A randomized controlled trial of filgrastim during remission induction and consolidation chemotherapy for adults with acute lymphoblastic leukemia: CALGB study 9111

Recombinant human granulocyte colony-stimulating factor (G-CSF; filgrastim) shortens the time to neutrophil recovery after intensive chemotherapy, but its role in the treatment of adults with acute lymphoblastic leukemia (ALL) is uncertain. We randomly assigned 198 adults with untreated ALL (median age, 35 years; range, 16 to 83) to receive either placebo or G-CSF (5 microgram/kg/d) subcutaneously, beginning 4 days after starting intensive remission induction chemotherapy and continuing until the neutrophil count was >/=1, 000/microL for 2 days. The study assignment was unblinded as individual patients achieved a complete remission (CR). Patients initially assigned to G-CSF then continued to receive G-CSF through 2 monthly courses of consolidation therapy. Patients assigned to placebo received no further study drug. The median time to recover neutrophils >/=1,000/microL during the remission induction course was 16 days (interquartile range [IQR], 15 to 18 days) for the patients assigned to receive G-CSF and 22 days (IQR, 19 to 29 days) for the patients assigned to placebo (P < .001). Patients in the G-CSF group had significantly shorter durations of neutropenia (<1, 000/microL) and thrombocytopenia (<50,000/microL) and fewer days in the hospital (median, 22 days v 28 days; P = .02) compared with patients receiving placebo. The patients assigned to receive G-CSF had a higher CR rate and fewer deaths during remission induction than did those receiving placebo (P = .04 by the chi-square test for trend). During Courses IIA and IIB of consolidation treatment, patients in the G-CSF group had significantly more rapid recovery of neutrophils >/=1,000/microL than did the control group by approximately 6 to 9 days. However, the patients in the G-CSF group did not complete the planned first 3 months of chemotherapy any more rapidly than did the patients in the placebo group. Overall toxicity was not lessened by the use of G-CSF. After a median follow-up of 4. 7 years, there were no significant differences in either the disease-free survival (P = .53) or the overall survival (P = .25) for the patients assigned to G-CSF (medians, 2.3 years and 2.4 years, respectively) compared with those assigned to placebo (medians, 1.7 and 1.8 years, respectively). Adults who received intensive chemotherapy for ALL benefited from G-CSF treatment, but its use did not markedly affect the ultimate outcome.     

Dynamics and organization of MAP kinase signal pathways

In the budding yeast, Saccharomyces cerevisiae, four separate but structurally related mitogen-activated protein kinase (MAPK) activation pathways are known. The best understood of these regulates mating. Pheromone binding to receptor informs cells of the proximity of a mating partner and induces differentiation to a mating competent state. The MAPK activation cascade mediating this signal is made up of Ste11 (a MEK kinase [MEKK]), Ste7 (a MAPK/ERK kinase [MEK]), and the redundant MAPK-related Fus3 and Kss1 enzymes. Another MAPK activation pathway is important for cell integrity and regulates cell wall construction. This cascade consists of Bck1 (a MEKK), the redundant Mkk1 and Mkk2 enzymes (MEKs), and Mpk1 (a MAPK). We exploited these two pathways to learn about the coordination and signal transmission fidelity of MAPK activation cascades. Two lines of evidence suggest that the activities of the mating and cell integrity pathways are coordinated during mating differentiation. First, cells deficient in Mpk1 are susceptible to lysis when they make a mating projection in response to pheromone. Second, Mpk1 activation during pheromone induction coincides with projection formation. The mechanism underlying this coordination is still unknown to us. Our working model is that projection formation generates a mobile second messenger for activation of the cell integrity pathway. Analysis of a STE7 mutation gave us some unanticipated but important insights into parameters important for fidelity of signal transmission. The Ste7 variant has a serine to proline substitution at position 368. Ste7-P368 has higher basal activity than the wild-type enzyme but still requires Ste11 for its function. Additionally, the proline substitution enables the variant to transmit the signal from mammalian Raf expressed in yeast. This novel activity suggests that Ste7-P368 is inherently more permissive than Ste7 in its interactions with MEKKs. Yet, Ste7-P368 cross function in the cell integrity pathway occurs only when it is highly overproduced or when Ste5 is missing. This behavior suggests that Ste5, which has been proposed to be a tether for the kinases in the mating pathway, contributes to Ste7 specificity and fidelity of signal transmission.     

