Powerful Inhibition of Experimental Human Pancreatic Cancers by Receptor Targeted Cytotoxic LH-RH analog AEZS-108

Pancreatic carcinoma is one of the cancers with the worse prognosis, thus any therapeutic improvement is imperative. Cytotoxic LH-RH analog, AN-152 (proprietary designation, AEZS-108), consisting of doxorubicin (DOX) conjugated to D-Lys6LH-RH, is now in clinical trials for targeted therapy of several sex hormone-dependent tumors that express LH-RH receptors. We investigated LH-RH receptors in human pancreatic carcinoma and the effects of AN-152 (AEZS-108) on experimental pancreatic cancers. We determined LH-RH receptor presence in human pancreatic cancer samples by immunohistochemistry and, in three human pancreatic cancer lines (SW-1990, Panc-1 and CFPAC-1), by binding assays and Western blotting. The effects of the cytotoxic LH-RH analog were investigated on growth of these same cancer lines xenografted into nude mice. We also analyzed differences between the antitumor effects of the cytotoxic analog and its cytotoxic radical alone, doxorubicin (DOX), on the expression of cancer-related genes by PCR arrays. LH-RH receptors were expressed in two randomly selected surgically removed human pancreatic cancer samples and in all three cancer lines. Cytotoxic LH-RH analogs powerfully inhibited growth of all three tumor lines in nude mice; AN-152 was significantly stronger than DOX on Panc-1 and CFPAC-1 cancers. PCR array showed that cytotoxic LH-RH analog AN-152 affected the expression of genes associated with cellular migration, invasion, metastasis and angiogenesis more favorably than DOX, however the changes in gene expression varied considerably among the three cancer lines. Cytotoxic LH-RH analog, AEZS-108, may be a useful agent for the treatment of LH-RH receptor positive advanced pancreatic carcinoma

Gene Expression Profiling and Association Studies Implicate the Neuregulin Signaling Pathway in Behçet's Disease Susceptibility

Behçet's disease (BD) is a complex disease with genetic and environmental risk factors implicated in its etiology; however, its pathophysiology is poorly understood. To decipher BD's genetic underpinnings, we combined gene expression profiling with pathway analysis and association studies. We compared the gene expression profiles in peripheral blood mononuclear cells (PBMCs) of 15 patients and 14 matched controls using Affymetrix microarrays and found that the neuregulin signaling pathway was over-represented among the differentially expressed genes. The Epiregulin (EREG), Amphiregulin (AREG), and Neuregulin-1 (NRG1) genes of this pathway stand out as they are also among the top differentially expressed genes. Twelve haplotype tagging SNPs at the EREG-AREG locus and 15 SNPs in NRG1 found associated in at least one published BD genome-wide association study were tested for association with BD in a dataset of 976 Iranian patients and 839 controls. We found a novel association with BD for the rs6845297 SNP located downstream of EREG, and replicated three associations at NRG1 (rs4489285, rs383632, and rs1462891). Multifactor dimensionality reduction analysis indicated the existence of epistatic interactions between EREG and NRG1 variants. EREG-AREG and NRG1, which are members of the epidermal growth factor (EGF) family, seem to modulate BD susceptibility through main effects and gene–gene interactions. These association findings support a role for the EGF/ErbB signaling pathway inBD pathogenesis that warrants further investigation and highlight the importance of combining genetic and genomic approaches to dissect the genetic architecture of complex diseases

IL10 Low-Frequency Variants in Behçet's Disease Patients

To explain the missing heritability after the genome-wide association studies era, sequencing studies allow the identification of low-frequency variants with a stronger effect on disease risk. Common variants in the interleukin 10 gene (IL10) have been consistently associated with Behçet's disease (BD) and the goal of this study is to investigate the role of low-frequency IL10 variants in BD susceptibility

Status of the SOLEIL femtosecond X-ray source

http://accelconf.web.cern.ch/AccelConf/FEL2012/papers/wepd04.pdfInternational audienceAn electron bunch slicing setup is presently under construction on the SOLEIL storage ring for delivering 100 fs (rms) long photon pulses to two undulator-based beamlines providing soft (TEMPO) and hard X-rays (CRISTAL). Thanks to the non-zero dispersion function present in all straight sections of the storage ring, the sliced bunches can be easily separated from the core bunches. The modulator is a wiggler composed of 20 periods of 164.4 mm. It produces a magnetic field of 1.8 T at a minimum gap of 14.5 mm. To modulate the kinetic energy of the electrons in the wiggler, a Ti:Sa laser will be used, which produces 50 fs pulses at 800 nm with a repetition rate of 2.5 kHz. The laser beam is splitted into two branches in order to provide 2 mJ to the modulator and 0.5 mJ as pump pulse for the CRISTAL and TEMPO end stations. Focusing optics and beam path, from the laser hutch to the inside of the storage ring tunnel are presently under finalization. In this paper, we will report on the specificities of the SOLEIL setup, the status of its installation and the expected performances

