A 3-D Track-Finding Processor for the CMS Level-1 Muon Trigger

We report on the design and test results of a prototype processor for the CMS Level-1 trigger that performs 3-D track reconstruction and measurement from data recorded by the cathode strip chambers of the endcap muon system. The tracking algorithms are written in C++ using a class library we developed that facilitates automatic conversion to Verilog. The code is synthesized into firmware for field-programmable gate-arrays from the Xilinx Virtex-II series. A second-generation prototype has been developed and is currently under test. It performs regional track-finding in a 60 degree azimuthal sector and accepts 3 GB/s of input data synchronously with the 40 MHz beam crossing frequency. The latency of the track-finding algorithms is expected to be 250 ns, including geometrical alignment correction of incoming track segments and a final momentum assignment based on the muon trajectory in the non-uniform magnetic field in the CMS endcaps.Comment: 7 pages, 5 figures, proceedings for the conference on Computing in High Energy and Nuclear Physics, March 24-28 2003, La Jolla, Californi

Melanoma Vaccines and Modulation of the Immune System in the Clinical Setting: Building from New Realities

To endow the immune system with the capacity to fight cancer has always attracted attention, although the clinical results obtained have been until recently disappointing. Cutaneous melanoma is a highly immunogenic tumor; therefore most of the attempts to produce cancer vaccines have been addressed to this disease. New advances in the comprehension of the mechanisms of antigen presentation by dendritic cells, in the immune responses triggered by adjuvants, as well as the understanding of the role of immunosuppressor molecules such as cytotoxic T-lymphocyte antigen-4 (CTLA-4), which led to the recent approval of the anti-CTLA-4 monoclonal antibody ipilimumab, have opened new hopes about the installment of immunotherapy as a new modality to treat cancer

The effect of temperature and ventilation condition on the toxic product yields from burning polymers

A major cause of death or permanent injury in fires is inhalation of toxic gases. Moreover, every fire is unique, and the range of products, highly dependant on fire conditions, produces a wide variety of toxic and irritant species responsible for the most fire fatalities. Therefore, to fully understand each contribution to the toxicity it is necessary to quantify the decomposition products of the material under the test. Fires can be divided into a number of stages from smouldering combustion to early well-ventilated flaming through to fully developed under-ventilated flaming. These stages can be replicated by certain bench-scale physical fire models using different fuel-to-oxygen ratios, controlled by the primary air flow, and expressed in terms of the equivalence ratio (the actual fuel/air ratio divided by the stoichiometric fuel/air ratio). This work presents combustion product yields generated using a small-scale fire model. The Purser Furnace apparatus (BS7990 and ISO TS 19700) enables different fire stages to be created. Identification and quantification of combustion gases and particularly their toxic components from different fire scenarios were undertaken by continuous Fourier transform infrared spectroscopy. The relationship between type of the fire particularly the temperature and ventilation conditions and the toxic product yields for four bulk polymers, low-density polyethylene, polystyrene (PS), Nylon 6.6 and polyvinyl chloride (PVC) is reported. For all the polymers tested, except PVC, there is a dramatic increase in the yield of products of incomplete combustion (CO and hydrocarbons) with increase in equivalence ratio, as might be expected. For PVC there is a consistently high level of products of incomplete combustion arising both from flame inhibition by HCl and oxygen depletion. There is a low sensitivity to furnace temperature over the range 650–850°C, except that at 650°C PS shows an unexpectedly high yield of CO under well-ventilated conditions and PVC shows a slightly higher hydrocarbon yield. This demonstrates the dependence of toxic product yields on the equivalence ratio, and the lack of dependence on furnace temperature, within this range

Cutaneous melanoma cancer stem cell characterization

El objetivo del presente trabajo de Tesis fue caracterizar las células stem tumorales demelanoma cutáneo, en particular si las células obtenidas luego del tratamiento con inhibidores dela vía de MAPK presentan características de células stem tumorales. En primer lugar se analizó la expresión de CD271 y CD133, marcadores de células stemtumorales de melanoma, en líneas celulares de melanoma humano y en biopsias de pacientes demelanoma metastásico y se encontró que la expresión de los mismos no permite identificar unapoblación con características de células stem tumorales. Con el objetivo de enriquecer en célulascon características stem tumorales, y considerando que entre las propiedades que se le atribuyena esta población se encuentra la resistencia a drogas, se estudió el efecto del tratamientoprolongado con inhibidores de BRAF (PLX4032) y MEK (GDC-0973) en líneas celulares demelanoma que presentan la mutación BRAF V600 y son sensibles a estos inhibidores. Se encontróque luego del tratamiento in vitro con los inhibidores PLX4032 y GDC-0973 durante variassemanas, la mayoría de las células moría pero algunas permanecían viables y quiescentes. Sedenominó a esta población celular SUR. Al discontinuar el tratamiento, las células SUR retomaronsu crecimiento y mantuvieron una sensibilidad a los inhibidores similar a las células parentales. Lascélulas SUR presentan elevados niveles de expresión de los marcadores de células stem tumorales CD271 y ABCB5, pero no de CD133, y presentan características asociadas a senescencia, como laactividad de -galactosidasa. Las células SUR retienen su capacidad tumorigénica, ya que soncapaces de generar tumores en ratones inmunodeficientes. Para caracterizar a la población decélulas SUR en profundidad se realizaron experimentos de secuenciación del exoma y deltranscriptoma, además de microarreglos de expresión y microarreglos de proteínas. Las células SUR son lisadas de forma eficiente por linfocitos T citotóxicos que reconocen los antígenos dediferenciación melanocítica MART-1 y gp100. Proponemos la adquisición de un fenotipo concaracterísticas de células stem tumorales como un mecanismo de resistencia plástico a losinhibidores de BRAF y MEK.The aim of this Ph.D. Thesis was to characterize melanoma cancer stem cells, in particular ifcells obtained after MAPK inhibitor treatment present cancer stem cell characteristics. First, we analyzed the expression of melanoma cancer stem cell markers CD271 and CD133 inhuman melanoma cell lines and in biopsies from metastatic melanoma patients. We were not ableto identify a population with cancer stem cell characteristics by the expression of these markers. Inorder to enrich in cells with a cancer stem cell characteristics, and considering that cancer stemcells present resistance to drugs and chemotherapy, we studied the effects of BRAF (PLX4032) and MEK (GDC-0973) inhibitor long-term treatment in sensitive V600E BRAF-mutated melanoma celllines. After several weeks of long-term in vitro treatment with PLX4032 and/or GDC-0973, themajority of the cells died whereas some remained viable and quiescent. We named this population SUR cells. Strikingly, discontinuing treatment of SUR cells with MAPK inhibitors allowed thepopulation to regrow and these cells retained drug sensitivity equal to that of parental cells. SURcells had increased expression levels of CD271 and ABCB5 and presented senescence associatedcharacteristics. SUR cells retain their tumorigenic potential, as they generate tumors inimmunodeficient mice. In order to characterize SUR cells we performed Whole Exome Sequencingand RNA seq experiments and expression microarrays and antibody arrays. Interestingly, SUR cellswere efficiently lysed by cytotoxic T lymphocytes recognizing MART-1 and gp100 melanomadifferentiation antigens. We propose the acquisition of this plastic quiescence cancer stem-likephenotype as a mechanism of resistance to BRAF and MEK inhibitors while retaining sensitivity toimmune effectors.Fil: Madorsky Rowdo, Florencia Paula. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina

The Track-Finding Processor for the Level-1 Trigger of the CMS Endcap Muon System

We report on the development and test of a prototype track-finding processor for the level-1 trigger of the CMS endcap muon system. The processor links track segments identified in the cathode strip chambers of the endcap muon system into complete three-dimensional tracks, and measures the transverse momentum of the best track candidates from the sagitta induced by the magnetic bending. The algorithms are implemented using SRAM and Xilinx Virtex FPGAs, and the measured latency is 15 clocks. We also report on the design of the pre-production prototype, which achieves further latency and size reduction using state-of-the-art technology. (4 refs)

