Membrane transport proteins in human melanoma: associations with tumour aggressiveness and metastasis

BACKGROUND: Malignant melanoma, generally described as incurable, is notoriously refractory to chemotherapy. The mechanisms contributing to this have not yet been defined and the contributions of drug efflux pumps, implicated in chemo-resistance of many other cancer types, have not been extensively investigated in melanoma. METHODS: In this study, expression of multi-drug resistant (MDR1/P-gp and MRP-1) proteins was examined, by immunohistochemistry, in archival specimens from 134 melanoma patients. This included 92 primary tumours and 42 metastases. RESULTS: On assessing all specimens, MRP-1 and MDR1/P-gp expression was found to be common, with the majority (81%) of melanomas expressing at least one of these efflux pumps. Although there is significant association between expression of these pumps (P=0.007), MRP-1 was found to be the predominant (67% of cases) form detected. chi(2) analysis showed significant associations between expression of MRP-1 and/or MDR1/P-gp and the aggressive nature of this disease specifically increased Breslow's depth, Clark's level and spread to lymph nodes. This association with aggressiveness and spread is further supported by the observation that a significantly higher percentage of metastases, than primary tumours, express MRP-1 (91% vs 57%; P<0.0001) and MDR1/P-gp (74% vs 50%; P=0.010). CONCLUSION: The predominant expression of these pumps and, in particular, MRP-1 suggests that they may be important contributors to the inherent aggressive and resistant nature of malignant melanoma

Agents in decentralised information ecosystems: the DIET approach

The complexity of the current global information infrastructure requires novel means of understanding and exploiting the dynamics of information. One means may be through the concept of an information ecosystem. An information ecosystem is analo gous to a natural ecosystem in which there are flo ws of materials and energy analo gous to information flow between many interacting individuals. This paper describes a multi-agent platform, DIET (Decentralised Information Ecosystem Technologies) that can be used to implement open, robust, adaptive and scalable ecosystem-inspired systems. We describe the design principles of the DIET software architecture, and present a simple example application based upon it. We go on to consider how the DIET system can be used to develop information brokering agents, and how these can contribute to the implementation of economic interactions between agents, as well as identifying some open questions relating to research in these areas. In this way we show the capacity of the DIET system to support applications using information agents.Future and Emerging Technologies arm of the IST Programme of the European Union, under the FET Proactive Initiative – Universal Information Ecosystems (FET, 1999), through project DIET (IST -1999-10088), BTexaCT Intelligent Systems Laboratory for stimulating discussion and comment

Gemcitabine and docetaxel as first-line treatment for advanced urothelial carcinoma: a phase II study

The purpose of the study was to investigate the toxicity and efficacy of the combination of gemcitabine and docetaxel in untreated advanced urothelial carcinoma. Patients with previously untreated, locally advanced/recurrent or metastatic urothelial carcinoma stage-IV disease were eligible. Patients with Performance status: PS ECOG >3 or age >75 years or creatinine clearance <50 ml min−1 were excluded. Study treatment consisted of docetaxel 75 mg m−2 (day 8) and gemcitabine 1000 mg m−2 (days 1+8), every 21 days for a total of six to nine cycles. A total of 31 patients with urothelial bladder cancer, 25 men and six women, aged 42–74 (median 64) years were enrolled. The majority of patients had a good PS (51.6%; PS 0). In all, 15 (48.3%) patients had locally advanced or recurrent disease only and 16 (54.8%) presented with distant metastatic spread, with multiple site involvement in 22.5%. Toxicity was primarily haematologic, and the most frequent grade 3–4 toxicities were anaemia 11 (6.7%) thrombocytopenia eight (4.9%), and neutropenia 45 (27.6%), with 10 (6.1%) episodes of febrile neutropenia. No toxic deaths occurred. A number of patients had some cardiovascular morbidity (38.7%). Nonhaematological toxicities except alopecia (29 patients) were mild. Overall response rate was 51.6%, including four complete responses (12.9%) and 12 partial responses (38.7%), while a further five patients had disease stabilisation (s.d. 16.1%). The median time to progression was 8 months (95% CI 5.1–9.2 months) and the median overall survival was 15 months (95% CI 11.2–18.5 months), with 1-year survival rate of 60%. In conclusion, this schedule of gemcitabine and docetaxel is very active and well tolerated as a first-line treatment for advanced/relapsing or metastatic urothelial carcinoma. Although its relative efficacy and tolerance as compared to classic MVAC should be assessed in a phase III setting, the favourable toxicity profile of this regimen may offer an interesting alternative, particularly in patients with compromised renal function or cardiovascular disease

MinervaDL: An Architecture for Information Retrieval and Filtering in Distributed Digital Libraries

We present Minerva{DL}, a digital library architecture that supports approximate information retrieval and filtering functionality under a single unifying framework. The architecture of {M}inerva{DL} is based on the peer-to-peer search engine {M}inerva, and is able to handle huge amounts of data provided by digital libraries in a distributed and self-organizing way. The two-tier architecture and the use of the distributed hash table as the routing substrate provides an infrastructure for creating large networks of digital libraries with minimal administration costs. We discuss the main components of this architecture, present the protocols that regulate node interactions, and experimentally evaluate our approach. This work has been partly supported by the {DELOS} {N}etwork of {E}xcellence and the {EU} {I}ntegrated {P}roject {AEOLUS}

Efficient Search and Approximate Information Filtering in a Distributed Peer-to-Peer Environment of Digital Libraries

We present a new architecture for efficient search and approximate information filtering in a distributed {P}eer-to-{P}eer ({P2P}) environment of Digital Libraries. The {M}inerva{L}ight search system uses {P2P} techniques over a structured overlay network to distribute and maintain a directory of peer statistics. Based on the same directory, the {MAPS} information filtering system provides an approximate publish/subscribe functionality by monitoring the most promising digital libraries for publishing appropriate documents regarding a continuous query. In this paper, we discuss our system architecture that combines searching and information filtering abilities. We show the system components of {M}inerva{L}ight and explain the different facets of an approximate pub/sub system for subscriptions that is high scalable, efficient, and notifies the subscribers about the most interesting publications in the {P2P} network of digital libraries. We also compare both approaches in terms of common properties and differences to show an overview of search and pub/sub using the same infrastructure

Information filtering and query indexing for an information retrieval model

In the information filtering paradigm, clients subscribe to a server with continuous queries or profiles that express their information needs. Clients can also publish documents to servers. Whenever a document is published, the continuous queries satisfying this document are found and notifications are sent to appropriate clients. This article deals with the filtering problem that needs to be solved efficiently by each server: Given a database of continuous queries db and a document d, find all queries q db that match d. We present data structures and indexing algorithms that enable us to solve the filtering problem efficiently for large databases of queries expressed in the model AWP. AWP is based on named attributes with values of type text, and its query language includes Boolean and word proximity operators