Evaluating a graphical notation for modelling software development methodologies

This work aims at evaluating a graphical notation for modelling software (and other kinds of) development methodologies, thus demonstrating how useful the graphical aspects can be for sharing knowledge between the people responsible for documenting information and those responsible for understanding and putting it into practice. We acknowledge the importance of having a common set of symbols that can be used to create, use and disseminate information for a larger audience than is possible today with a variety of alternatives and lack of a common ground. Using a cognitive dimensions framework, we make a standard evaluation of the elements and diagrams of the notation proposed to support the ISO/IEC 24744 methodology metamodel standard, considering the trade-offs between different dimensions. We suggest improvements to this existing notation based on this analysis, in the context of improving communication between creators and users of methodologies.     

A framework for avoiding steganography usage over HTTP

Steganographic techniques allow users to covertly transmit information, hiding the existence of the communication itself. These can be used in several scenarios ranging from evading censorship to discreetly extracting sensitive information from an organization. In this paper, we consider the problem of using steganography through a widely used network protocol (i.e. HTTP). We analyze the steganographic possibilities of HTTP, and propose an active warden model to hinder the usage of covert communication channels. Our framework is meant to be useful in many scenarios. It could be employed to ensure that malicious insiders are not able to use steganography to leak information outside an organization. Furthermore, our model could be used by web servers administrators to ensure that their services are not being abused, for example, as anonymous steganographic mailboxes. Our experiments show that steganographic contents can be successfully eliminated, but that dealing with high payload carriers such as large images may introduce notable delays in the communication process.     

Scalable,low complexity,and fast greedy scheduling heuristics for highly heterogeneous distributed computing systems

For heterogeneous distributed computing systems, important design issues are scalability and system optimization. Given such systems, it is crucial to develop low computational complexity algorithms to schedule tasks in a manner that exploits the heterogeneity of the resources and applications. In this paper, we report and evaluate three scalable, and fast scheduling heuristics for highly heterogeneous distributed computing systems. We conduct a comprehensive performance evaluation study using simulation. The benchmarking outlines the performance of the schedulers, representing scalability, makespan, flowtime, computational complexity, and memory utilization. The set of experimental results shows that our heuristics perform as good as the traditional approaches, for makespan and flowtime, while featuring lower complexity, lower running time, and lower used memory. The experimental results also detail the various scenarios under which certain algorithms excel and fail.     

Volatile Emissions Triggered by Multiple Herbivore Damage: Beet Armyworm and Whitefly Feeding on Cotton Plants

Plants are commonly attacked by more than one species of herbivore, potentially causing the induction of multiple, and possibly competing, plant defense systems. In the present paper, we determined the interaction between feeding by the phloem feeder silverleaf whitefly (SWF), Bemisia tabaci Gennadius (B-biotype = B. argentifolii Bellows and Perring), and the leaf-chewing beet armyworm (BAW), Spodoptera exigua Hübner, with regard to the induction of volatile compounds from cotton plants. Compared to undamaged control plants, infestation with SWF did not induce volatile emissions or affect the number and density of pigment glands that store volatile and nonvolatile terpenoid compounds, whereas infestation by BAW strongly induced plant volatile emission. When challenged by the two insect herbivores simultaneously, volatile emission was significantly less than for plants infested with only BAW. Our results suggest that tritrophic level interactions between cotton, BAW, and natural enemies of BAW, that are known to be mediated by plant volatile emissions, may be perturbed by simultaneous infestation by SWF. Possible mechanisms by which the presence of whiteflies may attenuate volatile emissions from caterpillar-damaged cotton plants are discussed.     

