Soil Bacteria and Fungi Respond on Different Spatial Scales to Invasion by the Legume Lespedeza cuneata

The spatial scale on which microbial communities respond to plant invasions may provide important clues as to the nature of potential invader–microbe interactions. Lespedeza cuneata (Dum. Cours.) G. Don is an invasive legume that may benefit from associations with mycorrhizal fungi; however, it has also been suggested that the plant is allelopathic and may alter the soil chemistry of invaded sites through secondary metabolites in its root exudates or litter. Thus, L. cuneata invasion may interact with soil microorganisms on a variety of scales. We investigated L. cuneata-related changes to soil bacterial and fungal communities at two spatial scales using multiple sites from across its invaded N. American range. Using whole-community DNA fingerprinting, we characterized microbial community variation at the scale of entire invaded sites and at the scale of individual plants. Based on permutational multivariate analysis of variance, soil bacterial communities in heavily invaded sites were significantly different from those of uninvaded sites, but bacteria did not show any evidence of responding at very local scales around individual plants. In contrast, soil fungi did not change significantly at the scale of entire sites, but there were significant differences between fungal communities of native versus exotic plants within particular sites. The differential scaling of bacterial and fungal responses indicates that L. cuneata interacts differently with soil bacteria and soil fungi, and these microorganisms may play very different roles in the invasion process of this plant

Genome Sequence of E. coli O104:H4 Leads to Rapid Development of a Targeted Antimicrobial Agent against This Emerging Pathogen

A recent widespread outbreak of Escherichia coli O104:H4 in Germany demonstrates the dynamic nature of emerging and re-emerging food-borne pathogens, particularly STECs and related pathogenic E. coli. Rapid genome sequencing and public availability of these data from the German outbreak strain allowed us to identify an O-antigen-specific bacteriophage tail spike protein encoded in the genome. We synthesized this gene and fused it to the tail fiber gene of an R-type pyocin, a phage tail-like bacteriocin, and expressed the novel bacteriocin such that the tail fiber fusion was incorporated into the bacteriocin structure. The resulting particles have bactericidal activity specifically against E. coli strains that produce the O104 lipopolysaccharide antigen, including the outbreak strain. This O-antigen tailspike-R-type pyocin strategy provides a platform to respond rapidly to emerging pathogens upon the availability of the pathogen's genome sequence

Detection of Dysplasia in Barrett's Esophagus With In Vivo Depth-Resolved Nuclear Morphology Measurements

Patients with Barrett’s esophagus (BE) show increased risk for developing esophageal adenocarcinoma and are routinely examined using upper endoscopy with biopsy to search for neoplastic changes. Angle-resolved low coherence interferometry (a/LCI) uses in vivo depth-resolved nuclear morphology measurements to detect dysplasia. We assessed the clinical utility of a/LCI in the endoscopic surveillance of BE patients

A phase I Clinical and Pharmacokinetic study of Tipifarnib in combination with Docetaxel in patients with advanced solid malignancies.

PURPOSE: This phase I study assessed the maximum tolerated doses (MTDs), safety, pharmacokinetics, and efficacy of combined tipifarnib and docetaxel treatment in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: The study protocol was sensitive to myelosuppression, as both drugs have been associated with this adverse event. Due to myelosuppression incidence, and in order to determine the MTD of docetaxel, multiple treatment regimens were employed. Tipifarnib was administered orally at 200 or 300 mg, twice daily (BID) for 21 days, 14 days, or 7 days for multiple 21-day cycles; intravenous (i.v.) docetaxel was administered on day 1 of each cycle at 60, 75, or 85 mg/m2. RESULTS: A total of 36 patients entered into the study. For each drug, MTDs were identified (tipifarnib: 300 mg BID for 14 days with 60 mg/m2 docetaxel; tipifarnib: 200 mg BID for 14 days with 75 mg/m2 docetaxel). The major dose-limiting toxicity was myelosuppression, particularly febrile neutropenia (44%). Mutual pharmacokinetic interactions (the effect of docetaxel on tipifarnib pharmacokinetics and the effect of tipifarnib on docetaxel pharmacokinetics) were not evident, as maximum plasma concentration (Cmax) and the area under the serum concentration-time curve (AUC) values of both tipifarnib and docetaxel were similar (p > or = 0.43) whether the two drugs were concomitantly administered or not. Seven of 31 evaluable patients (23%) had an objective response, 11 (35%) had stable disease (six > or = 24 weeks), and the overall clinical benefit rate (objective response and/or stable disease > or = 24 weeks) was 42%. CONCLUSIONS: Although the high incidence of febrile neutropenia necessitated a multiple scheduling adaptation of tipifarnib compared to the original protocol, the apparent lack of mutual pharmacokinetic interactions, the ability to coadminister tipifarnib and docetaxel near single-agent MTDs, and suggestive evidence of efficacy make this drug combination attractive for further examination.0Clinical Trial, Phase IJournal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial

Background Inhibition of phosphatidylinositol 3-kinase (PI3K) is a promising approach to overcome resistance to endocrine therapy in breast cancer. Pictilisib is an oral inhibitor of multiple PI3K isoforms. The aim of this study is to establish if addition of pictilisib to fulvestrant can improve progression-free survival in oestrogen receptor-positive, endocrine-resistant breast cancer. Methods In this two-part, randomised, double-blind, placebo-controlled, phase 2 study, we recruited postmenopausal women aged 18 years or older with oestrogen receptor-positive, HER2-negative breast cancer resistant to treatment with an aromatase inhibitor in the adjuvant or metastatic setting, from 123 medical centres across 21 countries. Part 1 included patients with or without PIK3CA mutations, whereas part 2 included only patients with PIK3CA mutations. Patients were randomly allocated (1:1 in part 1 and 2:1 in part 2) via a computer-generated hierarchical randomisation algorithm to daily oral pictilisib (340 mg in part 1 and 260 mg in part 2) or placebo starting on day 15 of cycle 1, plus intramuscular fulvestrant 500 mg on day 1 and day 15 of cycle 1 and day 1 of subsequent cycles in both groups. In part 1, we stratified patients by presence or absence of PIK3CA mutation, primary or secondary aromatase inhibitor resistance, and measurable or non-measurable disease. In part 2, we stratified patients by previous aromatase inhibitor treatment for advanced or metastatic disease or relapse during or within 6 months of an aromatase inhibitor treatment in the adjuvant setting and measurable or non-measurable disease. All patients and those administering treatment and assessing outcomes were masked to treatment assignment. The primary endpoint was progression-free survival in the intention-to-treat population for both parts 1 and 2 and also separately in patients with PIK3CA-mutated tumours in part 1. Tumour assessment (physical examination and imaging scans) was investigator-assessed and done at screening and after 8 weeks, 16 weeks, 24 weeks, and 32 weeks of treatment from day 1 of cycle 1 and every 12 weeks thereafter. We assessed safety in as-treated patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT01437566. Findings In part 1, between Sept 27, 2011, and Jan 11, 2013, we randomly allocated 168 patients to the pictilisib (89 [53%]) or placebo (79 [47%]) group. In part 2, between March 18, 2013, and Jan 2, 2014, we randomly allocated 61 patients to the pictilisib (41 [67%]) or placebo (20 [33%]) group. In part 1, we found no difference in median progression-free survival between the pictilisib (6·6 months [95% CI 3·9–9·8]) and placebo (5·1 months [3·6–7·3]) group (hazard ratio [HR] 0·74 [95% CI 0·52–1·06]; p=0·096). We also found no difference when patients were analysed according to presence (pictilisib 6·5 months [95% CI 3·7–9·8] vs placebo 5·1 months [2·6–10·4]; HR 0·73 [95% CI 0·42–1·28]; p=0·268) or absence (5·8 months [3·6–11·1] vs 3·6 months [2·8–7·3]; HR 0·72 [0·42–1·23]; p=0·23) of PIK3CA mutation. In part 2, we also found no difference in progression-free survival between groups (5·4 months [95% CI 3·8–8·3] vs 10·0 months [3·6–13·0]; HR 1·07 [95% CI 0·53–2·18]; p=0·84). In part 1, grade 3 or worse adverse events occurred in 54 (61%) of 89 patients in the pictilisib group and 22 (28%) of 79 in the placebo group. 19 serious adverse events related to pictilisib treatment were reported in 14 (16%) of 89 patients. Only one (1%) of 79 patients reported treatment-related serious adverse events in the placebo group. In part 2, grade 3 or worse adverse events occurred in 15 (36%) of 42 patients in the pictilisib group and seven (37%) of 19 patients in the placebo group. Four serious adverse events related to pictilisib treatment were reported in two (5%) of 42 patients. One treatment-related serious adverse event occurred in one (5%) of 19 patients in the placebo group. Interpretation Although addition of pictilisib to fulvestrant did not significantly improve progression-free survival, dosing of pictilisib was limited by toxicity, potentially limiting its efficacy. For future assessment of PI3K inhibition as an approach to overcome resistance to hormonal therapy, inhibitors with greater selectivity than that of pictilisib might be needed to improve tolerability and potentially increase efficacy. No further investigation of pictilisib in this setting is ongoing. Funding F Hoffmann-La Roche.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Low expression of a few genes indicates good prognosis in estrogen receptor positive breast cancer

<p>Abstract</p> <p>Background</p> <p>Many breast cancer patients remain free of distant metastasis even without adjuvant chemotherapy. While standard histopathological tests fail to identify these good prognosis patients with adequate precision, analyses of gene expression patterns in primary tumors have resulted in more successful diagnostic tests. These tests use continuous measurements of the mRNA concentrations of numerous genes to determine a risk of metastasis in lymph node negative breast cancer patients with other clinical traits.</p> <p>Methods</p> <p>A survival model is constructed from genes that are both connected with relapse and have expression patterns that define distinct subtypes, suggestive of different cellular states. This in silico study uses publicly available microarray databases generated with Affymetrix GeneChip technology. The genes in our model, as represented by array probes, have distinctive distributions in a patient cohort, consisting of a large normal component of low expression values; and a long right tail of high expression values. The cutoff between low and high expression of a probe is determined from the distribution using the theory of mixture models. The good prognosis group in our model consists of the samples in the low expression component of multiple genes.</p> <p>Results</p> <p>Here, we define a novel test for risk of metastasis in estrogen receptor positive (ER+) breast cancer patients, using four probes that determine distinct subtypes. The good prognosis group in this test, denoted AP4-, consists of the samples with low expression of each of the four probes. Two probes target <it>MKI67</it>, antigen identified by monoclonal antibody Ki-67, one targets <it>CDC6</it>, cell division cycle 6 homolog (S. cerevisiae), and a fourth targets <it>SPAG5</it>, sperm associated antigen 5. The long-term metastasis-free survival probability for samples in AP4- is sufficiently high to render chemotherapy of questionable benefit.</p> <p>Conclusion</p> <p>A breast cancer subtype defined by low expression of a few genes, using a minimum of statistical modeling, has significant prognostic power. This test is of potential clinical benefit in deciding a course of treatment for early stage breast cancer patients.</p