Rates of asthma attacks in patients with previously inadequately controlled mild asthma treated in clinical practice with combination drug therapy: an exploratory post-hoc analysis

<p>Abstract</p> <p>Background</p> <p>Differences could exist in the likelihood of asthma attacks in patients treated with inhaled corticosteroid (ICS), long-acting beta-agonist (LABA), and montelukast (MON) (ICS/LABA/MON) and patients treated with an inhaled corticosteroid (ICS) and montelukast (MON) (ICS/MON).</p> <p>Methods</p> <p>This was a post-hoc analysis of a pretest-posttest retrospective cohort study. Patients with mild persistent asthma and allergic rhinitis, who were taking an ICS either alone or in combination with a LABA, started concomitant MON treatment as part of their routine care. Rates of asthma- and allergic rhinitis-related medical resource use in the 12-months after the initial (index) MON prescription were compared in the ICS/MON and ICS/LABA/MON groups. An asthma attack was defined as an asthma-related hospitalization, ER visit, or use of an oral corticosteroid.</p> <p>Results</p> <p>Of the total of 344 patients, 181 (53%) received ICS/MON and 163 (47%) received ICS/LABA/MON in the post-index period for means of 10.5 and 11.4 months, respectively, (P < 0.05). Short-acting beta-agonists were used by 74.6% in the ICS/MON and 71.8% in the ICS/LABA/MON groups (P > 0.05). An asthma attack occurred in 4.4% of the ICS/MON group and 6.8% of the ICS/LABA/MON group (P > 0.05). The adjusted odds of an asthma attack in the post-index period in the ICS/LABA/MON group relative to the ICS/MON group was 1.24, 95% confidence interval 0.35–4.44.</p> <p>Conclusion</p> <p>In this observational study of combination drug treatment of mild persistent asthma and allergic rhinitis, no difference was observed between LABA/ICS/MON combination therapy and the ICS/MON combination without LABA use, for the rate of asthma attacks over one year.</p

APOBEC signature mutation generates an oncogenic enhancer that drives LMO1 expression in T-ALL

Oncogenic driver mutations are those that provide a proliferative or survival advantage to neoplastic cells, resulting in clonal selection. Although most cancer-causing mutations have been detected in the protein-coding regions of the cancer genome; driver mutations have recently also been discovered within noncoding genomic sequences. Thus, a current challenge is to gain precise understanding of how these unique genomic elements function in cancer pathogenesis, while clarifying mechanisms of gene regulation and identifying new targets for therapeutic intervention. Here we report a C-to-T single nucleotide transition that occurs as a somatic mutation in noncoding sequences 4 kb upstream of the transcriptional start site of the LMO1 oncogene in primary samples from patients with T-cell acute lymphoblastic leukaemia. This single nucleotide alteration conforms to an APOBEC-like cytidine deaminase mutational signature, and generates a new binding site for the MYB transcription factor, leading to the formation of an aberrant transcriptional enhancer complex that drives high levels of expression of the LMO1 oncogene. Since APOBEC-signature mutations are common in a broad spectrum of human cancers, we suggest that noncoding nucleotide transitions such as the one described here may activate potent oncogenic enhancers not only in T-lymphoid cells but in other cell lineages as well

Polycomb group proteins: navigators of lineage pathways led astray in cancer

Udgivelsesdato: 2009-NovThe Polycomb group (PcG) proteins are transcriptional repressors that regulate lineage choices during development and differentiation. Recent studies have advanced our understanding of how the PcG proteins regulate cell fate decisions and how their deregulation potentially contributes to cancer. In this Review we discuss the emerging roles of long non-coding RNAs (ncRNAs) and a subset of transcription factors, which we call cell fate transcription factors, in the regulation of PcG association with target genes. We also speculate about how their deregulation contributes to tumorigenesis

Site-specific DNA cleavage within the MLL breakpoint cluster region induced by topoisomerase II inhibitors [see comments]

The MLL gene located at 11q23 is frequently disrupted by chromosomal translocation in a wide spectrum of newly diagnosed acute leukemias. Recently, it has become apparent that the MLL gene is very frequently disrupted by chromosomal translocations in patients with secondary leukemias associated with chemotherapeutic regimens incorporating topoisomerase II inhibitors. These secondary leukemias associated with topoisomerase II inhibitors (most commonly teniposide, etoposide, or doxorubicin) have distinct clinical and biologic features which have led to the speculation that they are induced by treatment with topoisomerase II inhibitors. We have identified a site within the MLL breakpoint cluster region (bcr) that is highly sensitive to double- strand DNA cleavage induced by topoisomerase II inhibitors. This finding is quite specific and highly reproducible. Although it was initially discovered in malignant lymphoblasts isolated from a patient receiving multiagent chemotherapy, this site-specific double-strand DNA cleavage can be induced in tissue culture using malignant cell lines as well as peripheral blood from normal individuals. Site-specific cleavage occurs in a significant fraction of cells using a variety of model systems, is both time and dose dependent, and can be induced with either doxorubicin or etoposide. This site-specific cleavage maps to the same region as a consensus topoisomerase II cleavage site within the MLL bcr. These results suggest that site specific cleavage within the MLL bcr induced by topoisomerase II inhibitors may be an early step leading to MLL translocations and secondary leukemia.</jats:p

Förväntningar på megaprojekt : Kommunala strategier i Norrköping för Ostlänken

När staten rullar ut sin matta av infrastruktursatsningar ställer det höga krav på de angörande kommunerna. Men det skapar också förväntningar som utgör en helt ny och omfattande grund för planering. I Norrköping förbereds nu för Ostlänken vilket innebär djupgående effekter på såväl organisation som processer, även om många ideal för samtidens stadsutveckling känns igen. Brita Hermelin, Fredrik Wallin och Sara Gustafsson beskriver projektet och de lokala planeringsförberedelserna