Activating mutations of FMS-like tyrosine kinase 3 (FLT3), notably internal tandem duplications (ITDs), are associated with a grave prognosis in acute myeloid leukemia (AML). Transforming FLT3ITD ...signal transduction causes formation of reactive oxygen species (ROS) and inactivation of the protein-tyrosine phosphatase (PTP) DEP-1/PTPRJ, a negative regulator of FLT3 signaling. Here we addressed the underlying mechanisms and biological consequences. NADPH oxidase 4 (NOX4) messenger RNA and protein expression was found to be elevated in FLT3ITD-positive cells and to depend on FLT3ITD signaling and STAT5-mediated activation of the NOX4 promoter. NOX4 knockdown reduced ROS levels, restored DEP-1 PTP activity and attenuated FLT3ITD-driven transformation. Moreover, Nox4 knockout (Nox4(-/-)) murine hematopoietic progenitor cells were refractory to FLT3ITD-mediated transformation in vitro. Development of a myeloproliferative-like disease (MPD) caused by FLT3ITD-transformed 32D cells in C3H/HeJ mice, and of a leukemia-like disease in mice transplanted with MLL-AF9/ FLT3ITD-transformed murine hematopoietic stem cells were strongly attenuated by NOX4 downregulation. NOX4-targeting compounds were found to counteract proliferation of FLT3ITD-positive AML blasts and MPD development in mice. These findings reveal a previously unrecognized mechanism of oncoprotein-driven PTP oxidation, and suggest that interference with FLT3ITD-STAT5-NOX4-mediated overproduction of ROS and PTP inactivation may have therapeutic potential in a subset of AML.
Experimental results are presented on single-bit-upsets (SBU) and multiple-bit-upsets (MBU) on a 45 nm SOI SRAM. The accelerated testing results show the SBU-per-bit cross section is relatively ...constant with technology scaling but the MBU cross section is increasing. The MBU data show the importance of acquiring and analyzing the data with respect to the location of the multiple-bit upsets since the relative location of the cells is important in determining which MBU upsets can be corrected with error correcting code (ECC) circuits. For the SOI SRAMs, a large MBU orientation effect is observed with most of the MBU events occurring along the same SRAM bit-line; allowing ECC circuits to correct most of these MBU events.
Experimental data are presented showing that low energy (<2 MeV) proton irradiation can upset exploratory 65 nm node, silicon-on-insulator circuits. Alpha particle SER data, modeling and simulation ...results provide a plausible mechanism. This work suggests that track structures need to be understood and effectively modeled, especially for small, modern devices.
Experimental results are presented on proton induced single-event-upsets (SEU) on a 65 nm silicon-on-insulator (SOI) SRAM. The low energy proton SEU results are very different for the 65 nm SRAM as ...compared with SRAMs fabricated in previous technology generations. Specifically, no upset threshold is observed as the proton energy is decreased down to 1 MeV; and a sharp rise in the upset cross-section is observed below 1 MeV. The increase below 1 MeV is attributed to upsets caused by direct ionization from the low energy protons. The implications of the low energy proton upsets are discussed for space applications of 65 nm SRAMs; and the implications for radiation assurance testing are also discussed.
XIA has provided IBM with a prototype ultralow background alpha particle counter for evaluation. Results show a significant decrease in background compared to other commercial counters allowing for ...rapid measurement of low-emissivity materials.
This paper describes upsets of 65 nm flip-flops caused by Single-Event-Transients in clock-tree circuits. The upset rate is predicted through modeling, and compared to upset rates measured on a 65 nm ...test chip with 15 MeV carbon ions and 148 MeV protons.
Experimental and modeling results are presented on the critical charge required to upset exploratory 65 nm silicon-on-insulator (SOI) circuits. Using a mono-energetic, collimated, beam of particles ...the charge deposition was effectively modulated and modeled
In this paper, we review the current status of single-event upsets caused by alpha-particles in IBM circuits and technology. While both alpha-particles and cosmic radiation can induce upsets, the ...alpha-particle-induced upset rate has become an increasingly important issue because alpha-particle-induced upsets are no longer limited to memory circuits. Latch circuits have become highly sensitive to alpha-particles. The alpha-particle-induced upset rate of latch circuits is one of the most critical issues for microprocessors requiring both high performance and high reliability. PUBLICATION ABSTRACT
The susceptibility of modern integrated-circuit devices to single-event upsets (SEUs) depends on both the alpha-particle emission rate and the energy of the alpha-particles emitted. In addition, the ...terrestrial neutron energy and flux, which produce secondary charged fragments in the device and circuit at the location of operation, contribute to the SEU rate. In this paper, we discuss methods that are used to measure alpha-particle emissivity from semiconductor and packaging materials, as well as methods that we used and our results for life testing and accelerated SEU testing of modern devices. PUBLICATION ABSTRACT
The laser energy thresholds for SEU for SOI 1-Mbit SRAMs built in Sandia's 0.35-μm SOI technology were measured using carrier generation by two-photon absorption. The laser measurements were ...correlated to heavy-ion threshold LET measurements to determine an empirical relationship between laser energy threshold and heavy-ion threshold LET. This empirical relationship was used to estimate the threshold LETs for other circuits built in Sandia's 0.35-μm SOI technology and SRAMs built in IBM's 45 and 65-nm SOI technologies. For an ASIC built in Sandia's 0.35-μm SOI technology the estimated threshold from laser measurements was close to the measured heavy-ion threshold LET. However, for a dual-port SRAM also built in Sandia's 0.35-μm SOI technology and for the 45- and 65-nm IBM SOI SRAMs, the threshold LETs estimated from laser measurements did not correlate to the measured heavy-ion threshold LETs. For the IBM SRAMs, the likely cause of the discrepancy between the threshold LETs estimated from laser measurements and the threshold LETs measured by heavy-ion testing is due to the laser pulse simultaneously injecting charge into multiple transistors within a memory cell and/or in adjacent memory cells. This is due to the relatively large size of the laser spot size compared to the size of the SEU sensitive volume of the IBM SOI devices. The hardness assurance implications of these results are discussed.
