Targeted therapy in melanoma

Malignant melanoma is a highly lethal disease unless detected early. Single-agent chemotherapy is well tolerated but is associated with very low response rates. Combination chemotherapy and biochemotherapy may improve objective response rates but do not prolong survival and are associated with greater toxicity. Immunotherapeutic approaches such as high-dose interleukin-2 are associated with durable responses in a small percentage of patients, but are impractical for many patients due to accessibility and toxicity issues. Elucidations of the molecular mechanisms of carcinogenesis in melanoma have expanded the horizon of opportunity to alter the natural history of the disease. Multiple signal transduction pathways seem to be aberrant and drugs that target them have been and continue to be in development. In this review we present data on the most promising targeted agents in development, including B-raf inhibitors and other signal transduction inhibitors, oligonucleotides, proteasome inhibitors, as well as inhibitors of angiogenesis. Most agents are in early phase trials although some have already reached phase III evaluation. As knowledge and experience with targeted therapy advance, new challenges appear to be arising particularly in terms of resistance and appropriate patient selection

Digital Waste Sorting: A Goal-Based, Self-Learning Approach to Label Spam Email Campaigns

Fast analysis of correlated spam emails may be vital in the effort of finding and prosecuting spammers performing cybercrimes such as phishing and online frauds. This paper presents a self-learning framework to automatically divide and classify large amounts of spam emails in correlated labeled groups. Building on large datasets daily collected through honeypots, the emails are firstly divided into homogeneous groups of similar messages campaigns), which can be related to a specific spammer. Each campaign is then associated to a class which specifies the goal of the spammer, i.e. phishing, advertisement, etc. The proposed framework exploits a categorical clustering algorithm to group similar emails, and a classifier to subsequently label each email group. The main advantage of the proposed framework is that it can be used on large spam emails datasets, for which no prior knowledge is provided. The approach has been tested on more than 3200 real and recent spam emails, divided in more than 60 campaigns, reporting a classification accuracy of 97% on the classified data.pringer International Publishing Switzerland 2015 S. Foresti (Ed.): STM 2015, LNCS 9331, pp. 3?19, 2015. DOI: 10.1007/978-3-319-24858-5

Summary of Topological Study of Chaotic CBC Mode of Operation

International audience—In cryptography, block ciphers are the most fundamental elements in many symmetric-key encryp-tion systems. The Cipher Block Chaining, denoted CBC, presents one of the most famous mode of operation that uses a block cipher to provide confidentiality or authenticity. In this research work, we intend to summarize our results that have been detailed in our previous series of articles. The goal of this series has been to obtain a complete topological study of the CBC block cipher mode of operation after proving his chaotic behavior according to the reputed definition of Devaney

Algorithmes pour l'estimation des données dans les réseaux de capteurs

International audienceLa collecte des données est un des enjeux majeurs dans les réseaux de capteurs. En effet, les communications induites par la transmission de données réduisent considérablement la durée de vie du réseau. Une des techniques utilisées pour réduire la quantité de données transférées est l'agrégation et selon le type des données étudiées, une des possibilités est l'utilisation de série temporelle ARMA. Dans cet article, nous proposons quatre algorithmes d'agrégation de données s'appuyant sur le modèle AR permettant ainsi la diminution de la consommation d'énergie dans les réseaux de capteurs et augmentant la durée de vie de ceux-ci

The Epigenetic Regulation of Chemotherapy Resistance in Melanoma

Melanoma is rapidly increasing in incidence throughout the world. Early stages are curable with surgical approaches with excellent prognosis. However, a substantial proportion of patients progress to metastatic disease with survival rates of less than 5% making melanoma the culprit for over 65% of all skin-cancer related deaths. Novel agents targeting the immune system and the signaling pathways of melanoma are generating new promise, but chemotherapy remains an important therapeutic alternative, despite low response rates. The resistance of melanoma to chemotherapy is in part due to DNA repair mechanisms that allow cells to survive alkylation damage. Several novel agents targeting the abrogation of DNA repair pathways alone and in combination with cytotoxic agents have been developed with varying measures of success. In this dissertation, we first identified the epigenetic silencing of the DNA mismatch repair (MMR) gene MLH1 as a determinant of response and survival for melanoma patients treated with alkylator-based chemotherapy (dacarbazine/ temozolomide). We then determined the safe dosage of the epigenetic agent decitabine that can be administered in combination with temozolomide. The safety, tolerability and efficacy of the combination of decitabine and temozolomide were evaluated in a Phase II population. We finally determined the pharmacokinetic and pharmacodynamic effects of treatment with the combination of decitabine and temozolomide in the blood and tumor tissues of metastatic melanoma patients