Commissioning of the CSC Level 1 Trigger Optical Links at CMS

The Endcap Muon (EMU) Cathode Strip Chamber (CSC) detector at the CMS experiment at CERN has been fully installed and operational since summer of 2008. The system of 180 optical links connects the middle and upper levels of the CSC Level 1 Trigger chain. Design and commissioning of all optical links present several challenges, including reliable clock distribution, link synchronization and alignment, status monitoring and system testing. We gained an extensive experience conducting various tests, participating in local and global cosmic runs and in initial stage of the LHC operation. In this paper we present our hardware, firmware and software solutions and first results of the optical link commissioning

Design Considerations for an Upgraded Track-Finding Processor in the Level-1 Endcap Muon Trigger of CMS for SLHC operations

The conceptual design for a Level-1 muon track-finder trigger for the CMS endcap muon system is proposed that can accommodate the increased particle occupancy and system constraints of the proposed SLHC accelerator upgrade and the CMS detector upgrades. A brief review of the architecture of the current track-finder for LHC trigger operation is given, with potential bottlenecks indicated for SLHC operation. The upgraded track-finding processors described here would receive as many as two track segments detected from every cathode strip chamber comprising the endcap muon system, up to a total of 18 per 60° azimuthal sector. This would dramatically improve the efficiency of the track reconstruction in a high occupancy environment over the current design. However, such an improvement would require significantly higher bandwidth and logic resources. We propose to use the fastest available serial links, running asynchronously to the machine clock to use their full bandwidth. The work of creating a firmware model for the upgraded Sector Processor is in progress; details of its implementation will be discussed. Another enhancement critical for the overall Level-1 trigger capability for physics studies in phase 2 of the SLHC is to include the inner silicon tracking systems into the design of the Level-1 trigger

Epigenetic inhibitors eliminate senescent melanoma BRAFV600E cells that survive long-term BRAF inhibition

It is estimated that ~50% of patients with melanoma harbour B-Raf (BRAF)V600 driver mutations, with the most common of these being BRAFV600E, which leads to the activation of mitogen-activated protein kinase proliferative and survival pathways. BRAF inhibitors are used extensively to treat BRAF-mutated metastatic melanoma; however, acquired resistance occurs in the majority of patients. The effects of long-term treatment with PLX4032 (BRAFV600 inhibitor) were studied in vitro on sensitive V600E BRAF-mutated melanoma cell lines. After several weeks of treatment with PLX4032, the majority of the melanoma cells died; however, a proportion of cells remained viable and quiescent, presenting senescent cancer stem cell-like characteristics. This surviving population was termed SUR cells, as discontinuing treatment allowed the population to regrow while retaining equal drug sensitivity to that of parental cells. RNA sequencing analysis revealed that SUR cells exhibit changes in the expression of 1,415 genes (P<0.05) compared with parental cells. Changes in the expression levels of a number of epigenetic regulators were also observed. These changes and the reversible nature of the senescence state were consistent with epigenetic regulation; thus, it was investigated as to whether the senescent state could be reversed by epigenetic inhibitors. It was found that both parental and SUR cells were sensitive to different histone deacetylase (HDAC) inhibitors, such as SAHA and MGCD0103, and to the cyclin-dependent kinase (CDK)9 inhibitor, CDKI-73, which induced apoptosis and reduced proliferation both in the parental and SUR populations. The results suggested that the combination of PLX4032 with HDAC and CDK9 inhibitors may achieve complete elimination of SUR cells that persist after BRAF inhibitor treatment, and reduce the development of resistance to BRAF inhibitors.Fil: Madorsky Rowdo, Florencia Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Baron, Antonela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Gallagher, Stuart John. Centenary Institute; AustraliaFil: Hersey, Peter. Centenary Institute; AustraliaFil: Emran, Abdullah A. L.. Centenary Institute; AustraliaFil: Von Euw, Erika María. University of California at Los Angeles; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Barrio, Maria Marcela. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Mordoh, Jose. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentin