E5501: phase II study of topotecan sequenced with etoposide/cisplatin, and irinotecan/cisplatin sequenced with etoposide for extensive-stage small-cell lung cancer.

PURPOSE: Sequence-dependent improved efficacy of topoisomerase I followed by topoisomerase 2 inhibitors was assessed in a randomized phase II study in extensive-stage small-cell lung cancer (SCLC). METHODS: Patients with previously untreated extensive-stage SCLC with measurable disease, ECOG performance status of 0-3 and stable brain metastases were eligible. Arm A consisted of topotecan (0.75 mg/m(2)) on days 1, 2 and 3, etoposide (70 mg/m(2)) and cisplatin (20 mg/m(2)) (PET) on days 8, 9 and 10 in a 3-week cycle. Arm B consisted of irinotecan (50 mg/m(2)) and cisplatin (20 mg/m(2)) on days 1 and 8 followed by etoposide (85 mg/m(2) PO bid) on days 3 and 10 (PIE) in a 3-week cycle. RESULTS: We enrolled 140 patients and randomized 66 eligible patients to each arm. Only 54.5 % of all patients completed the planned maximum 6 cycles. There were grade ≥3 treatment-related adverse events in approximately 70 % of the patients on both arms including 6 treatment-related grade 5 events. The overall response rates (CR + PR) were 69.7 % (90 % CI 59.1-78.9, 95 % CI 57.1-80.4 %) for arm A and 57.6 % (90 % CI 46.7-67.9, 95 % CI 44.8-69.7 %) for arm B. The median progression-free survival and overall survival were 6.4 months (95 % CI 5.4-7.5 months) and 11.9 months (95 % CI 9.6-13.7 months) for arm A and 6.0 months (95 % CI 5.4-7.0 months) and 11.0 months (95 % CI 8.6-13.1 months) for arm B. CONCLUSION: Sequential administration of topoisomerase inhibitors did not improve on the historical efficacy of standard platinum-doublet chemotherapy for extensive-stage SCLC

Protein Complexes and Proteolytic Activation of the Cell Wall Hydrolase RipA Regulate Septal Resolution in Mycobacteria

Peptidoglycan hydrolases are a double-edged sword. They are required for normal cell division, but when dysregulated can become autolysins lethal to bacteria. How bacteria ensure that peptidoglycan hydrolases function only in the correct spatial and temporal context remains largely unknown. Here, we demonstrate that dysregulation converts the essential mycobacterial peptidoglycan hydrolase RipA to an autolysin that compromises cellular structural integrity. We find that mycobacteria control RipA activity through two interconnected levels of regulation in vivo—protein interactions coordinate PG hydrolysis, while proteolysis is necessary for RipA enzymatic activity. Dysregulation of RipA protein complexes by treatment with a peptidoglycan synthase inhibitor leads to excessive RipA activity and impairment of correct morphology. Furthermore, expression of a RipA dominant negative mutant or of differentially processed RipA homologues reveals that RipA is produced as a zymogen, requiring proteolytic processing for activity. The amount of RipA processing differs between fast-growing and slow-growing mycobacteria and correlates with the requirement for peptidoglycan hydrolase activity in these species. Together, the complex picture of RipA regulation is a part of a growing paradigm for careful control of cell wall hydrolysis by bacteria during growth, and may represent a novel target for chemotherapy development

Twin RNA Polymerase–associated Proteins Control Virulence Gene Expression in Francisella tularensis

The MglA protein is the only known regulator of virulence gene expression in Francisella tularensis, yet it is unclear how it functions. F. tularensis also contains an MglA-like protein called SspA. Here, we show that MglA and SspA cooperate with one another to control virulence gene expression in F. tularensis. Using a directed proteomic approach, we show that both MglA and SspA associate with RNA polymerase (RNAP) in F. tularensis, and that SspA is required for MglA to associate with RNAP. Furthermore, bacterial two-hybrid and biochemical assays indicate that MglA and SspA interact with one another directly. Finally, through genome-wide expression analyses, we demonstrate that MglA and SspA regulate the same set of genes. Our results suggest that a complex involving both MglA and SspA associates with RNAP to positively control virulence gene expression in F. tularensis. The F. tularensis genome is unusual in that it contains two genes encoding different α subunits of RNAP, and we show here that these two α subunits are incorporated into RNAP. Thus, as well as identifying SspA as a second critical regulator of virulence gene expression in F. tularensis, our findings provide a framework for understanding the mechanistic basis for virulence gene control in a bacterium whose transcription apparatus is unique

AGS Position Statement: Making Medical Treatment Decisions for Unbefriended Older Adults

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135987/1/jgs14586_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135987/2/jgs14586.pd

Eruptive modes and hiatus of volcanism at West Mata seamount, NE Lau basin : 1996–2012

Author Posting. © American Geophysical Union, 2014. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry, Geophysics, Geosystems 15 (2014): 4093–4115, doi:10.1002/2014GC005387.We present multiple lines of evidence for years to decade-long changes in the location and character of volcanic activity at West Mata seamount in the NE Lau basin over a 16 year period, and a hiatus in summit eruptions from early 2011 to at least September 2012. Boninite lava and pyroclasts were observed erupting from its summit in 2009, and hydroacoustic data from a succession of hydrophones moored nearby show near-continuous eruptive activity from January 2009 to early 2011. Successive differencing of seven multibeam bathymetric surveys of the volcano made in the 1996–2012 period reveals a pattern of extended constructional volcanism on the summit and northwest flank punctuated by eruptions along the volcano's WSW rift zone (WSWRZ). Away from the summit, the volumetrically largest eruption during the observational period occurred between May 2010 and November 2011 at ∼2920 m depth near the base of the WSWRZ. The (nearly) equally long ENE rift zone did not experience any volcanic activity during the 1996–2012 period. The cessation of summit volcanism recorded on the moored hydrophone was accompanied or followed by the formation of a small summit crater and a landslide on the eastern flank. Water column sensors, analysis of gas samples in the overlying hydrothermal plume and dives with a remotely operated vehicle in September 2012 confirmed that the summit eruption had ceased. Based on the historical eruption rates calculated using the bathymetric differencing technique, the volcano could be as young as several thousand years.Support for R.W.E. during this study was by internal NOAA funding to the NOAA Vents Program (now Earth-Ocean Interactions Program). The NSF Ridge 2000 and MARGINS programs played a major role in the planning and justification for the 2009 rapid response proposal that funded the May 2009 expedition. MBARI provided support and outstanding postprocessing of the multibeam bathymetry from the D. Allan B. AUV multibeam sonar used in this study. NSF also provided major funding for the 2009 expedition (OCE930025 and OCE-0934660 to JAR) and for the 210Po-210Pb radiometric dating (OCE-0929881 and for the 210Po-210Pb radiometric dating (OCE-0929881 to KHR)). The NOAA Office of Exploration and Research provided major funding for the 2009 and 2012 field programs.2015-04-3

'To live and die [for] Dixie': Irish civilians and the Confederate States of America

Around 20,000 Irishmen served in the Confederate army in the Civil War. As a result, they left behind, in various Southern towns and cities, large numbers of friends, family, and community leaders. As with native-born Confederates, Irish civilian support was crucial to Irish participation in the Confederate military effort. Also, Irish civilians served in various supporting roles: in factories and hospitals, on railroads and diplomatic missions, and as boosters for the cause. They also, however, suffered in bombardments, sieges, and the blockade. Usually poorer than their native neighbours, they could not afford to become 'refugees' and move away from the centres of conflict. This essay, based on research from manuscript collections, contemporary newspapers, British Consular records, and Federal military records, will examine the role of Irish civilians in the Confederacy, and assess the role this activity had on their integration into Southern communities. It will also look at Irish civilians in the defeat of the Confederacy, particularly when they came under Union occupation. Initial research shows that Irish civilians were not as upset as other whites in the South about Union victory. They welcomed a return to normalcy, and often 'collaborated' with Union authorities. Also, Irish desertion rates in the Confederate army were particularly high, and I will attempt to gauge whether Irish civilians played a role in this. All of the research in this paper will thus be put in the context of the Drew Gilpin Faust/Gary Gallagher debate on the influence of the Confederate homefront on military performance. By studying the Irish civilian experience one can assess how strong the Confederate national experiment was. Was it a nation without a nationalism

Time-Resolved Transposon Insertion Sequencing Reveals Genome-Wide Fitness Dynamics during Infection

ABSTRACT Transposon insertion sequencing (TIS) is a powerful high-throughput genetic technique that is transforming functional genomics in prokaryotes, because it enables genome-wide mapping of the determinants of fitness. However, current approaches for analyzing TIS data assume that selective pressures are constant over time and thus do not yield information regarding changes in the genetic requirements for growth in dynamic environments (e.g., during infection). Here, we describe structured analysis of TIS data collected as a time series, termed pattern analysis of conditional essentiality (PACE). From a temporal series of TIS data, PACE derives a quantitative assessment of each mutant’s fitness over the course of an experiment and identifies mutants with related fitness profiles. In so doing, PACE circumvents major limitations of existing methodologies, specifically the need for artificial effect size thresholds and enumeration of bacterial population expansion. We used PACE to analyze TIS samples of Edwardsiella piscicida (a fish pathogen) collected over a 2-week infection period from a natural host (the flatfish turbot). PACE uncovered more genes that affect E. piscicida’s fitness in vivo than were detected using a cutoff at a terminal sampling point, and it identified subpopulations of mutants with distinct fitness profiles, one of which informed the design of new live vaccine candidates. Overall, PACE enables efficient mining of time series TIS data and enhances the power and sensitivity of TIS-based analyses

The Grizzly, October 1, 1991

Whittaker Relates Gulf Experience • Sorority Pledging Underway • U.S.E.A.C. Conference a Success • Ursinus Students Feel the Excitement of Habitat • College Tutorial Project Thrives • U.C. Welcomes New Instructors • Leadershop 1991 • U.S.G.A. Finds a Home • A Plea for Help • GN\u27R: Illusion ... of Good Music • State Museum Exhibits Berman Sculptures • Jane Ira Bloom Jazzes It Up • Sky Sands Strikes Ursinus • Aerobics Attack • The Tempting Temple • Field Hockey Faces Tough Times • Bears Terrorized by Western Maryland • Lady Bears Finish 4th • Bears Tee Off • Runners Get Recognition • Soccer Splits Two • Cross Country Cruises to 3rd Place • Gift to Give • Alcohol Policy Enforcement Tightens • Intellect Over Image • Wismer Whine • Healing the Wounds of the Gulf War • The Search For the Chemical Promisehttps://digitalcommons.ursinus.edu/grizzlynews/1278/thumbnail.jp

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts