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Search Results: 1 - 10 of 318842 matches for " Robert J Crowder "
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Treating breast cancer through novel inhibitors of the phosphatidylinositol 3'-kinase pathway
Robert J Crowder, Matthew J Ellis
Breast Cancer Research , 2005, DOI: 10.1186/bcr1307
Abstract: The phosphatidylinositol 3'-kinase (PI3K) signaling cascade is involved in regulating many cellular processes that are required for tumorigenesis, including protein synthesis and glucose metabolism, cell survival, proliferation, cell migration, and angiogenesis. Recent investigations indicate that constitutive activation of the PI3K pathway promotes resistance to estrogen receptor and human epidermal growth factor receptor (HER)2 directed therapy for breast cancer patients [1,2]. The major mechanism for abnormal PI3K activation in cancer is thought to be somatic mutation in the genes that encode positive and negative effectors of this pathway. These insights suggest that many breast cancers exhibit a 'genetic dependency' on PI3K pathway mutations that can be exploited for therapeutic gain. For example, abnormal PI3K activation in breast cancer can occur though amplification of the HER2 gene, the gene product of which is effectively targeted with the monoclonal antibody trastuzumab [3]. In addition, loss of expression of PTEN, a powerful negative regulator of PI3K signaling, or functional loss of PTEN due to PTEN gene mutations occurs in up to 50% of breast tumors and results in constitutive PI3K pathway signaling [4,5]. Loss of PTEN expression produces resistance to breast cancer endocrine therapy and trastuzumab treatment, and is a predictor of poor prognosis [1,2,5]. More recently, activating mutations in the PIK3CA gene, which encodes the PI3K p110α catalytic subunit, were found to occur in about 20–40% of breast tumors [6-9]. Interestingly, one study involving a large cohort of breast tumor samples [9] reported that PIK3CA gene mutations are mutually exclusive with PTEN gene loss, and that PIK3CA mutations correlate with HER2 expression and estrogen receptor positive status in breast tumors, although these correlations were not seen in other studies involving smaller samples sizes [7,8]. The RPS6KB1 gene, which encodes the mammalian target of rapamycin (mTOR) ef
Preclinical modeling of combined phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive breast cancer
Cesar G Sanchez, Cynthia X Ma, Robert J Crowder, Therese Guintoli, Chanpheng Phommaly, Feng Gao, Li Lin, Matthew J Ellis
Breast Cancer Research , 2011, DOI: 10.1186/bcr2833
Abstract: The PI3K catalytic subunit inhibitor BKM120, the mammalian target of rapamycin (mTOR) inhibitor RAD001 and the dual PI3K/mTOR inhibitor BGT226 were tested against ER-positive breast cancer cell lines before and after long-term estrogen deprivation (LTED). The impact of estradiol deprivation and the ER downregulator fulvestrant on PI3K pathway inhibitor-induced apoptosis was assessed. PIK3CA hotspot mutation analysis was performed in 51 recurrent or metastatic breast cancers and correlated with ER status and survival.Drug-induced apoptosis was most marked in short-term estrogen-deprived cells with PIK3CA mutation and phosphatase and tensin homolog loss. Apoptosis was most highly induced by BGT226, followed by BKM120, and then RAD001. Estradiol antagonized PI3K inhibitor-induced apoptosis following short-term estrogen deprivation, emphasizing a role for estrogen-deprivation therapy in promoting PI3K inhibitor activity in the first-line setting. ER-positive MCF7 LTED cells exhibited relative resistance to PI3K pathway inhibition that was reversed by fulvestrant. In contrast, T47D LTED cells exhibited ER loss and ER-independent PI3K agent sensitivity. PIK3CA mutation was prevalent in relapsed ER-positive disease (48%) and was associated with persistent ER positivity and a late relapse pattern.Estrogen deprivation increased the apoptotic effects of PI3K and dual PI3K/mTOR inhibitors in ER-positive disease, providing a rationale for PI3K/aromatase inhibitor combinations as first-line therapy. In LTED cells, differential effects on ER expression may be a relevant consideration. When ER was persistently expressed, fulvestrant strongly promoted PI3K drug activity. When ER was lost, PI3K inhibitor monotherapy was sufficient to induce high-level apoptosis. Although tumors with PIK3CA mutation had a late recurrence pattern, these mutations were common in metastatic disease and were most often associated with persistent ER expression. Targeting PIK3CA mutant tumors with a PI3K p
LISA Source Confusion
Jeff Crowder,Neil J. Cornish
Physics , 2004, DOI: 10.1103/PhysRevD.70.082004
Abstract: The Laser Interferometer Space Antenna (LISA) will detect thousands of gravitational wave sources. Many of these sources will be overlapping in the sense that their signals will have a non-zero cross-correlation. Such overlaps lead to source confusion, which adversely affects how well we can extract information about the individual sources. Here we study how source confusion impacts parameter estimation for galactic compact binaries, with emphasis on the effects of the number of overlaping sources, the time of observation, the gravitational wave frequencies of the sources, and the degree of the signal correlations. Our main findings are that the parameter resolution decays exponentially with the number of overlapping sources, and super-exponentially with the degree of cross-correlation. We also find that an extended mission lifetime is key to disentangling the source confusion as the parameter resolution for overlapping sources improves much faster than the usual square root of the observation time.
Beyond LISA: Exploring Future Gravitational Wave Missions
Jeff Crowder,Neil J. Cornish
Physics , 2005, DOI: 10.1103/PhysRevD.72.083005
Abstract: The Advanced Laser Interferometer Antenna (ALIA) and the Big Bang Observer (BBO) have been proposed as follow on missions to the Laser Interferometer Space Antenna (LISA). Here we study the capabilities of these observatories, and how they relate to the science goals of the missions. We find that the Advanced Laser Interferometer Antenna in Stereo (ALIAS), our proposed extension to the ALIA mission, will go considerably further toward meeting ALIA's main scientific goal of studying intermediate mass black holes. We also compare the capabilities of LISA to a related extension of the LISA mission, the Laser Interferometer Space Antenna in Stereo (LISAS). Additionally, we find that the initial deployment phase of the BBO would be sufficient to address the BBO's key scientific goal of detecting the Gravitational Wave Background, while still providing detailed information about foreground sources.
LISA Data Analysis using MCMC methods
Neil J. Cornish,Jeff Crowder
Physics , 2005, DOI: 10.1103/PhysRevD.72.043005
Abstract: The Laser Interferometer Space Antenna (LISA) is expected to simultaneously detect many thousands of low frequency gravitational wave signals. This presents a data analysis challenge that is very different to the one encountered in ground based gravitational wave astronomy. LISA data analysis requires the identification of individual signals from a data stream containing an unknown number of overlapping signals. Because of the signal overlaps, a global fit to all the signals has to be performed in order to avoid biasing the solution. However, performing such a global fit requires the exploration of an enormous parameter space with a dimension upwards of 50,000. Markov Chain Monte Carlo (MCMC) methods offer a very promising solution to the LISA data analysis problem. MCMC algorithms are able to efficiently explore large parameter spaces, simultaneously providing parameter estimates, error analyses and even model selection. Here we present the first application of MCMC methods to simulated LISA data and demonstrate the great potential of the MCMC approach. Our implementation uses a generalized F-statistic to evaluate the likelihoods, and simulated annealing to speed convergence of the Markov chains. As a final step we super-cool the chains to extract maximum likelihood estimates, and estimates of the Bayes factors for competing models. We find that the MCMC approach is able to correctly identify the number of signals present, extract the source parameters, and return error estimates consistent with Fisher information matrix predictions.
Extracting galactic binary signals from the first round of Mock LISA Data Challenges
Jeff Crowder,Neil J. Cornish
Physics , 2007, DOI: 10.1088/0264-9381/24/19/S20
Abstract: We report on the performance of an end-to-end Bayesian analysis pipeline for detecting and characterizing galactic binary signals in simulated LISA data. Our principal analysis tool is the Blocked-Annealed Metropolis Hasting (BAM) algorithm, which has been optimized to search for tens of thousands of overlapping signals across the LISA band. The BAM algorithm employs Bayesian model selection to determine the number of resolvable sources, and provides posterior distribution functions for all the model parameters. The BAM algorithm performed almost flawlessly on all the Round 1 Mock LISA Data Challenge data sets, including those with many highly overlapping sources. The only misses were later traced to a coding error that affected high frequency sources. In addition to the BAM algorithm we also successfully tested a Genetic Algorithm (GA), but only on data sets with isolated signals as the GA has yet to be optimized to handle large numbers of overlapping signals.
Darwin Meets Einstein: LISA Data Analysis Using Genetic Algorithms
Jeff Crowder,Neil J. Cornish,Lucas Reddinger
Physics , 2006, DOI: 10.1103/PhysRevD.73.063011
Abstract: This work presents the first application of the method of Genetic Algorithms (GAs) to data analysis for the Laser Interferometer Space Antenna (LISA). In the low frequency regime of the LISA band there are expected to be tens of thousands galactic binary systems that will be emitting gravitational waves detectable by LISA. The challenge of parameter extraction of such a large number of sources in the LISA data stream requires a search method that can efficiently explore the large parameter spaces involved. As signals of many of these sources will overlap, a global search method is desired. GAs represent such a global search method for parameter extraction of multiple overlapping sources in the LISA data stream. We find that GAs are able to correctly extract source parameters for overlapping sources. Several optimizations of a basic GA are presented with results derived from applications of the GA searches to simulated LISA data.
Spatial Dynamics of Sea Turtle Abundance and Shrimping Intensity in the U.S. Gulf of Mexico
Carrie J. McDaniel,Larry B. Crowder,Jeffery A. Priddy
Ecology and Society , 2000,
Abstract: In order to examine the scientific feasibility of area closures for sea turtle protection, we determined the spatial dynamics of sea turtles for the U.S. Gulf of Mexico by analyzing National Marine Fisheries Service (NMFS) aerial survey data in September, October, and November of 1992, 1993, and 1994. Turtle sightings were grouped into depth zones and NMFS fishery statistical zones, and strip transect methods were used to estimate the relative abundance of sea turtles in each subzone. Average shrimping intensity was calculated for each subzone for all months of 1992, 1993, and 1994, as well as for the months and locations of the aerial survey. The spatial overlap of sea turtle abundance and shrimping intensity suggested regions where interactions are likely to occur. Sea turtles were observed at much higher rates along the coast of Florida than in the Western Gulf; the highest density of sea turtles was observed in the Florida Keys region (0.525 turtles/km2). Shrimping intensity was highest in the Western Gulf along the coast of Texas and Louisiana, for both annual and fall estimates. Among alternative management scenarios, area closures in conjunction with continued Turtle Excluder Device (TED) requirements would probably best prevent sea turtles from future extinction. By implementing shrimping closures off of South Padre Island, Texas, a potential second nesting population of Kemp's ridleys (Lepidochelys kempi) could be protected. Closing waters where shrimping intensity is low and sea turtle abundance is high (e.g., South Florida waters) would protect sea turtles without economically impacting a large number of shrimpers.