Progress of the LUNEX5 Project

http://accelconf.web.cern.ch/AccelConf/FEL2013/papers/wepso05.pdfInternational audienceLUNEX5 (free electron Laser Using a New accelerator for the Exploitation of X-ray radiation of 5th generation) aims at investigating the production of short, intense, and coherent pulses in the soft X-ray region. A 400 MeV superconducting linear accelerator and a laser wakefield accelerator (LWFA), will feed a single Free Electron Laser line with High order Harmonic in Gas and Echo Enable Harmonic Generation seeding. After the Conceptual Design Report (CDR), R&D has been launched on specific magnetic elements (cryo-ready 3 m long in-vacuum undulator, a variable strong permanent magnet quadrupoles), on diagnostics (Smith-Purcell, electro-optics). In recent transport studies of a LWFA based on more realistic beam parameters (1 % energy spread, 1 μm beam size and 1 mrad divergence) than the ones assumed in the CDR, a longitudinal and transverse manipulation enables to provide theoretical amplification. A test experiment is under preparation. It is noted in this context that among the French scientific community's interest in experiments at operating FELs is increasing

LUNEX5: A French FEL Test Facility Light Source Proposal

http://accelconf.web.cern.ch/AccelConf/IPAC2012/papers/tuppp005.pdfInternational audienceLUNEX5 is a new Free Electron Laser (FEL) source project aimed at delivering short and coherent X-ray pulses to probe ultrafast phenomena at the femto-second scale, to investigate extremely low density samples as well as to image individual nm scale objects

Revisiting the technical validation of tumour biomarker assays: how to open a Pandora's box

A tumour biomarker is a characteristic that is objectively measured and evaluated in tumour samples as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. The development of a biomarker contemplates distinct phases, including discovery by hypothesis-generating preclinical or exploratory studies, development and qualification of the assay for the identification of the biomarker in clinical samples, and validation of its clinical significance. Although guidelines for the development and validation of biomarkers are available, their implementation is challenging, owing to the diversity of biomarkers being developed. The term 'validation' undoubtedly has several meanings; however, in the context of biomarker research, a test may be considered valid if it is 'fit for purpose'. In the process of validation of a biomarker assay, a key point is the validation of the methodology. Here we discuss the challenges for the technical validation of immunohistochemical and gene expression assays to detect tumour biomarkers and provide suggestions of pragmatic solutions to address these challenges

The LUNEX5 project

http://accelconf.web.cern.ch/AccelConf/FEL2012/papers/froa03.pdfInternational audienceLUNEX5 (free electron Laser Using a New accelerator for the Exploitation of X-ray radiation of 5th generation) aims at investigating the production of short, intense, and coherent pulses in the soft X-ray region. The project consists of a Free Electron Laser (FEL) line enabling the most advanced seeding configurations: High order Harmonic in Gas (HHG) seeding and Echo Enable Harmonic Generation (EEHG) with in-vacuum (potentially cryogenic) undulators of 15 and 30 mm period. Two accelerator types feed this FEL line : a 400 MeV Conventional Linear Accelerator (CLA) using superconducting cavities compatible with a future upgrade towards high repetition rate, for the investigations of the advanced FEL schemes; and a 0.4 - 1 GeV Laser Wake Field Accelerator (LWFA), to be qualified in view of FEL application, in the single spike or seeded regime. Two pilot user experiments for timeresolved studies of isolated species and solid state matter dynamics will take benefit of LUNEX5 FEL radiation and provide feedback of the performance of the different schemes under real user conditions

S-100 protein positive cells in nasopharyngeal carcinoma (NPC): absence of prognostic significance. A clinicopathological and immunohistochemical study of 40 cases

An immunohistochemical study of S-100 protein in 43 nasopharyngeal carcinomas (NPC) of known clinical evolution (33 primary and 10 metastatic) is presented. Sixty per cent of primary site cases as well as all metastatic forms showed S-100 protein positive cells intermingled with tumour cells. These S-100 positive elements were identified as Langerhans cells. No significant differences were found when correlating S-100 protein positivity and histological NPC variants, neither in age nor in sex of patients. Statistical analysis failed to demonstrate any positive correlation between S-100 protein reactivity and clinical survival