Genomic insights into the rapid emergence and evolution of MDR in Staphylococcus pseudintermedius.

OBJECTIVES: MDR methicillin-resistant Staphylococcus pseudintermedius (MRSP) strains have emerged rapidly as major canine pathogens and present serious treatment issues and concerns to public health due to their, albeit low, zoonotic potential. A further understanding of the genetics of resistance arising from a broadly susceptible background of S. pseudintermedius is needed. METHODS: We sequenced the genomes of 12 S. pseudintermedius isolates of varied STs and resistance phenotypes. RESULTS: Nine distinct clonal lineages had acquired either staphylococcal cassette chromosome (SCC) mec elements and/or Tn5405-like elements carrying up to five resistance genes [aphA3, sat, aadE, erm(B), dfrG] to generate MRSP, MDR methicillin-susceptible S. pseudintermedius and MDR MRSP populations. The most successful and clinically problematic MDR MRSP clones, ST68 SCCmecV(T) and ST71 SCCmecII-III, have further accumulated mutations in gyrA and grlA conferring resistance to fluoroquinolones. The carriage of additional mobile genetic elements (MGEs) was highly variable, suggesting that horizontal gene transfer is frequent in S. pseudintermedius populations. CONCLUSIONS: Importantly, the data suggest that MDR MRSP evolved rapidly by the acquisition of a very limited number of MGEs and mutations, and that the use of many classes of antimicrobials may co-select for the spread and emergence of MDR and XDR strains. Antimicrobial stewardship will need to be comprehensive, encompassing human medicine and veterinary disciplines to successfully preserve antimicrobial efficacy

Investigating the activity spectrum for Ring-Substituted 8-Hydroxyquinolines

In this study, a series of fourteen ring-substituted 8-hydroxyquinoline derivatives were prepared. The synthesis procedures are presented. The compounds were analyzed using RP-HPLC to determine lipophilicity. They were tested for their activity related to inhibition of photosynthetic electron transport (PET) in spinach (Spinacia olerácea L.) chloroplasts. Primary in vitro screening of the synthesized compounds was also performed against four mycobacterial strains and against eight fungal strains. Several compounds showed biological activity comparable with or higher than the standards isoniazid or fluconazole. For all the compounds, the relationships between the lipophilicity and the chemical structure of the studied compounds are discussed

Turbulent cross-field transport of non-thermal electrons in coronal loops: theory and observations

<p><b>Context:</b> A fundamental problem in astrophysics is the interaction between magnetic turbulence and charged particles. It is now possible to use Ramaty High Energy Solar Spectroscopic Imager (RHESSI) observations of hard X-rays (HXR) emitted by electrons to identify the presence of turbulence and to estimate the magnitude of the magnetic field line diffusion coefficient at least in dense coronal flaring loops.</p> <p><b>Aims:</b> We discuss the various possible regimes of cross-field transport of non-thermal electrons resulting from broadband magnetic turbulence in coronal loops. The importance of the Kubo number K as a governing parameter is emphasized and results applicable in both the large and small Kubo number limits are collected.</p> <p><b>Methods:</b> Generic models, based on concepts and insights developed in the statistical theory of transport, are applied to the coronal loops and to the interpretation of hard X-ray imaging data in solar flares. The role of trapping effects, which become important in the non-linear regime of transport, is taken into account in the interpretation of the data.</p> <p><b>Results:</b> For this flaring solar loop, we constrain the ranges of parallel and perpendicular correlation lengths of turbulent magnetic fields and possible Kubo numbers. We show that a substantial amount of magnetic fluctuations with energy ~1% (or more) of the background field can be inferred from the measurements of the magnetic diffusion coefficient inside thick-target coronal loops.</p&gt

GAS6 expression identifies high-risk adult AML patients: potential implications for therapy

Emerging data demonstrate important roles for the TYRO3/AXL/MERTK receptor tyrosine kinase (TAM RTK) family in diverse cancers. We investigated the prognostic relevance of GAS6 expression, encoding the common TAM RTK ligand, in 270 adults (n=71 aged \u3c60 \u3eyears; n=199 aged \u3e= 60 years) with de novo cytogenetically normal acute myeloid leukemia (CN-AML). Patients expressing GAS6 (GAS6+), especially those aged \u3e= 60 years, more often failed to achieve a complete remission (CR). In all patients, GAS6+ patients had shorter disease-free (DFS) and overall (OS) survival than patients without GAS6 expression (GAS6-). After adjusting for other prognostic markers, GAS6+ predicted CR failure (P=0.02), shorter DFS (P=0.004) and OS (P=0.04). To gain further biological insights, we derived a GAS6-associated gene-expression signature (

