Anti-leukemia effects of omipalisib in acute myeloid leukemia: inhibition of PI3K/AKT/mTOR signaling and suppression of mitochondrial biogenesis.

Omipalisib (GSK2126458), a potent dual PI3K/mTOR inhibitor, is reported to exhibit anti-tumor effect in several kinds of cancers. More than 50% of acute myeloid leukemia (AML) patients display a hyperactivation of PI3K/AKT/mTOR signaling. We investigated the anti-proliferative effect of omipalisib in AML cell lines with varied genetic backgrounds. The OCI-AML3 and THP-1 cell lines had a significant response to omipalisib, with IC50 values of 17.45 nM and 8.93 nM, respectively. We integrated transcriptomic profile and metabolomic analyses, and followed by gene set enrichment analysis (GSEA) and metabolite enrichment analysis. Our findings showed that in addition to inhibiting PI3K/AKT/mTOR signaling and inducing cell cycle arrest at the G0/G1 phase, omipalisib also suppressed mitochondrial respiration and biogenesis. Furthermore, omipalisib downregulated several genes associated with serine, glycine, threonine, and glutathione metabolism, and decreased their protein and glutathione levels. In vivo experiments revealed that omipalisib significantly inhibited tumor growth and prolonged mouse survival without weight loss. Gedatolisib and dactolisib, another two PI3K/mTOR inhibitors, exerted similar effects without affecting mitochondria biogenesis. These results highlight the multifaceted anti-leukemic effect of omipalisib, revealing its potential as a novel therapeutic agent in AML treatment.

Deciphering the Role of Pyrvinium Pamoate in the Generation of Integrated Stress Response and Modulation of Mitochondrial Function in Myeloid Leukemia Cells through Transcriptome Analysis.

Pyrvinium pamoate, a widely-used anthelmintic agent, reportedly exhibits significant anti-tumor effects in several cancers. However, the efficacy and mechanisms of pyrvinium against myeloid leukemia remain unclear. The growth inhibitory effects of pyrvinium were tested in human AML cell lines. Transcriptome analysis of Molm13 myeloid leukemia cells suggested that pyrvinium pamoate could trigger an unfolded protein response (UPR)-like pathway, including responses to extracellular stimulus [p-value = 2.78 × 10-6] and to endoplasmic reticulum stress [p-value = 8.67 × 10-7], as well as elicit metabolic reprogramming, including sulfur compound catabolic processes [p-value = 2.58 × 10-8], and responses to a redox state [p-value = 5.80 × 10-5]; on the other hand, it could elicit a pyrvinium blunted protein folding function, including protein folding [p-value = 2.10 × 10-8] and an ATP metabolic process [p-value = 3.95 × 10-4]. Subsequently, pyrvinium was verified to induce an integrated stress response (ISR), demonstrated by activation of the eIF2α-ATF4 pathway and inhibition of mTORC1 signaling, in a dose- and time-dependent manner. Additionally, pyrvinium could co-localize with mitochondria and then decrease the mitochondrial basal oxidative consumption rate, ultimately dysregulating the mitochondrial function. Similar effects were observed in cabozantinib-resistant Molm13-XR cell lines. Furthermore, pyrvinium treatment retarded Molm13 and Molm13-XR xenograft tumor growth. Thus, we concluded that pyrvinium exerts anti-tumor activity, at least, via the modulation of the mitochondrial function and by triggering ISR.

A 30.3 fA/√Hz Biosensing Current Front-End With 139 dB Cross-Scale Dynamic Range.

This paper presents an 8-channel array of low-noise (30.3 fA/√Hz) current sensing front-ends with on-chip microelectrode electrochemical sensors. The analog front-end (AFE) consists of a 1st-order continuous-time delta-sigma (CT ΔΣ) modulator that achieves 123 fA sensitivity over a 10 Hz bandwidth and 139 dB cross-scale dynamic range with a 2-bit programmable current reference. A digital predictor and tri-level pulse width modulated (PWM) current-steering DAC realize the equivalent performance of a multi-bit ΔΣ in an area- and power-efficient manner. The AFE consumes 50.3 µW and 0.11 mm2 per readout channel. The proposed platform was used to observe protein-ligand interactions in real-time using transient induced molecular electronic spectroscopy (TIMES), a label- and immobilization-free biosensing technique.

