A two-stage switched-capacitor integrator for high gain inverter-like architectures

A discrete-time, switched capacitor integrator is presented. The integrator is based on a two-stage architecture where the first stage converts the input voltage into a charge that is accumulated into the second stage. The main strength of the proposed circuit is a higher dc gain with respect to previous solutions, making it optimal for low-voltage inverter-like integrators. A further advantage is the fact that, in contrast with existing solutions, the output voltage is valid across the whole clock cycle. Theoretical analysis of the circuit is performed to calculate the dependence of the integrator dc gain and input-referred offset voltage on the corresponding parameters of the constituting amplifiers. Discrete-time simulations are performed to estimate the gain and phase error with respect to an ideal integrator. The results of electrical simulations performed on an inverter-like prototype, designed with the UMC 0.18-μm CMOS process, are presented to show the impact of non-idealities from the amplifiers and switches

Design of current feedback instrumentation amplifiers with rail-to-rail input-output ranges

System level modeling is applied to a recently proposed indirect current feedback (ICF) chopper instrumentation amplifier based on a Gm-C low pass filter architecture. The aim of the study is solving important limitations of the previous architecture in terms of output range and bandwidth-to-chopper frequency ratio. The possibility of obtaining a rail-to-rail input common mode range is also investigated. An improved architecture is proposed and analyzed by means of simulations that consider the main non-idealities of the building blocks

A compact sub-1V class AB operational amplifier for low-voltage switched-capacitor circuits

A compact sub-1V class-AB operational amplifier to be used as a building block for low-voltage switched-capacitor architectures is presented. The proposed amplifier works properly with supply voltages in the range 0.9 V-1.4 V, providing a gain-bandwidth product of 8 MHz, and a maximum output short-circuit current of 1 mA with 120 μA quiescent supply current. The performances of the operational amplifier are demonstrated by means of electrical simulations performed on a prototype designed with the UMC 0.18 μm/3.3 V process. The total area of the cell, estimated from a preliminary layout, is 75Ã\u97105 μm2

Improved class-AB output stage for Sub-1 v fully-differential operational amplifiers

An existent architecture for low voltage class-AB output stages is analyzed finding critical issues for which effective original solutions are proposed. The approach has been applied to the design of a compact class-AB fully-differential operational amplifier, capable of operating at a supply voltage of 0.8 V, providing a maximum output current of 7.5 mA with only 156 uA of quiescent supply current. The proposed amplifier constitutes a convenient building block for switched-capacitor circuits and low-voltage sensor interfaces. The performances of the amplifier are demonstrated by means of electrical simulations performed on a prototype designed with the UMC 0.18 μ m CMOS process. The total estimated area of the cell is 0.023 mm 2

Analysis and Simulation of Chopper Stabilization Techniques Applied to Delta-Sigma Converters

MATLAB/Simulink modeling of offset and flicker noise in Delta-Sigma modulators has been developed, providing a fast tool for the estimation of ADC performances. Since high accuracy and resolution are fundamental in sensor applications, a brief analysis of the main noise sources in second order Delta-Sigma modulators is presented, together with the typical solutions found in the literature. Generalization of system-level chopper technique for the rejection of the converter overall offset and low-frequency noise has been proposed and their effectiveness is evaluated by means of high-level simulations

THERAPEUTIC TARGETING OF RAF-INDUCED PARADOXICAL ERK ACTIVATION WITH A VERTICAL COMBINATION HITTING MULTIPLE STEPS ALONG THE MAPK CASCADE

Aim: Mounting evidence suggests that RAF-mediated MEK activation plays a crucial role in paradox MAPK (re)activation, leading to resistance and therapeutic failure with agents hitting a single step along the MAPK cascade. Methods: We examined the molecular and functional effects of single and combined MEK (trametinib, T), BRAF(dabrafenib, D), and pan-RAF (RAF265, R) inhibition, using WB and conservative isobologram analysis to assess functional synergism and explored genetic determinants of synergistic interactions. Results: In BRAF-mut models, both D and T effectively inactivated MAPK and inhibited cell growth, with no synergistic growth inhibition with their combination (CI: 0.7-1.3x106). Conversely, in KRAS-mut lung (2/5 cell lines) and pancreatic (4/6 cell lines) cancer models, in which selective BRAF inhibition induced paradox hyperphosphorylation of MEK, ERK, and p90RSK, combined D+T synergistically suppressed malignant growth (CI: 0.1-0.7). At concentrations inhibiting all RAF isoforms, R did not induce paradox MAPK activation and did not result in growth inhibitory synergism when combined withT. Highly synergistic in vitro growth inhibition was also observed with D+T in 2/5 patient-derived lung cancer stem cells. KRAS mutations appeared to be necessary, but not sufficient, to determine paradox MAPK activation and functional synergism with D+T, as assessed in two KRAS isogenic cell lines (H1299 expressing individual codon 12 mutants and HCT116 clones differing for homo or heterozygous G13D). Conversely, in lung cancer models driven by EGFR family activation (EGFR-mut HCC827 and H1650 cells and HER-2 overexpressing Calu-3 cells), paradox MAPK activation upon selective BRAF inhibition was dependent on upstream receptor activity and could be efficiently blocked by the EGFR/HER-2 inhibitor Lapatinib. Conclusions: Overall, our data indicate that RAF-mediated, paradox MAPK activation may be sustained by both upstream (RTK activation) and downstream (KRAS mutations) mechanisms and that in appropriate cellular contexts vertical RAF/MEK inhibition-based combination strategies may exert highly synergistic antitumor effects

A vertical combination strategy hitting multiple steps along the MAPK cascade: Molecular mechanisms of action and putative genetic determinants of synergism

Preclinical evidence shows that hitting a single point along the RAF/MEK/ERK cascade disrupts intra-pathway negative feedback loop, may cause paradoxical pathway activation and may lead to functional resistance. Thus, the \u201cvertical\u201d combination of agents simultaneously inhibiting RAF and MEK has been proposed as a strategy to synergistically inhibit tumor growth and delay resistance. Experimental procedures: Molecular and functional effects of single and combined MEK (using trametinib, T), BRAF (using dabrafenib, D), and RAF (using the pan-RAF inhibitor, RAF265, R) inhibition were dissected by WB analysis and conservative isobologram analysis to assess functional synergism, using a fixed dose-ratio experimental design. Summary data: We examined the in vitro molecular and functional consequences of D and T, alone or in combination, in a panel of different human BRAFV600E melanoma cell lines; both drugs inhibited cell growth and inactivated the MAPK pathway, but little or no synergistic growth inhibition was observed with their combination (CI: 0.7 - 1.3x106). Conversely, combined D+T suppressed malignant growth with highly synergistic effects in KRAS-mutant lung (2/5 cell lines tested) and pancreatic (4/6 cell lines tested) cancer models (CI: 0.1 - 0.7), in which selective BRAF inhibition induced hyperphosphorylation of MEK, ERK, and p90RSK (paradox effect). At concentrations inhibiting both BRAF and CRAF, R did not induce paradox MAPK activation and did not result in growth inhibitory synergism when combined with T. To define the role of RAS gene status in determining sensitivity/resistance to single and combined RAF and MEK blockade, we analyzed two isogenic tumor cell line models: H1299 expressing individual codon 12 KRAS mutants and isogenic HCT116 clones differing for the presence of a homo or heterozygous G13D KRAS mutation. Conversely, in lung cancer models driven by either EGFR mutations (HCC827, H1650) or HER-2 overexpression (Calu-3), selective BRAF inhibition also induced a paradox MAPK activation, which could be blocked using a reversible EGFR/HER-2 inhibitor (Lapatinib); in this context, combination (D+T) resulted in a non-synergic growth inhibitory effects. Conclusions: Overall, our data indicate that, in appropriate cellular contexts, vertical RAF/MEK inhibition-based combination strategies exert highly synergistic antitumor effects across different cancer models