Tuberculostearic Acid-Containing Phosphatidylinositols as Markers of Bacterial Burden in Tuberculosis

One-fourth of the global human population is estimated to be infected with strains of the Mycobacterium tuberculosis complex (MTBC), the causative agent of tuberculosis (TB). Using lipidomic approaches, we show that tuberculostearic acid (TSA)-containing phosphatidylinositols (PIs) are molecular markers for infection with clinically relevant MTBC strains and signify bacterial burden. For the most abundant lipid marker, detection limits of ∼10$^{2}$ colony forming units (CFUs) and ∼10$^{3}$ CFUs for bacterial and cell culture systems were determined, respectively. We developed a targeted lipid assay, which can be performed within a day including sample preparation─roughly 30-fold faster than in conventional methods based on bacterial culture. This indirect and culture-free detection approach allowed us to determine pathogen loads in infected murine macrophages, human neutrophils, and murine lung tissue. These marker lipids inferred from mycobacterial PIs were found in higher levels in peripheral blood mononuclear cells of TB patients compared to healthy individuals. Moreover, in a small cohort of drug-susceptible TB patients, elevated levels of these molecular markers were detected at the start of therapy and declined upon successful anti-TB treatment. Thus, the concentration of TSA-containing PIs can be used as a correlate for the mycobacterial burden in experimental models and in vitro systems and may prospectively also provide a clinically relevant tool to monitor TB severity

LICC: L-BLP25 in patients with colorectal carcinoma after curative resection of hepatic metastases--a randomized, placebo-controlled, multicenter, multinational, double-blinded phase II trial

Background: 15-20% of all patients initially diagnosed with colorectal cancer develop metastatic disease and surgical resection remains the only potentially curative treatment available. Current 5-year survival following R0-resection of liver metastases is 28-39%, but recurrence eventually occurs in up to 70%. To date, adjuvant chemotherapy has not improved clinical outcomes significantly. The primary objective of the ongoing LICC trial (L-BLP25 In Colorectal Cancer) is to determine whether L-BLP25, an active cancer immunotherapy, extends recurrence-free survival (RFS) time over placebo in colorectal cancer patients following R0/R1 resection of hepatic metastases. L-BLP25 targets MUC1 glycoprotein, which is highly expressed in hepatic metastases from colorectal cancer. In a phase IIB trial, L-BLP25 has shown acceptable tolerability and a trend towards longer survival in patients with stage IIIB locoregional NSCLC. Methods: This is a multinational, phase II, multicenter, randomized, double-blind, placebo-controlled trial with a sample size of 159 patients from 20 centers in 3 countries. Patients with stage IV colorectal adenocarcinoma limited to liver metastases are included. Following curative-intent complete resection of the primary tumor and of all synchronous/metachronous metastases, eligible patients are randomized 2:1 to receive either L-BLP25 or placebo. Those allocated to L-BLP25 receive a single dose of 300 mg/m2 cyclophosphamide (CP) 3 days before first L-BLP25 dose, then primary treatment with s.c. L-BLP25 930 mug once weekly for 8 weeks, followed by s.c. L-BLP25 930 mug maintenance doses at 6-week (years 1&2) and 12-week (year 3) intervals unless recurrence occurs. In the control arm, CP is replaced by saline solution and L-BLP25 by placebo. Primary endpoint is the comparison of recurrence-free survival (RFS) time between groups. Secondary endpoints are overall survival (OS) time, safety, tolerability, RFS/OS in MUC-1 positive cancers. Exploratory immune response analyses are planned. The primary endpoint will be assessed in Q3 2016. Follow-up will end Q3 2017. Interim analyses are not planned. Discussion: The design and implementation of such a vaccination study in colorectal cancer is feasible. The study will provide recurrence-free and overall survival rates of groups in an unbiased fashion. Trial Registration EudraCT Number 2011-000218-2

Migratable Web Services: Increasing Performance and Privacy in Service Oriented Architectures

{bchammer | linnemann} @ ifis.uni-luebeck.de www.ifis.uni-luebeck.de Common web service architectures follow the classical client-server model with the client bound to the web service by a static physical connection. In this paper we show that this model is too restricted for some business scenarios and motivate the paradigm and the advantages of migratable web services. Migratable web services are instances of conventional web services that can change their executing host at runtime without loosing the actual state and the connection to their clients. Migratable web services exceed remote installation of code because the current state of a web service instance is preserved. We present a prototypical implementation based on Apache Axis which allows the seamless migration of arbitrary web service instances between different hosts. The connection to the clients is not affected by migration processes as the physical client-server model is abstracted to a logical client server model. The discovering of migrated service instances may use centralized as well as decentralized approaches. We present a JXTA based P2P grid that is used to discover an instance of a web service after multiple unnoticed migrations

Migrating stateful web services using Apache Axis and

{bchammer | linnemann} @ ifis.uni-luebeck.de Common web service architectures follow the classical client-server model with the client bound to the web service by a static physical connection. In this paper we show that this model is too restricted for some business scenarios and motivate the paradigm and the advantages of migratable web services. Migratable web services are instances of conventional web services that can change their executing host without loosing the actual state and the connection to their clients. Migratable web services exceed remote installation of code. We present an Apache Axis based architecture which allows the seamless migration of arbitrary web service instances between hosts. The connection to the clients is not affected by migration processes as the physical client-server model is abstracted to a logical client server model. A JXTA based P2P grid is used by an infrequently requesting client to discover its personal instance of a web service after multiple unnoticed migrations

Autonomous Index Optimization in XML Databases

Defining suitable indexes is a major task when optimizing a database. Usually, a human database administrator defines a set of indexes in the design phase of the database. This can be done manually or with the help of so called index wizard tools analyzing predefined database operations. Even having an optimal initial set of indexes when setting up a database, there is no guarantee that these indexes will suit future demands. Rather, it is realistic that the typical usage of the database will change after a while because new queries appear, for instance. In consequence, the existing indexes are suboptimal. The typical way to handle this problem is that a database administrator maintains the database permanently. In XML database management systems (XDBMS) this problem becomes even worse: Because XML queries cover both content and structure the number of possible queries and indexes is significantly higher. Additionally, for XML data without schema information, queries and indexes cannot be defined in advance, because the structure and the content of the data is not restricted. Both facts tend to result in higher maintenance costs for XML indexes compared to relational indexes. In this paper we show by performance measurements that an adaptive XDBMS that analyzes its workload periodically and creates/drops XML indexes automatically guarantees a high performance over the total life time of a database. Although we present our index system called KeyX the idea and the results are transferable to other XML indexing approaches