High Consistency Ramp Design Method for Low Noise Column Level Readout Chain.

In order to address the inconsistency problem caused by parasitic backend wiring among multiple ramp generators and among multiple columns in large-array CMOS image sensors (CIS), this paper proposes a high-precision compensation technology combining average voltage technology, adaptive negative feedback dynamic adjustment technology, and digital correlation double sampling technology to complete the design of an adaptive ramp signals inconsistency calibration scheme. The method proposed in this article has been successfully applied to a CIS with a pixel array of 8192(H) × 8192(V), based on the 55 nm 1P4M CMOS process, with a pixel size of 10×10μm2. The chip area is 88(H) × 89(V) mm2, and the frame rate is 10 fps.

Synchronous Driving Method for Stitching Pixel Arrays Based on an Adaptive Correction Technique.

With the application of stitching technology in large-pixel-array CMOS image sensors, the problem of non-synchronized output signals from pixel array bilateral driver circuits has become progressively more serious and has led to the DC perforation of bilateral driver circuits, while conventional clock tree synchronization design methodology does not apply to stitching technology. Therefore, this paper analyses reasons for the inconsistency in the output signals of bilateral driving circuits and proposes a synchronous driving method applicable to stitching pixel arrays based on the idea of on-chip output signal delay detection and calibration. This method detects and corrects the non-synchrony of the row driver output signals on both sides according to changes in the operating environment of the chip.

High Dynamic Pixel Structure Based on an Adaptive Integrating Capacitor.

Infrared image sensing technology has received widespread attention due to its advantages of not being affected by the environment, good target recognition, and high anti-interference ability. However, with the improvement of the integration of the infrared focal plane, the dynamic range of the photoelectric system is difficult to improve, that is, the restrictive trade-off between noise and full well capacity is particularly prominent. Since the capacitance of the inversion MOS capacitor changes with the gate-source voltage adaptively, the inversion MOS capacitor is used as the capacitor in the infrared pixel circuit, which can solve the contradiction between noise in low light and full well capacity in high light.

Quatramer™ encapsulation of dual-targeted PI3-Kδ/HDAC6 inhibitor, HSB-510, suppresses growth of breast cancer.

Multiple studies have shown that the progression of breast cancer depends on multiple signaling pathways, suggesting that therapies with multitargeted anticancer agents will offer improved therapeutic benefits through synergistic effects in inhibiting cancer growth. Dual-targeted inhibitors of phosphoinositide 3-kinase (PI3-K) and histone deacetylase (HDAC) have emerged as promising cancer therapy candidates. However, poor aqueous solubility and bioavailability limited their efficacy in cancer.

High-Linearity and High-Speed ROIC of Ultra-Large Array Infrared Detectors Based on Adaptive Compensation and Enhancement.

In order to solve the problem of limited linearity and frame rate in the large array infrared (IR) readout integrated circuit (ROIC), a high-linearity and high-speed readout method based on adaptive offset compensation and alternating current (AC) enhancement is proposed in this paper. The efficient correlated double sampling (CDS) method in pixels is used to optimize the noise characteristics of the ROIC and output CDS voltage to the column bus. An AC enhancement method is proposed to quickly establish the column bus signal, and an adaptive offset compensation method is used at the column bus terminal to eliminate the nonlinearity caused by the pixel source follower (SF).

Design, Synthesis, and Biological Evaluation of Quinazolin-4-one-Based Hydroxamic Acids as Dual PI3K/HDAC Inhibitors.

A series of quinazolin-4-one based hydroxamic acids was rationally designed and synthesized as novel dual PI3K/HDAC inhibitors by incorporating an HDAC pharmacophore into a PI3K inhibitor (Idelalisib) via an optimized linker. Several of these dual inhibitors were highly potent (IC < 10 nM) and selective against PI3Kγ, δ and HDAC6 enzymes and exhibited good antiproliferative activity against multiple cancer cell lines. The lead compound , induced necrosis in several mutant and FLT3-resistant AML cell lines and primary blasts from AML patients, while showing no cytotoxicity against normal PBMCs, NIH3T3, and HEK293 cells.

Correction: Evaluation of ERK as a therapeutic target in acute myelogenous leukemia.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Inhibition of the deubiquitinase USP10 induces degradation of SYK.

Background: There is growing evidence that spleen tyrosine kinase (SYK) is critical for acute myeloid leukaemia (AML) transformation and maintenance of the leukemic clone in AML patients. It has also been found to be over-expressed in AML patients, with activating mutations in foetal liver tyrosine kinase 3 (FLT3), particularly those with internal tandem duplications (FLT3-ITD), where it transactivates FLT3-ITD and confers resistance to treatment with FLT3 tyrosine kinase inhibitors (TKIs).

Methods: We have previously described a pharmacological approach to treating FLT3-ITD-positive AML that relies on proteasome-mediated FLT3 degradation via inhibition of USP10, the deubiquitinating enzyme (DUB) responsible for cleaving ubiquitin from FLT3.

Discovery of a Highly Potent and Selective Indenoindolone Type 1 Pan-FLT3 Inhibitor.

For a subpopulation of acute myeloid leukemia (AML) patients, the mutationally activated tyrosine kinase FLT3, has emerged as a promising target for therapy. The development of drug resistance due to mutation is a growing concern for mutant FLT3 inhibitors, such as PKC412, Quizartinib, PLX3397, and Crenolanib. Thus, there is a need to develop novel FLT3 inhibitors that overcome these mutations.

MUC1-C oncoprotein promotes FLT3 receptor activation in acute myeloid leukemia cells.

Blasts from approximately one-third of patients with acute myeloid leukemia (AML) harbor activating mutations in the FMS-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase that confer a poor prognosis. The Mucin 1-C-terminal subunit (MUC1-C) oncoprotein is aberrantly expressed in AML blasts and stem cells; however, there is no known interaction between MUC1-C and FLT3. The present studies demonstrate that MUC1-C associates with wild-type and mutant FLT3 in AML cells.

The STAT5 Inhibitor Pimozide Displays Efficacy in Models of Acute Myelogenous Leukemia Driven by FLT3 Mutations.

Activation of the transcription factor STAT5 is essential for the pathogenesis of acute myelogenous leukemia (AML) containing the FLT3 internal tandem duplication (ITD) mutation. FLT3 ITD is a constitutively active tyrosine kinase that drives the activation of STAT5, leading to the growth and survival of AML cells. Although there has been some success in identifying tyrosine kinase inhibitors that block the function of FLT3 ITD, there remains a continued need for effective treatment of this disease.

AKT1 induces caspase-mediated cleavage of the CDK inhibitor p27Kip1 during cell cycle progression in leukemia cells transformed by FLT3-ITD.

p27Kip1 cleavage and caspase-3 regulate cell cycle in human myeloma cells and B cells, however regulation of p27Kip1 cleavage during the cell cycle is not known. In BaF3-FLT3-ITD cells, p27Kip1 undergoes C-terminal cleavage. Inhibition of the PI3K/AKT pathway is associated with decreased cleavage of p27Kip1 and G1 phase arrest.

Combining the FLT3 inhibitor PKC412 and the triterpenoid CDDO-Me synergistically induces apoptosis in acute myeloid leukemia with the internal tandem duplication mutation.

Mutations of the FLT3 receptor tyrosine kinase consisting of internal tandem duplications (ITD) have been detected in blasts from 20% to 30% of patients with acute myeloid leukemia (AML) and are associated with a poor prognosis. FLT3/ITD results in constitutive autophosphorylation of the receptor and factor-independent survival in leukemia cell lines. The C-28 methyl ester of the oleane triterpenoid (CDDO-Me) is a multifunctional molecule that induces apoptosis of human myeloid leukemia cells.

A role for WRN in telomere-based DNA damage responses.

Telomeres cap the ends of eukaryotic chromosomes and prevent them from being recognized as DNA breaks. We have shown that certain DNA damage responses induced during senescence and, at times of telomere uncapping, also can be induced by treatment of cells with small DNA oligonucleotides homologous to the telomere 3' single-strand overhang (T-oligos), implicating this overhang in generation of these telomere-based damage responses. Here, we show that T-oligo-treated fibroblasts contain gammaH2AX foci and that these foci colocalize with telomeres.