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Overexpression of the polyspecific efflux transporter, P-glycoprotein (P-gp, MDR1, ABCB1), is a major mechanism by which cancer cells acquire multidrug resistance (MDR), the resistance to diverse chemotherapeutic drugs. Inhibiting drug transport by P-gp can resensitize cancer cells to chemotherapy, but there are no P-gp inhibitors available to patients. Clinically unsuccessful P-gp inhibitors tend to bind at the pump's transmembrane drug binding domains and are often P-gp transport substrates, resulting in lowered intracellular concentration of the drug and altered pharmacokinetics. In prior work, we used computationally accelerated drug discovery to identify novel P-gp inhibitors that target the pump's cytoplasmic nucleotide binding domains. Our first-draft study provided conclusive evidence that the nucleotide binding domains of P-gp are viable targets for drug discovery. Here we develop an enhanced, computationally accelerated drug discovery pipeline that expands upon our prior work by iteratively screening compounds against multiple conformations of P-gp with molecular docking. Targeted molecular dynamics simulations with our homology model of human P-gp were used to generate docking receptors in conformations mimicking a putative drug transport cycle. We offset the increased computational complexity using custom Tanimoto chemical datasets, which maximize the chemical diversity of ligands screened by docking. Using our expanded, virtual-assisted pipeline, we identified nine novel P-gp inhibitors that reverse MDR in two types of P-gp overexpressing human cancer cell lines, reflecting a 13.4% hit rate. Of these inhibitors, all were non-toxic to non-cancerous human cells, and six were not likely to be transport substrates of P-gp. Our novel P-gp inhibitors are chemically diverse and are good candidates for lead optimization. Our results demonstrate that the nucleotide binding domains of P-gp are an underappreciated target in the effort to reverse P-gp-mediated multidrug resistance in cancer.

Overexpression of the polyspecific efflux transporter, P-glycoprotein (P-gp, MDR1, ABCB1 ), is a major mechanism by which cancer cells acquire multidrug resistance (MDR), the resistance to diverse chemotherapeutic drugs. Inhibiting drug transport by P-gp can resensitize cancer cells to chemotherapy, but there are no P-gp inhibitors available to patients. Clinically unsuccessful P-gp inhibitors tend to bind at the pump’s transmembrane drug binding domains and are often P-gp transport substrates, resulting in lowered intracellular concentration of the drug and altered pharmacokinetics. In prior work, we used computationally accelerated drug discovery to identify novel P-gp inhibitors that target the pump’s cytoplasmic nucleotide binding domains. Our first-draft study provided conclusive evidence that the nucleotide binding domains of P-gp are viable targets for drug discovery. Here we develop an enhanced, computationally accelerated drug discovery pipeline that expands upon our prior work by iteratively screening compounds against multiple conformations of P-gp with molecular docking. Targeted molecular dynamics simulations with our homology model of human P-gp were used to generate docking receptors in conformations mimicking a putative drug transport cycle. We offset the increased computational complexity using custom Tanimoto chemical datasets, which maximize the chemical diversity of ligands screened by docking. Using our expanded, virtual-assisted pipeline, we identified nine novel P-gp inhibitors that reverse MDR in two types of P-gp overexpressing human cancer cell lines, reflecting a 13.4% hit rate. Of these inhibitors, all were non-toxic to non-cancerous human cells, and six were not likely to be transport substrates of P-gp. Our novel P-gp inhibitors are chemically diverse and are good candidates for lead optimization. Our results demonstrate that the nucleotide binding domains of P-gp are an underappreciated target in the effort to reverse P-gp-mediated multidrug resistance in cancer.

