Precision Beam Position Monitor for EUROTeV

In the framework of EUROTeV, a Precision Beam Position Monitor (PBPM) has been designed, manufactured and tested. The new PBPM, based on the inductive BPM presently used in the CERN CLIC Test Facility (CTF3), aims to achieve a resolution of 100 nm and an accuracy of 10 μm in a 6 mm aperture. A dedicated test bench has been designed and constructed to fully characterize and optimize the PBPM. This paper describes the final design, presents the test bench results and reports on the beam tests carried out in the CERN CTF3 Linac

The novel mTOR inhibitor RAD001 (Everolimus) induces antiproliferative effects in human pancreatic neuroendocrine tumor cells

Background/Aim: Tumors exhibiting constitutively activated PI(3) K/Akt/mTOR signaling are hypersensitive to mTOR inhibitors such as RAD001 (everolimus) which is presently being investigated in clinical phase II trials in various tumor entities, including neuroendocrine tumors (NETs). However, no preclinical data about the effects of RAD001 on NET cells have been published. In this study, we aimed to evaluate the effects of RAD001 on BON cells, a human pancreatic NET cell line that exhibits constitutively activated PI(3) K/Akt/mTOR signaling. Methods: BON cells were treated with different concentrations of RAD001 to analyze its effect on cell growth using proliferation assays. Apoptosis was examined by Western blot analysis of caspase-3/PARP cleavage and by FACS analysis of DNA fragmentation. Results: RAD001 potently inhibited BON cell growth in a dose-dependent manner which was dependent on the serum concentration in the medium. RAD001-induced growth inhibition involved G0/G1-phase arrest as well as induction of apoptosis. Conclusion: In summary, our data demonstrate antiproliferative and apoptotic effects of RAD001 in NET cells in vitro supporting its clinical use in current phase II trials in NET patients. Copyright (c) 2007 S. Karger AG, Basel

Biopsy confirmation of metastatic sites in breast cancer patients:clinical impact and future perspectives

Determination of hormone receptor (estrogen receptor and progesterone receptor) and human epidermal growth factor receptor 2 status in the primary tumor is clinically relevant to define breast cancer subtypes, clinical outcome,and the choice of therapy. Retrospective and prospective studies suggest that there is substantial discordance in receptor status between primary and recurrent breast cancer. Despite this evidence and current recommendations,the acquisition of tissue from metastatic deposits is not routine practice. As a consequence, therapeutic decisions for treatment in the metastatic setting are based on the features of the primary tumor. Reasons for this attitude include the invasiveness of the procedure and the unreliable outcome of biopsy, in particular for biopsies of lesions at complex visceral sites. Improvements in interventional radiology techniques mean that most metastatic sites are now accessible by minimally invasive methods, including surgery. In our opinion, since biopsies are diagnostic and changes in biological features between the primary and secondary tumors can occur, the routine biopsy of metastatic disease needs to be performed. In this review, we discuss the rationale for biopsy of suspected breast cancer metastases, review issues and caveats surrounding discordance of biomarker status between primary and metastatic tumors, and provide insights for deciding when to perform biopsy of suspected metastases and which one (s) to biopsy. We also speculate on the future translational implications for biopsy of suspected metastatic lesions in the context of clinical trials and the establishment of bio-banks of biopsy material taken from metastatic sites. We believe that such bio-banks will be important for exploring mechanisms of metastasis. In the future,advances in targeted therapy will depend on the availability of metastatic tissue

Hazardous cross-reaction in a thyroid fine needle aspiration.

Thyroid fine-needle aspiration cytology (FNAC) is one of the most performed medical procedures worldwide. <sup>1</sup> It is used as a diagnostic test to separate benign thyroid nodules (colloidal and hyperplastic nodules) from thyroid malignancies, either primary (papillary thyroid carcinoma (PTC), medullary thyroid carcinoma (MTC), poorly differentiated thyroid carcinoma (PDTC), anaplastic thyroid carcinoma (ATC)) or less often metastatic. <sup>2</sup> The negative and positive predictive values (NPV and PPV) of this procedure in The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) are respectively 97% and 98% for the benign and malignant categories. This article is protected by copyright. All rights reserved

« Dans ce monde, il n’est rien d’assuré que la mort et les impôts ». Étude de la taxe de la nécropole à Edfou au IIIe siècle av. J.-C.

Cet article propose une nouvelle étude de la taxe de la nécropole à Edfou au IIIe siècle av. J.-C. Cet impôt funéraire est connu depuis la publication par M. Malinine, en 1961, d’un dossier de vingt et un reçus démotiques sur ostraca. La reprise des différents travaux effectués sur cette taxe ainsi que l’analyse du formulaire et de nouvelles lectures (huit inédits sont ajoutés au dossier d’origine) permettent un nouveau regard sur l’organisation de la perception de cette taxe.This paper offers a new examination of the tax of the necropolis at Edfu in the third century B.C. This funerary tax was made known by M. Malinine in 1961 with the publication of a collection of 21 demotic receipts on ostraka. By considering the ensuing various studies on this tax as well as the analysis of the form and new readings (8 unpublished receipts have been added to the original collection) we obtain a new view on the organization of the collection of this tax

Renal Cell Carcinoma: Focus on Safety and Efficacy of Temsirolimus

Metastatic renal cell carcinoma has harboured a poor prognosis for decades with immunotherapy being the only available therapy with high toxicity and modest effect. Dependance of renal cell carcinoma oncogenesis on the mTOR pathway has led to clinical development of temsirolimus in this setting. This sirolimus derivative has shown clinical efficacy in monotherapy for poor-risk renal cell carcinoma leading to an overall survival of 10.8 months in the pivotal phase III trial of this agent. Its specific adverse events consist of metabolic dysregulation (hyperlipemia, hyperglycemia), mucositis, rash and pneumonitis which can be severe and need careful monitoring and management. In this review, we will discuss of the clinical development of this molecule, its efficacy, its safety profile and future perspectives

Reduction in HER-2 protein expression in a breast tumor HER-2 positive after only one injection of Trastuzumab: a case report

HER-2 is overexpressed in 20 to 30% of breast cancer. Generally, metastases of a breast tumor have the same HER-2 status, although some discordances were reported

Targeting cyclin D3/CDK6 activity for treatment of Parkinson’s disease.

30 p.-7 fig.-1 tab.At present, treatment for Parkinson’s disease (PD) is only symptomatic, therefore it is important to identify new targets tackling the molecular causes of the disease. We previously found that lymphoblasts from sporadic PD patients display increased activity of the cyclin D3/CDK6/pRb pathway and higher proliferation than control cells. These features were considered systemic manifestations of the disease, as aberrant activation of cell cycle is involved in neuronal apoptosis. The main goal of this work was to elucidate whether the inhibition of cyclin D3/CDK6-associated kinase activity could be useful in PD treatment. For this purpose, we investigated the effects of two histone deacetylase (HDAC) inhibitors, suberoylanilide hydroxamic acid (SAHA) and sodium butyrate (NaB), and the m-TOR inhibitor rapamycin on cell viability and cyclin D3/CDK6 activity. Moreover, the potential neuroprotective action of these drugs was evaluated in 6-hydroxy-dopamine (6-OHDA) treated dopaminergic SH-SY5Y cells and primary rat mesencephalic cultures. Here we report that both compounds normalized the proliferative activity of PD lymphoblasts and reduced the 6-OHDA-induced cell death in neuronal cells by preventing the overactivation of the cyclin D3/CDK6/pRb cascade.Considering that these drugs are already used in clinic for treatment of other diseases with good tolerance, it is plausible that they may serve as novel therapeutic drugs for PD.This work has been supported by grants from Ministerio de Economía y Competitividad (SAF2011-28603) and Fundación Ramón Areces.Peer reviewe

Mammalian Target of Rapamycin (mTOR) Activity Dependent Phospho-Protein Expression in Childhood Acute Lymphoblastic Leukemia (ALL)

