A novel RNA aptamer identifies plasma membrane ATP synthase beta subunit as an early marker and therapeutic target in aggressive cancer

PURPOSE: Primary breast and prostate cancers can be cured, but metastatic disease cannot. Identifying cell factors that predict metastatic potential could guide both prognosis and treatment. METHODS: We used Cell-SELEX to screen an RNA aptamer library for differential binding to prostate cancer cell lines with high vs. low metastatic potential. Mass spectroscopy, immunoblot, and immunohistochemistry were used to identify and validate aptamer targets. Aptamer properties were tested in vitro, in xenograft models, and in clinical biopsies. Gene expression datasets were queried for target associations in cancer. RESULTS: We identified a novel aptamer (Apt63) that binds to the beta subunit of F1Fo ATP synthase (ATP5B), present on the plasma membrane of certain normal and cancer cells. Apt63 bound to plasma membranes of multiple aggressive breast and prostate cell lines, but not to normal breast and prostate epithelial cells, and weakly or not at all to non-metastasizing cancer cells; binding led to rapid cell death. A single intravenous injection of Apt63 induced rapid, tumor cell-selective binding and cytotoxicity in MDA-MB-231 xenograft tumors, associated with endonuclease G nuclear translocation and DNA fragmentation. Apt63 was not toxic to non-transformed epithelial cells in vitro or adjacent normal tissue in vivo. In breast cancer tissue arrays, plasma membrane staining with Apt63 correlated with tumor stage (p < 0.0001, n = 416) and was independent of other cancer markers. Across multiple datasets, ATP5B expression was significantly increased relative to normal tissue, and negatively correlated with metastasis-free (p = 0.0063, 0.00039, respectively) and overall (p = 0.050, 0.0198) survival. CONCLUSION: Ecto-ATP5B binding by Apt63 may disrupt an essential survival mechanism in a subset of tumors with high metastatic potential, and defines a novel category of cancers with potential vulnerability to ATP5B-targeted therapy. Apt63 is a unique tool for elucidating the function of surface ATP synthase, and potentially for predicting and treating metastatic breast and prostate cancer

Relative luminosity measurement of the LHC with the ATLAS forward calorimeter

In this paper it is shown that a measurement of the relative luminosity changes at the LHC may be obtained by analysing the currents drawn from the high voltage power supplies of the electromagnetic section of the forward calorimeter of the ATLAS detector. The method was verified with a reproduction of a small section of the ATLAS forward calorimeter using proton beams of known beam energies and variable intensities at the U-70 accelerator at IHEP in Protvino, Russia. The experimental setup and the data taking during a test beam run in April 2008 are described in detail. A comparison of the measured high voltage currents with reference measurements from beam intensity monitors shows a linear dependence on the beam intensity. The non-linearities are measured to be less than 0.5 % combining statistical and systematic uncertainties.Comment: 16 page

Construction, assembly and testing of the ATLAS hadronic end-cap calorimeter

The construction and assembly of the four wheels of the ATLAS hadronic end-cap calorimeter and their insertion into the two end-cap cryostats are described. The results of the qualification tests prior to installation of the two cryostats in the ATLAS experimental cavern are reviewed

Simulation of impact ionization process in deep submicron n-channel MOSFETS

The ensemble Monte Carlo simulation of deep submicron silicon MOSFET with length is performed. The effective threshold energy of impact ionization process in the MOSFET is calculated in the framework of Keldysh mode

The Monte Carlo semiconductor device structures simulation approach using the object-oriented programming technology

Рассмотрены некоторые аспекты разработки программного комплекса моделирования процессов переноса носителей заряда в интегральных полупроводниковых структурах методом Монте-Карло. Основное внимание уделено построению эффективной объектной иерархии, которая дает возможность повторного использования написанного ранее кода, а также минимизирует проблемы, возникающие при разработке программного комплекса несколькими программистами. В качестве иллюстрации работоспособности описанного комплекса приведены результаты расчета вольт-амперной характеристики (ВАХ) интегрального n-канального МОП-транзистора и проведено их сравнение с известными экспериментальными данными