Cyclin-dependent kinase 12 (CDK12) overexpression is implicated in breast cancer, but whether it has a primary or only a cooperative tumorigenic role is unclear. Here, we show that transgenic CDK12 ...overexpression in the mouse mammary gland per se is sufficient to drive the emergence of multiple and multifocal tumors, while, in cooperation with known oncogenes, it promotes earlier tumor onset and metastasis. Integrative transcriptomic, metabolomic and functional data reveal that hyperactivation of the serine-glycine-one-carbon network is a metabolic hallmark inherent to CDK12-induced tumorigenesis. Consistently, in retrospective patient cohort studies and in patient-derived xenografts, CDK12-overexpressing breast tumors show positive response to methotrexate-based chemotherapy targeting CDK12-induced metabolic alterations, while being intrinsically refractory to other types of chemotherapy. In a retrospective analysis of hormone receptor-negative and lymph node-positive breast cancer patients randomized in an adjuvant phase III trial to 1-year low-dose metronomic methotrexate-based chemotherapy or no maintenance chemotherapy, a high CDK12 status predicts a dramatic reduction in distant metastasis rate in the chemotherapy-treated vs. not-treated arm. Thus, by coupling tumor progression with metabolic reprogramming, CDK12 creates an actionable vulnerability for breast cancer therapy and might represent a suitable companion biomarker for targeted antimetabolite therapies in human breast cancers.
Superfluid helium nanodroplets are often considered as transparent and chemically inert nanometer-sized cryo-matrices for high-resolution or time-resolved spectroscopy of embedded molecules and ...clusters. On the other hand, when the helium nanodroplets are resonantly excited with XUV radiation, a multitude of ultrafast processes are initiated, such as relaxation into metastable states, formation of nanoscopic bubbles or excimers, and autoionization channels generating low-energy free electrons. Here, we discuss the full spectrum of ultrafast relaxation processes observed when helium nanodroplets are electronically excited. In particular, we perform an in-depth study of the relaxation dynamics occurring in the lowest 1s2s and 1s2p droplet bands using high resolution, time-resolved photoelectron spectroscopy. The simplified excitation scheme and improved resolution allow us to identify the relaxation into metastable triplet and excimer states even when exciting below the droplets' autoionization threshold, unobserved in previous studies.
The ultrafast relaxation dynamics of excited helium nanodroplets were studied using time-resolved photoelectron spectroscopy. We observed an efficient population of triplet atomic states as well as the formation of the first excimer state of He
2
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This paper presents a new physics-based statistical model for random telegraph noise in Flash memories. From the probabilistic superposition of elementary Markov processes describing the ...trapping/detrapping events taking place in the cell tunnel oxide, the model can explain the main features of the random telegraph noise threshold-voltage instability. The results on the statistical distribution of the threshold-voltage difference between two subsequent read accesses show good agreement between measurements and model predictions, even considering the time drift of the distribution tails. Moreover, the model gives a detailed spectroscopic analysis of the oxide defects responsible for the random telegraph noise, allowing a spatial and energetic localization of the traps involved in the threshold-voltage instability process.
We studied the angular dependence of heavy-ion induced errors and threshold voltage shifts in Flash memories. Combining experiments and Geant4-based simulations, we provide new insight about the ...sensitive volume in floating gate cells. At high LET, the sensitive volume for cells belonging to the heavy-ion induced secondary peak corresponds to a large part of the floating gate. The sensitive volume for upsets may be larger or smaller, depending on the relative position of the secondary peak with respect to the relevant reference voltage.
The impact of program/erase (P/E) cycling on the random telegraph noise (RTN) threshold voltage instability of NOR and NAND flash memories is studied in detail. RTN is shown to introduce exponential ...tails in the distribution of the threshold voltage variation between two subsequent read operations on the cells. Tail height is shown to increase as a function of the stress levels, with a larger relative increase for the NAND case. The slope of the distribution instead remains nearly independent of the number of applied P/E cycles. This reveals that trap generation takes place according to the native trap distribution over the active area and means that the tail slope is a basic RTN parameter, depending on the cell process details for a fixed technology. These results are important for the design of the threshold voltage levels in multilevel nor and NAND technologies.
When collaborative project delivery models such as integrated project delivery (IPD) combine project resources, share decision-making rights, and distribute risk-and-reward among participants, the ...project can be conceptualized as a common-pool resource scenario. Multiple project appropriators have contractual rights to withdraw units from the shared resource system (i.e., the project budget). This theorization suggests project managers avoid the tragedy of the project by crafting effective self-governance structures in the face of pluralism. Using IPD as an example, this article suggests these project governance structures reflect Ostrom’s design principles for the successful governance of long-enduring common-pool resource scenarios.
We discuss new experimental results on the post-radiation annealing of Floating Gate errors in Flash memories with both NAND and NOR architecture. We investigate the dependence of annealing on the ...program level, linking the reduction in the number of Floating Gate errors to the evolution of the threshold voltage of each single cell. To understand the underlying physics we also discuss how temperature affects the number of Floating Gate errors.
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