Expression and prognostic impact of lncRNAs in acute myeloid leukemia

Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides, located within the intergenic stretches or overlapping antisense transcripts of protein coding genes. LncRNAs are involved in numerous biological roles including imprinting, epigenetic regulation, apoptosis, and cell cycle. To determine whether lncRNAs are associated with clinical features and recurrent mutations in older patients (aged \u3e/=60 y) with cytogenetically normal (CN) acute myeloid leukemia (AML), we evaluated lncRNA expression in 148 untreated older CN-AML cases using a custom microarray platform. An independent set of 71 untreated older patients with CN-AML was used to validate the outcome scores using RNA sequencing. Distinctive lncRNA profiles were found associated with selected mutations, such as internal tandem duplications in the FLT3 gene (FLT3-ITD) and mutations in the NPM1, CEBPA, IDH2, ASXL1, and RUNX1 genes. Using the lncRNAs most associated with event-free survival in a training cohort of 148 older patients with CN-AML, we derived a lncRNA score composed of 48 lncRNAs. Patients with an unfavorable compared with favorable lncRNA score had a lower complete response (CR) rate [P \u3c 0.001, odds ratio = 0.14, 54% vs. 89%], shorter disease-free survival (DFS) [P \u3c 0.001, hazard ratio (HR) = 2.88] and overall survival (OS) (P \u3c 0.001, HR = 2.95). The validation set analyses confirmed these results (CR, P = 0.03; DFS, P = 0.009; OS, P = 0.009). Multivariable analyses for CR, DFS, and OS identified the lncRNA score as an independent marker for outcome. In conclusion, lncRNA expression in AML is closely associated with recurrent mutations. A small subset of lncRNAs is correlated strongly with treatment response and survival

Prognostic and Biologic Relevance of Clinically Applicable Long Noncoding RNA Profiling in Older Patients with Cytogenetically Normal Acute Myeloid Leukemia

We have previously shown that expression levels of 48 long noncoding RNAs (lncRNA) can generate a prognostic lncRNA score that independently associates with outcome of older patients with cytogenetically normal acute myeloid leukemia (CN-AML). However, the techniques used to identify and measure prognostic lncRNAs (i.e., RNA sequencing and microarrays) are not tailored for clinical testing. Herein, we report on an assay (based on the nCounter platform) that is designed to produce targeted measurements of prognostic lncRNAs in a clinically applicable manner. We analyzed a new cohort of 76 older patients with CN-AML and found that the nCounter assay yielded reproducible measurements and that the lncRNA score retained its prognostic value; patients with high lncRNA scores had lower complete remission (CR) rates (P = 0.009; 58% vs. 87%), shorter disease-free (P = 0.05; 3-year rates: 0% vs. 21%), overall (OS; P = 0.02, 3-year rates: 10% vs. 29%), and event-free survival (EFS; P = 0.002, 3-year rates: 0% vs. 18%) than patients with low lncRNA scores. In multivariable analyses, the lncRNA score independently associated with CR rates (P = 0.02), OS (P = 0.02), and EFS (P = 0.02). To gain biological insights, we examined our initial cohort of 71 older patients with CN-AML, previously analyzed with RNA sequencing. Genes involved in immune response and B-cell receptor signaling were enriched in patients with high lncRNA scores. We conclude that clinically applicable lncRNA profiling is feasible and potentially useful for risk stratification of older patients with CN-AML. Furthermore, we identify potentially targetable molecular pathways that are active in the high-risk patients with high lncRNA scores

Breast cancer and aging: results of the U13 conference breast cancer panel

Breast cancer is predominantly a disease of older women, yet there is a knowledge gap due to the persisting misalignment between the age distribution of women with breast cancer and the age distribution of participants in clinical trials. The purpose of this report is to state the U13 conference breast cancer panel’s recommendations regarding therapeutic clinical trials that will fill gaps in knowledge regarding the care of older patients with breast cancer. The U13 conference was a collaboration between the Cancer and Aging Research Group and the National Institute on Aging and the National Cancer Institute (NCI). Clinical trials should be developed for frail and vulnerable patients who would not enroll on the standard phase III trials, as well as efforts need to be made to increase enrollment of fit older patients on standard phase III trials. As a result of this conference, panel members are working with the NCI and cooperative groups to address these knowledge gaps. With the aging population and increasing incidence of breast cancer with age, it is essential to study the feasibility, toxicity, and efficacy of cancer therapy in this at-risk population