Modern treatment strategies have improved the prognosis of childhood ALL; however, treatment still fails in 25–30% of patients. Further improvement of treatment may depend on the development of targeted therapies. mTOR kinase, a central mediator of several signaling pathways, has recently attracted remarkable attention as a potential target in pediatric ALL. However, limited data exists about the activity of mTOR. In the present study, the amount of mTOR activity dependent phospho-proteins was characterized by ELISA in human leukemia cell lines and in lymphoblasts from childhood ALL patients (n = 49). Expression was measured before and during chemotherapy and at relapses. Leukemia cell lines exhibited increased mTOR activity, indicated by phospho-S6 ribosomal protein (p-S6) and phosphorylated eukaryotic initiation factor 4E binding protein (p-4EBP1). Elevated p-4EBP1 protein levels were detected in ALL samples at diagnosis; efficacy of chemotherapy was followed by the decrease of mTOR activity dependent protein phosphorylation. Optical density (OD) for p-4EBP1 (ELISA) was significantly higher in patients with poor prognosis at diagnosis, and in the samples of relapsed patients. Our results suggest that measuring mTOR activity related phospho-proteins such as p-4EBP1 by ELISA may help to identify patients with poor prognosis before treatment, and to detect early relapses. Determining mTOR activity in leukemic cells may also be a useful tool for selecting patients who may benefit from future mTOR inhibitor treatments

Characteristic mTOR activity in Hodgkin-lymphomas offers a potential therapeutic target in high risk disease – a combined tissue microarray, in vitro and in vivo study

BACKGROUND: Targeting signaling pathways is an attractive approach in many malignancies. The PI3K/Akt/mTOR pathway is activated in a number of human neoplasms, accompanied by lower overall and/or disease free survival. mTOR kinase inhibitors have been introduced in the therapy of renal cell carcinoma and mantle cell lymphoma, and several trials are currently underway. However, the pathological characterization of mTOR activity in lymphomas is still incomplete. METHODS: mTOR activity and the elements of mTOR complexes were investigated by immunohistochemistry on tissue microarrays representing different human non-Hodgkin-lymphomas (81 cases) and Hodgkin-lymphomas (87 cases). The expression of phospho-mTOR, phospho-4EBP1, phospho-p70S6K, phospho-S6, Rictor, Raptor and Bcl-2, Bcl-xL, Survivin and NF-kappaB-p50 were evaluated, and mTOR activity was statistically analyzed along with 5-year survival data. The in vitro and in vivo effect of the mTOR inhibitor rapamycin was also examined in human Hodgkin-lymphoma cell lines. RESULTS: The majority (>50%) of mantle cell lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, anaplastic large-cell lymphoma and Hodgkin-lymphoma cases showed higher mTOR activity compared to normal lymphoid tissues. Hodgkin-lymphoma was characterized by high mTOR activity in 93% of the cases, and Bcl-xL and NF-kappaB expression correlated with this mTOR activity. High mTOR activity was observed in the case of both favorable and unfavorable clinical response. Low mTOR activity was accompanied by complete remission and at least 5-year disease free survival in Hodgkin-lymphoma patients. However, statistical analysis did not identify correlation beetween mTOR activity and different clinical data of HL patients, such as survival. We also found that Rictor (mTORC2) was not overexpressed in Hodgkin-lymphoma biopsies and cell lines. Rapamycin inhibited proliferation and induced apoptosis in Hodgkin-lymphoma cells both in vitro and in vivo, moreover, it increased the apoptotic effect of chemotherapeutic agents. CONCLUSIONS: Targeting mTOR activity may be a potential therapeutic tool in lymphomas. The presence of mTOR activity probably indicates that the inclusion of mTOR inhibition in the therapy of Hodgkin-lymphomas may be feasible and beneficial, especially when standard protocols are ineffective, and it may also allow dose reduction in order to decrease late treatment toxicity. Most likely, the combination of mTOR inhibitors with other agents will offer the highest efficiency for achieving the best clinical response