Synthèse de métallophosphates microstructurés obtenus par génération in situ de l'agent structurant

Une nouvelle voie de synthèse de matériaux microstructurés à base de phosphore est présentée. Elle permet de réduire le nombre de réactifs et consiste à utiliser un composé phosphoré servant à la fois de source de phosphore et de précurseur d agent structurant. Ce dernier est généré in situ dans le milieu de synthèse. Nous présentons le cas de l utilisation de l hexaméthylphosphoramide, l oxyde de tripyrrolidinophosphine, l hexaéthyltriaminophosphine et la trimorpholinophosphine dont la décomposition a fait l objet d une étude par RMN liquide 1H et 31P. Suite aux analyses effectuées à partir de mélanges de composition molaire différente, il apparait qu une élévation de température, la présence d ions H3O+ et de l éthylène glycol soient des critères qui favorisent la décomposition des molécules d alkylphosphoramides. Les synthèses réalisées en présence d une source de gallium ont conduit à la cristallisation de gallophosphates de structure connue. De façon inattendue, deux agents structurants sont identifiés dans le fluorogallophosphate ULM-3 : la diméthylamine et NH4+. Les synthèses réalisées en présence d une source d aluminium ont conduit à la cristallisation d une nouvelle phase dont la structure est en cours de résolution et à la cristallisation d aluminophosphates de structure connue. Les analyses par RMN liquide 1H et 31P nous ont permis de proposer des mécanismes de décomposition d alkylphosphoramides dans les différents milieux de synthèse.This work focuses on the development of a new synthesis route by reducing the number of reactants for the synthesis of phosphate-based materials. This synthesis strategy was developed by using alkylphosphoramide which can play both the role of precursor of the structure-directing agent (SDA) and the phosphorus source. In this work we present the case of hexamethylphosphoramide, tris(N,N-tetramethylene)phosphoric acid triamide, tris(diethylamino)phosphine and trimorpholinophosphine oxide. 1H and 31P liquid NMR spectroscopy was used to fully characterize the decomposition of the alkylphosphoramide. It has been found that the heating temperature, the presence of an acid and ethylene glycol play a crucial role on the alkylphosphoramide decomposition. The synthesis results obtained for the gallophosphate and aluminophosphate systems are reported. The in situ generation of the SDA and the phosphorus source allowed preparing known crystallized gallophosphates and aluminophosphates. For the fluorogallophosphate ULM-3, the 1H liquid NMR spectrum shows clearly the presence of dimethylamine and ammonium cations as structure-directing agents. A new aluminophosphate has been obtained. Finally, a decomposition mechanism of the alkylphosphoramides was proposed for the different reaction media under study.MULHOUSE-SCD Sciences (682242102) / SudocSudocFranceF

Chordoma: The Nonsarcoma Primary Bone Tumor

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139965/1/onco1344.pd

A formal dynamic semantics of Java: an essential ingredient of Java security, Journal of Telecommunications and Information Technology, 2002, nr 4

Security is becoming a major issue in our highly networked and computerized era. Malicious code detection is an essential step towards securing the execution of applications in a highly inter-connected context. In this paper, we present a formal definition of Java dynamic semantics. This semantics has been used as a basis to develop efficient, rigorous and provably correct static analysis tools and a certifying compiler aimed to detect and prevent the presence of malicious code in Java applications. We propose a small step operational semantics of a large subset for Java. The latter includes features that have not been completely addressed in the related work or addressed in another semantics style. We provide a fully-fledged semantic handling of exceptions, reachable statements, modifiers and class initialization

Clinical review: Serious adverse events associated with the use of rituximab - a critical care perspective

The advent of biologic agents has provided a more specific and targeted approach to the treatment of various hematological malignancies and other autoimmune disorders. Such biologic agents have been relatively well tolerated with fewer adverse events reported as compared with many other chemotherapeutic agents. Rituximab is a monoclonal antibody to the B-cell marker CD20 and is a common biologic agent widely used for the treatment of B-cell lymphoma, lymphoproliferative disorders, and inflammatory conditions that are refractory to conventional treatment, including rheumatoid arthritis and some vasculitides. However, through randomized controlled trials and post-marketing surveillance, an increasing number of serious adverse events are being associated with the use of rituximab, often leading to or complicating an intensive care unit admission. The purpose of this review is to focus on the severe complications that are associated with the use of rituximab and that require critical care. Management and prevention strategies for the most common complications along with some examples of its uses within the critical care setting are also discussed. © 2012 BioMed Central Ltd

Epidermal Growth Factor Receptor Expression and Mutational Analysis in Synovial Sarcomas and Malignant Peripheral Nerve Sheath Tumors

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140003/1/onco0459.pd