Label-free image-encoded microfluidic cell sorter with a scanning Bessel beam.

The microfluidic-based, label-free image-guided cell sorter offers a low-cost, high information content, and disposable solution that overcomes many limitations in conventional cell sorters. However, flow confinement for most microfluidic devices is generally only one-dimensional using sheath flow. As a result, the equilibrium distribution of cells spreads beyond the focal plane of commonly used Gaussian laser excitation beams, resulting in a large number of blurred images that hinder subsequent cell sorting based on cell image features. To address this issue, we present a Bessel-Gaussian beam image-guided cell sorter with an ultra-long depth of focus, enabling focused images of >85% of passing cells. This system features label-free sorting capabilities based on features extracted from the output temporal waveform of a photomultiplier tube (PMT) detector. For the sorting of polystyrene beads, SKNO1 leukemia cells, and Scenedesmus green algae, our results indicate a sorting purity of 97%, 97%, and 98%, respectively, showing that the temporal waveforms from the PMT outputs have strong correlations with cell image features. These correlations are also confirmed by off-line reconstructed cell images from a temporal-spatial transformation algorithm tailored to the scanning Bessel-Gaussian beam.

Detecting Protein-Ligand Interaction from Integrated Transient Induced Molecular Electronic Signal (i-TIMES).

Quantitative information about protein-ligand interactions is central to drug discovery. To obtain the quintessential reaction dissociation constant, ideally measurements of reactions should be performed without perturbations by molecular labeling or immobilization. The technique of transient induced molecular electrical signal (TIMES) has provided a promising technique to meet such requirements, and its performance in a microfluidic environment further offers the potential for high throughput and reduced consumption of reagents. In this work, we further the development by using integrated TIMES signal (i-TIMES) to greatly enhance the accuracy and reproducibility of the measurement. While the transient response may be of interest, the integrated signal directly measures the total amount of surface charge density resulted from molecules near the surface of electrode. The signals enable quantitative characterization of protein-ligand interactions. We have demonstrated the feasibility of i-TIMES technique using different biomolecules including lysozyme, N,N',N″-triacetylchitotriose (TriNAG), aptamer, p-aminobenzamidine (pABA), bovine pancreatic ribonuclease A (RNaseA), and uridine-3'-phosphate (3'UMP). The results show i-TIMES is a simple and accurate technique that can bring tremendous value to drug discovery and research of intermolecular interactions.

Measuring Electric Charge and Molecular Coverage on Electrode Surface from Transient Induced Molecular Electronic Signal (TIMES).

Charge density and molecular coverage on the surface of electrode play major roles in the science and technology of surface chemistry and biochemical sensing. However, there has been no easy and direct method to characterize these quantities. By extending the method of Transient Induced Molecular Electronic Signal (TIMES) which we have used to measure molecular interactions, we are able to quantify the amount of charge in the double layers at the solution/electrode interface for different buffer strengths, buffer types, and pH values. Most uniquely, such capabilities can be applied to study surface coverage of immobilized molecules. As an example, we have measured the surface coverage for thiol-modified single-strand deoxyribonucleic acid (ssDNA) as anchored probe and 6-Mercapto-1-hexanol (MCH) as blocking agent on the platinum surface. Through these experiments, we demonstrate that TIMES offers a simple and accurate method to quantify surface charge and coverage of molecules on a metal surface, as an enabling tool for studies of surface properties and surface functionalization for biochemical sensing and reactions.

Self-crack-filled graphene films by metallic nanoparticles for high-performance graphene heterojunction solar cells.

Graphene, with cracks filled with gold nanoparticles, is grown by chemical vapor deposition on a Cu substrate. The crack-filled graphene not only exhibits superior electrical properties but also forms a better junction with other semiconductors. A high-quality crack-filled graphene/Si Schottky junction solar cell is achieved, demonstrating the highest fill factor (0.79) and best efficiency (12.3%).