveillance and control measures for nosocomial infections.</p

Cytokine Profiles in Asthma Families Depend on Age and Phenotype

Background: Circulating cytokine patterns may be relevant for the diagnosis of asthma, for the discrimination of certain phenotypes, and prognostic factors for exacerbation of disease. Methodology/Principal Findings: In this study we investigated serum samples from 944 individuals of 218 asthma-affected families by a multiplex, microsphere based system detecting at high sensitivity eleven asthma associated mediators: eotaxin (CCL11), granulocyte macrophage stimulating factor (GM-CSF), interferon gamma (IFNγ), interleukin-4 (IL-4), IL-5, IL-8, IL-10, IL-12 (p40), IL-13, IL-17 and tumor necrosis factor alpha (TNFα). Single cytokine levels were largely similar between asthmatic and healthy individuals when analysing asthma as single disease entity. Regulatory differences between parental and pediatric asthma were reflected by six of the eleven mediators analyzed (eotaxin, IL-4, IL-5, IL-10, IL-12, TNFα). IL-12 (p40) and IL-5 were the best predictor for extrinsic asthma in children with an increased odds ratio of 2.85 and 1.96 per log pg/ml increase (IL-12 (p40): 1.2-6.8, p = 0.019, and IL-5: 1.2-2.5, p = 0.025). Frequent asthma attacks in children are associated with elevated IL-5 serum levels (p = 0.013). Cytokine patterns seem to be individually balanced in both, healthy and diseased adults and children, with various cytokines correlating among each other (IL-17 and IFNγ (rs = 0.67), IL-4 and IL-5 (rs = 0.55), IFNγ and GM-CSF (rs = 0.54)). Conclusion/Significance: Our data support mainly an age- but also an asthma phenotype-dependent systemic immune regulation. © 2010 Pukelsheim et al

Multiple-input multiple-output causal strategies for gene selection

Traditional strategies for selecting variables in high dimensional classification problems aim to find sets of maximally relevant variables able to explain the target variations. If these techniques may be effective in generalization accuracy they often do not reveal direct causes. The latter is essentially related to the fact that high correlation (or relevance) does not imply causation. In this study, we show how to efficiently incorporate causal information into gene selection by moving from a single-input single-output to a multiple-input multiple-output setting.Journal ArticleResearch Support, N.I.H. ExtramuralResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Acute wound management: revisiting the approach to assessment, irrigation, and closure considerations

Abstract Background As millions of emergency department (ED) visits each year include wound care, emergency care providers must remain experts in acute wound management. The variety of acute wounds presenting to the ED challenge the physician to select the most appropriate management to facilitate healing. A complete wound history along with anatomic and specific medical considerations for each patient provides the basis of decision making for wound management. It is essential to apply an evidence‐based approach and consider each wound individually in order to create the optimal conditions for wound healing. Aims A comprehensive evidence‐based approach to acute wound management is an essential skill set for any emergency physician or acute care practitioner. This review provides an overview of current evidence and addresses frequent pitfalls. Methods A systematic review of the literature for acute wound management was performed. Results A structured MEDLINE search was performed regarding acute wound management including established wound care guidelines. The data obtained provided the framework for evidence‐based recommendations and current best practices for wound care. Conclusion Acute wound management varies based on the wound location and characteristics. No single approach can be applied to all wounds; however, a systematic approach to acute wound care integrated with current best practices provides the framework for exceptional wound management