Implementing a Business Process Management System Using ADEPT: A Real-World Case Study

This article describes how the agent-based design of ADEPT (advanced decision environment for processed tasks) and implementation philosophy was used to prototype a business process management system for a real-world application. The application illustrated is based on the British Telecom (BT) business process of providing a quote to a customer for installing a network to deliver a specified type of telecommunication service. Particular emphasis is placed upon the techniques developed for specifying services, allowing heterogeneous information models to interoperate, allowing rich and flexible interagent negotiation to occur, and on the issues related to interfacing agent-based systems and humans. This article builds upon the companion article (Applied Artificial Intelligence Vol.14, no 2, pgs. 145-189) that provides details of the rationale and design of the ADEPT technology deployed in this application

MicroRNA profiling reveals marker of motor neuron disease in ALS models

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder marked by the loss of motor neurons (MNs) in the brain and spinal cord, leading to fatally debilitating weakness. Because this disease predominantly affects MNs, we aimed to characterize the distinct expression profile of that cell type to elucidate underlying disease mechanisms and to identify novel targets that inform on MN health during ALS disease time course. microRNAs (miRNAs) are short, noncoding RNAs that can shape the expression profile of a cell and thus often exhibit cell-type-enriched expression. To determine MN-enriched miRNA expression, we used Cre recombinase-dependent miRNA tagging and affinity purification in mice. By defining thein vivomiRNA expression of MNs, all neurons, astrocytes, and microglia, we then focused on MN-enriched miRNAs via a comparative analysis and found that they may functionally distinguish MNs postnatally from other spinal neurons. Characterizing the levels of the MN-enriched miRNAs in CSF harvested from ALS models of MN disease demonstrated that one miRNA (miR-218) tracked with MN loss and was responsive to an ALS therapy in rodent models. Therefore, we have used cellular expression profiling tools to define the distinct miRNA expression of MNs, which is likely to enrich future studies of MN disease. This approach enabled the development of a novel, drug-responsive marker of MN disease in ALS rodents.SIGNIFICANCE STATEMENTAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons (MNs) in the brain and spinal cord are selectively lost. To develop tools to aid in our understanding of the distinct expression profiles of MNs and, ultimately, to monitor MN disease progression, we identified small regulatory microRNAs (miRNAs) that were highly enriched or exclusive in MNs. The signal for one of these MN-enriched miRNAs is detectable in spinal tap biofluid from an ALS rat model, where its levels change as disease progresses, suggesting that it may be a clinically useful marker of disease status. Furthermore, rats treated with ALS therapy have restored expression of this MN RNA marker, making it an MN-specific and drug-responsive marker for ALS rodents.</jats:p

Calculating Unknown Eigenvalues with a Quantum Algorithm

Quantum algorithms are able to solve particular problems exponentially faster than conventional algorithms, when implemented on a quantum computer. However, all demonstrations to date have required already knowing the answer to construct the algorithm. We have implemented the complete quantum phase estimation algorithm for a single qubit unitary in which the answer is calculated by the algorithm. We use a new approach to implementing the controlled-unitary operations that lie at the heart of the majority of quantum algorithms that is more efficient and does not require the eigenvalues of the unitary to be known. These results point the way to efficient quantum simulations and quantum metrology applications in the near term, and to factoring large numbers in the longer term. This approach is architecture independent and thus can be used in other physical implementations

Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.

Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor

Association Between Results of a Gene Expression Signature Assay and Recurrence-Free Interval in Patients With Stage II Colon Cancer in Cancer and Leukemia Group B 9581 (Alliance)

PURPOSE: Conventional staging methods are inadequate to identify patients with stage II colon cancer (CC) who are at high risk of recurrence after surgery with curative intent. ColDx is a gene expression, microarray-based assay shown to be independently prognostic for recurrence-free interval (RFI) and overall survival in CC. The objective of this study was to further validate ColDx using formalin-fixed, paraffin-embedded specimens collected as part of the Alliance phase III trial, C9581. PATIENTS AND METHODS: C9581 evaluated edrecolomab versus observation in patients with stage II CC and reported no survival benefit. Under an initial case-cohort sampling design, a randomly selected subcohort (RS) comprised 514 patients from 901 eligible patients with available tissue. Forty-nine additional patients with recurrence events were included in the analysis. Final analysis comprised 393 patients: 360 RS (58 events) and 33 non-RS events. Risk status was determined for each patient by ColDx. The Self-Prentice method was used to test the association between the resulting ColDx risk score and RFI adjusting for standard prognostic variables. RESULTS: Fifty-five percent of patients (216 of 393) were classified as high risk. After adjustment for prognostic variables that included mismatch repair (MMR) deficiency, ColDx high-risk patients exhibited significantly worse RFI (multivariable hazard ratio, 2.13; 95% CI, 1.3 to 3.5; P < .01). Age and MMR status were marginally significant. RFI at 5 years for patients classified as high risk was 82% (95% CI, 79% to 85%), compared with 91% (95% CI, 89% to 93%) for patients classified as low risk. CONCLUSION: ColDx is associated with RFI in the C9581 subsample in the presence of other prognostic factors, including MMR deficiency. ColDx could be incorporated with the traditional clinical markers of risk to refine patient prognosis

Variants in interferon-alpha pathway genes and response to pegylated interferon-Alpha2a plus ribavirin for treatment of chronic hepatitis C virus infection in the hepatitis C antiviral long-term treatment against cirrhosis trial

Combination treatment with pegylated-interferon-alpha (PEG IFN-Α) and ribavirin, the current recommended therapy for chronic hepatitis C virus (HCV) infection, results in a sustained virological response (SVR) in only about half of patients. Because genes involved in the interferon-alpha pathway may affect antiviral responses, we analyzed the relationship between variants in these genes and SVR among participants in the Hepatitis C Antiviral Long-Term treatment Against Cirrhosis (HALT-C) trial. Patients had advanced chronic hepatitis C that had previously failed to respond to interferon-based treatment. Participants were treated with peginterferon-Α2a and ribavirin during the trial. Subjects with undetectable HCV RNA at week 72 were considered to have had an SVR. Subjects with detectable HCV RNA at week 20 were considered nonresponders. We used TaqMan assays to genotype 56 polymorphisms found in 13 genes in the interferon-alpha pathway. This analysis compares genotypes for participants with an SVR to nonresponders. The primary analysis was restricted to European American participants because a priori statistical power was low among the small number (n = 131) of African American patients. We used logistic regression to control the effect of other variables that are associated with treatment response. Among 581 European American patients, SVR was associated with IFNAR1 IVS1-22G (adjusted odds ratio, 0.57; P = 0.02); IFNAR2 Ex2-33C (adjusted odds ratio, 2.09; P = 0.02); JAK1 IVS22+112T (adjusted odds ratio, 1.66; P = 0.04); and ADAR Ex9+14A (adjusted odds ratio, 1.67; P = 0.03). For the TYK2 -2256A promoter region variant, a borderline association was present among European American participants (OR, 1.51; P = 0.05) and a strong relationship among African American patients; all 10 with SVR who were genotyped for TYK2 -2256 carried the A variant compared with 68 of 120 (57%) nonresponders ( P = 0.006). Conclusion: Genetic polymorphisms in the interferon-Α pathway may affect responses to antiviral therapy of chronic hepatitis C. (H EPATOLOGY 2009.)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63061/1/22877_ftp.pd

An IL28B Genotype-Based Clinical Prediction Model for Treatment of Chronic Hepatitis C

BACKGROUND:Genetic variation in IL28B and other factors are associated with sustained virological response (SVR) after pegylated-interferon/ribavirin treatment for chronic hepatitis C (CHC). Using data from the HALT-C Trial, we developed a model to predict a patient's probability of SVR based on IL28B genotype and clinical variables. METHODS:HALT-C enrolled patients with advanced CHC who had failed previous interferon-based treatment. Subjects were re-treated with pegylated-interferon/ribavirin during trial lead-in. We used step-wise logistic regression to calculate adjusted odds ratios (aOR) and create the predictive model. Leave-one-out cross-validation was used to predict a priori probabilities of SVR and determine area under the receiver operator characteristics curve (AUC). RESULTS:Among 646 HCV genotype 1-infected European American patients, 14.2% achieved SVR. IL28B rs12979860-CC genotype was the strongest predictor of SVR (aOR, 7.56; p<.0001); the model also included HCV RNA (log10 IU/ml), AST:ALT ratio, Ishak fibrosis score and prior ribavirin treatment. For this model AUC was 78.5%, compared to 73.0% for a model restricted to the four clinical predictors and 60.0% for a model restricted to IL28B genotype (p<0.001). Subjects with a predicted probability of SVR <10% had an observed SVR rate of 3.8%; subjects with a predicted probability >10% (43.3% of subjects) had an SVR rate of 27.9% and accounted for 84.8% of subjects actually achieving SVR. To verify that consideration of both IL28B genotype and clinical variables is required for treatment decisions, we calculated AUC values from published data for the IDEAL Study. CONCLUSION:A clinical prediction model based on IL28B genotype and clinical variables can yield useful individualized predictions of the probability of treatment success that could increase SVR rates and decrease the frequency of futile treatment among patients with CHC

Thin-foil magnetic force system for high-numerical-aperture microscopy

Forces play a key role in a wide range of biological phenomena from single-protein conformational dynamics to transcription and cell division, to name a few. The majority of existing microbiological force application methods can be divided into two categories: those that can apply relatively high forces through the use of a physical connection to a probe and those that apply smaller forces with a detached probe. Existing magnetic manipulators utilizing high fields and high field gradients have been able to reduce this gap in maximum applicable force, but the size of such devices has limited their use in applications where high force and high-numerical-aperture (NA) microscopy must be combined. We have developed a magnetic manipulation system that is capable of applying forces in excess of 700 pN on a 1 μm paramagnetic particle and 13 nN on a 4.5 μm paramagnetic particle, forces over the full 4π sr, and a bandwidth in excess of 3 kHz while remaining compatible with a commercially available high-NA microscope objective. Our system design separates the pole tips from the flux coils so that the magnetic-field geometry at the sample is determined by removable thin-foil pole plates, allowing easy change from experiment to experiment. In addition, we have combined the magnetic manipulator with a feedback-enhanced, high-resolution (2.4 nm), high-bandwidth (10 kHz), long-range (100 μm xyz range) laser tracking system. We demonstrate the usefulness of this system in a study of the role of forces in higher-order chromosome structure and function

Co-infection of Influenza B and Streptococci causing severe pneumonia and septic shock in healthy women

<p>Abstract</p> <p>Background</p> <p>Since the Influenza A pandemic in 1819, the association between the influenza virus and <it>Streptococcus pneumoniae </it>has been well described in literature. While a leading role has been so far attributed solely to Influenza A as the primary infective pathogen, Influenza B is generally considered to be less pathogenic with little impact on morbidity and mortality of otherwise healthy adults. This report documents the severe synergistic pathogenesis of Influenza B infection and bacterial pneumonia in previously healthy persons not belonging to a special risk population and outlines therapeutic options in this clinical setting.</p> <p>Case Presentation</p> <p>During the seasonal influenza epidemic 2007/2008, three previously healthy women presented to our hospital with influenza-like symptoms and rapid clinical deterioration. Subsequent septic shock due to severe bilateral pneumonia necessitated intensive resuscitative measures including the use of an interventional lung assist device. Microbiological analysis identified severe dual infections of Influenza B with <it>Streptococcus pyogenes </it>in two cases and <it>Streptococcus pneumoniae </it>in one case. The patients presented with no evidence of underlying disease or other known risk factors for dual infection such as age (< one year, > 65 years), pregnancy or comorbidity.</p> <p>Conclusions</p> <p>Influenza B infection can pose a risk for severe secondary infection in previously healthy persons. As patients admitted to hospital due to severe pneumonia are rarely tested for Influenza B, the incidence of admission due to this virus might be greatly underestimated, therefore, a more aggressive search for influenza virus and empirical treatment might be warranted. While the use of an interventional lung assist device offers a potential treatment strategy for refractory respiratory acidosis in addition to protective lung ventilation, the combined empiric use of a neuraminidase-inhibitor and antibiotics in septic patients with pulmonary manifestations during an epidemic season should be considered.</p