Probing substrate binding to Metallo-β-Lactamase L1 from Stenotrophomonas maltophilia by using site-directed mutagenesis
Anne L Carenbauer, James D Garrity, Gopal Periyannan, Robert B Yates, Michael W Crowder
BMC Biochemistry , 2002, DOI: 10.1186/1471-2091-3-4
Abstract: Site-directed mutations were generated of amino acids previously predicted to be important in substrate binding. Steady-state kinetic studies using the mutant enzymes and 9 different substrates demonstrated varying Km and kcat values for the different enzymes and substrates and that no direct correlation between Km and the effect of the mutation on substrate binding could be drawn. Stopped-flow fluorescence studies using nitrocefin as the substrate showed that only the S224D and Y228A mutants exhibited weaker nitrocefin binding.The data presented herein indicate that Ser224, Ile164, Phe158, Tyr228, and Asn233 are not essential for tight binding of substrate to metallo-β-lactamase L1. The results in this work also show that Km values are not reliable for showing substrate binding, and there is no correlation between substrate binding and the amount of reaction intermediate formed during the reaction. This work represents the first experimental testing of one of the computational models of the metallo-β-lactamases.The overuse of antibiotics in the clinic and for agricultural uses has resulted in a tremendous selective pressure for antibiotic resistant bacteria. These bacteria become resistant by a number of mechanisms, such as producing enzymes that hydrolyze or inactivate the antibiotics, producing efflux pumps that transport the antibiotic out of the cell, or modifying their cell wall components so they no longer bind effectively to the antibiotics [1-3]. The most common, least expensive, and effective antibiotics are the β-lactam containing antibiotics, such as the penicillins, cephalosporins, and carbapenems [2,4,5]. These antibiotics are mechanism-based inhibitors of transpeptidase, a bacterial enzyme required for the production of a strong viable cell wall [6,7]. In response to the widespread use of β-lactam containing antibiotics, bacteria have acquired the ability to produce β-lactamases, which are enzymes that hydrolyze and inactivate β-lactam containing anti
EMS Stretcher “Misadventures” in a Large, Urban EMS System: A Descriptive Analysis of Contributing Factors and Resultant Injuries
Jeffrey M. Goodloe,Christopher J. Crowder,Annette O. Arthur,Stephen H. Thomas
Emergency Medicine International , 2012, DOI: 10.1155/2012/745706
Abstract: Purpose. There is a paucity of data regarding EMS stretcher-operation-related injuries. This study describes and analyzes characteristics associated with undesirable stretcher operations, with or without resultant injury in a large, urban EMS agency. Methods. In the study agency, all stretcher-related “misadventures” are required to be documented, regardless of whether injury results. All stretcher-related reports between July 1, 2009 and June 30, 2010 were queried in retrospective analysis, avoiding Hawthorne effect in stretcher operations. Results. During the year studied, 129,110 patients were transported. 23 stretcher incidents were reported (0.16 per 1,000 transports). No patient injury occurred. Four EMS providers sustained minor injuries. Among contributing aspects, the most common involved operations surrounding the stretcher-ambulance safety latch, 14/23 (60.9%). From a personnel injury prevention perspective, there exists a significant relationship between combative patients and crew injury related to stretcher operation, Fisher’s exact test 0.048. Conclusions. In this large, urban EMS system, the incidence of injury related to stretcher operations in the one-year study period is markedly low, with few personnel injuries and no patient injuries incurred. Safety for EMS personnel and patients could be advanced by educational initiatives that highlight specific events and conditions contributing to stretcher-related adverse events. 1. Introduction The majority of patient transportation in the prehospital emergency medical care environment involves the use of mobile stretchers. Stretcher utilization occurs in three distinct phases: (1) unloading from the ambulance; (2) loading into the ambulance; (3) transporting over surface structures. Several commercially manufactured devices have been designed to best accomplish these activities. Constraints on the stretcher system are myriad, including weight and size of the patient, ease of use, and durability. With these limitations in mind, finding the balance of performance and safety is an important mission. Thus, ambulance stretcher operations constitute a necessary, yet risky, part of the provision of prehospital emergency medical services. Despite generally widespread acknowledgement of risk to patient and EMS professional alike, there remains a paucity of data addressing ambulance stretcher associated injury analysis. A review of the past decade’s literature in the PubMed database (http://www.ncbi.nlm.nih.gov/pubmed) searching with the unrestricted term of??“ambulance stretcher” yields few relevant
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