Addressing universal access in social networks: an inclusive search mechanism

Social network services (SNSs) have brought new possibilities and challenges to the design of software environments that respect people’s cultural differences. These systems may represent an opportunity for social and digital inclusion. However, search mechanisms in these systems impose serious barriers for people in the process of acquiring digital literacy. One of the barriers is the difficulty of using the adequate terms/keywords to perform content searches. This paper presents an approach to allow ordinary, non-technology proficient people to access the content of a network through the use of search parameters that make sense to them. The proposal is grounded on Semantic Web technologies (Web ontology) combined with Organizational Semiotics concepts and methods to identify the users’ profile and language. A case study was conducted with the search mechanism integrated into a SNS, and a preliminary evaluation reveals the advantages and drawbacks of the approach.     

Metabolic behavior in rats of a nonprotein microemulsion resembling low-density lipoprotein

A protein-free microemulsion (LDE) with a lipid composition resembling that of low-density lipoprotein (LDL) was used in metabolic studies in rats to compare LDE with the native lipoprotein. LDE labeled with radioactive lipids was injected into the bloodstream of male Wistar rats, and plasma kinetics of the labeled lipids were followed on plasma samples collected at regular intervals for 12 h after injection. The 24-h LDE uptake by different tissues was also measured in tissue samples excised after the animals had been sacrificed. We found that LDE plasma kinetics were similar to those described for native LDL [fractional clearance rate (FCR) of cholesteryl ester, 0.42±0.11 h⁻¹]. The major site for LDE uptake was the liver, and the tissue distribution of the LDE injected radioactivity was as one would expect for LDL. To test whether LDE was taken up by the specific LDL receptors, the LDE emulsion was injected into rats treated with 17α-ethinylestradiol, which is known to increase the activity of these receptors; as expected, removal of LDE from the bloodstream increased (FCR=0.90±0.35 h⁻¹). On the other hand, saturation of the receptors that remove remnants by prior infusion of massive amounts of lymph chylomicrons did not change LDE plasma kinetics. These results indicate that LDE is cleared from plasma by B,E receptors and not by the E receptors that remove remnants. Incorporation of free cholesterol into LDE increased LDE plasma clearance. Incubation studies also showed that LDE incorporates a variety of apolipoproteins, including apo E, a ligand for recognition of lipoproteins by specific receptors. Our data suggest that LDE can be a useful tool to test LDL metabolism and B,E receptor function.     

Extended Reflexive Ontologies for the Generation of Clinical Recommendations

Decision recommendations are a set of alternative options for clinical decisions (e.g., diagnosis, prognosis, treatment selection, follow-up, and prevention) that are provided to decision makers by knowledge-based Clinical Decision Support Systems (k-CDSS) as aids. We propose to follow a “reasoning over domain” approach for the generation of decision recommendations by gathering and inferring conclusions from production rules. In order to rationalize our approach, we present a specification that will sustain the logic models supported in the knowledge bases we use for persistence. We introduce first the underlying knowledge model and then the necessary extensions that will convey toward the solution of the reported needs. The starting point of our approach is the proposition of Reflexive Ontologies (RO). Here, we go a step further, proposing an extension of RO that includes the handling and reasoning that production rules provide. Our approach speeds up the recommendation generation process.     

Patchy solution of a Francis–Byrnes–Isidori partial differential equation

The solution to the nonlinear output regulation problem requires one to solve a first‐order partial differential equation, known as the Francis–Byrnes–Isidori equations. In this paper, we propose a method to compute approximate solutions to the Francis–Byrnes–Isidori equations when the zero dynamics of the plant are hyperbolic and the exosystem is two dimensional. With our method, we are able to produce approximations that converge uniformly to the true solution. Our method relies on the periodic nature of two‐dimensional analytic center manifolds. Copyright © 2012 John Wiley & Sons, Ltd.