Extravasation is an inadvertent injection or leakage of fluid and drugs in the extravascular or subcutaneous space. The extravasation by massive transfused blood results in the elevation of intra-compartmental pressures. Severely increased pressure may lead to acute compartment syndrome (ACS). A 50-year-old man underwent craniectomy for traumatic subdural hemorrhage of the brain. During intraoperative periods, the blood components were transfused by rapid transfusion device and manual pressurized pumping through the central and peripheral lines because of hemorrhagic hypovolemic shock. Approximately 30 minutes after transfusion, we found a hardened right low leg that was obscured by the surgical drape. Immediately, fasciotomy was performed to release all four compartments. The early recognition and treatment of ACS were important factors contributing to anatomical structure salvage and preservation of function. Anesthesia providers should check the site of the insertion of the intravenous catheter, especially while pressurized massive transfusion via the peripheral intravenous catheter.

Herein, the impact of cross‐temperature on 3D NAND flash memory is modeled by considering adjacent cells using machine learning. The cells comprising NAND flash memory exhibit diverse states and connectivity patterns. To effectively capture this complexity, the 3D NAND flash is converted to graph structure and the graph neural network (GNN) is leveraged, known for its exceptional performance in handling graph data. To the best of the authors' knowledge, this is the first attempt to model 3D NAND flash memory using GNN. This method has good generalization performance across various retention times and temperatures, achieving a remarkable overlap of 95.28% between ground truth and predicted distributions. Moreover, two applications of this method are introduced that contribute to the NAND flash memory improvement. One is a GNN‐assist program, which leverages well‐trained GNN to suppress the Vth $V_{\\text{th}}$degradation affected by cross‐temperature, resulting in reduced Vth $V_{\\text{th}}$shift and narrower Vth $V_{\\text{th}}$distribution width. The other is the sensitivity decomposition to identify parameters influencing the cell at cross‐temperature. It is found that cross‐temperature impact extends beyond physically connected cells to adjacent cells at close distances. Overall, this work provides valuable insights into modeling 3D NAND flash memory using GNNs and offers practical methods for enhancing NAND flash memory reliability. Herein, a graph neural network models the electric characteristics for cross‐temperature in 3D NAND flash memory. The threshold voltage of individual cells is predicted with the graph structure data that is transformed from the structural characteristics of 3D NAND flash memory. Then, two applications are proposed to enhance the reliability of 3D NAND flash memory.

The incremental step pulse programming slope (ISPP) with random variation was investigated by measuring numerous three−dimensional (3D) NAND flash memory cells with a vertical nanowire channel. We stored multiple bits in a cell with the ISPP scheme and read each cell pulse by pulse. The excessive tunneling from the channel to the storage layer determines the program efficiency overshoot. Then, a broadening of the threshold voltage distribution was observed due to the abnormal program cells. To analyze the randomly varying abnormal program behavior itself, we distinguished between the read variation and over−programming in measurements. Using a 3D Monte−Carlo simulation, which is a probabilistic approach to solve randomness, we clarified the physical origins of over−programming that strongly influence the abnormal program cells in program step voltage, and randomly distributed the trap site in the nitride of a nanoscale 3D NAND string. These causes have concurrent effects, but we divided and analyzed them quantitatively. Our results reveal the origins of the variation and the overshoot in the ISPP, widening the threshold voltage distribution with traps randomly located at the nanoscale. The findings can enhance understanding of random over−programming and help mitigate the most problematic programming obstacles for multiple−bit techniques.

A machine-learning (ML) technique was used to optimize the energetic-trap distributions of nano-scaled charge trap nitride (CTN) in 3D NAND Flash to widen the threshold voltage (Vth) window, which is crucial for NAND operation. The energetic-trap distribution is a critical material property of the CTN that affects the Vth window between the erase and program Vth. An artificial neural network (ANN) was used to model the relationship between the energetic-trap distributions as an input parameter and the Vth window as an output parameter. A well-trained ANN was used with the gradient-descent method to determine the specific inputs that maximize the outputs. The trap densities (NTD and NTA) and their standard deviations (σTD and σTA) were found to most strongly impact the Vth window. As they increased, the Vth window increased because of the availability of a larger number of trap sites. Finally, when the ML-optimized energetic-trap distributions were simulated, the Vth window increased by 49% compared with the experimental value under the same bias condition. Therefore, the developed ML technique can be applied to optimize cell transistor processes by determining the material properties of the CTN in 3D NAND Flash.

A machine-learning (ML) technique was used to optimize the energetic-trap distributions of nano-scaled charge trap nitride (CTN) in 3D NAND Flash to widen the threshold voltage ( ) window, which is crucial for NAND operation. The energetic-trap distribution is a critical material property of the CTN that affects the window between the erase and program . An artificial neural network (ANN) was used to model the relationship between the energetic-trap distributions as an input parameter and the window as an output parameter. A well-trained ANN was used with the gradient-descent method to determine the specific inputs that maximize the outputs. The trap densities ( and ) and their standard deviations ( and ) were found to most strongly impact the window. As they increased, the window increased because of the availability of a larger number of trap sites. Finally, when the ML-optimized energetic-trap distributions were simulated, the window increased by 49% compared with the experimental value under the same bias condition. Therefore, the developed ML technique can be applied to optimize cell transistor processes by determining the material properties of the CTN in 3D NAND Flash.

Overexpression of the polyspecific efflux transporter, P-glycoprotein (P-gp, MDR1, ), is a major mechanism by which cancer cells acquire multidrug resistance (MDR), the resistance to diverse chemotherapeutic drugs. Inhibiting drug transport by P-gp can resensitize cancer cells to chemotherapy, but there are no P-gp inhibitors available to patients. Clinically unsuccessful P-gp inhibitors tend to bind at the pump's transmembrane drug binding domains and are often P-gp transport substrates, resulting in lowered intracellular concentration of the drug and altered pharmacokinetics. In prior work, we used computationally accelerated drug discovery to identify novel P-gp inhibitors that target the pump's cytoplasmic nucleotide binding domains. Our first-draft study provided conclusive evidence that the nucleotide binding domains of P-gp are viable targets for drug discovery. Here we develop an enhanced, computationally accelerated drug discovery pipeline that expands upon our prior work by iteratively screening compounds against multiple conformations of P-gp with molecular docking. Targeted molecular dynamics simulations with our homology model of human P-gp were used to generate docking receptors in conformations mimicking a putative drug transport cycle. We offset the increased computational complexity using custom Tanimoto chemical datasets, which maximize the chemical diversity of ligands screened by docking. Using our expanded, virtual-assisted pipeline, we identified nine novel P-gp inhibitors that reverse MDR in two types of P-gp overexpressing human cancer cell lines, reflecting a 13.4% hit rate. Of these inhibitors, all were non-toxic to non-cancerous human cells, and six were not likely to be transport substrates of P-gp. Our novel P-gp inhibitors are chemically diverse and are good candidates for lead optimization. Our results demonstrate that the nucleotide binding domains of P-gp are an underappreciated target in the effort to reverse P-gp-mediated multidrug resistance in cancer.

Overexpression of the polyspecific efflux transporter, P-glycoprotein (P-gp, MDR1, ABCB1), is a major mechanism by which cancer cells acquire multidrug resistance (MDR), the resistance to diverse chemotherapeutic drugs. Inhibiting drug transport by P-gp can resensitize cancer cells to chemotherapy. However, there are no P-gp inhibitors available to patients. Clinically unsuccessful P-gp inhibitors tend to bind at the pump's transmembrane drug binding domains and are often P-gp transport substrates, resulting in lowered intracellular concentration of the drug and altered pharmacokinetics. In prior work, we used virtual-assisted drug discovery to identify novel P-gp inhibitors that target the pump's cytoplasmic nucleotide binding domains and showed that these domains are viable drug discovery targets. Here we develop an enhanced virtual-assisted pipeline that expands upon prior work by iteratively screening compounds against multiple regions and conformations of P-gp. This increased computational complexity is offset by custom Tanimoto chemical datasets which compress the initial docking library while maximizing chemical diversity. Molecules that were similar to resultant hits were subsequently retrieved and screened. We identified nine novel P-gp inhibitors that reverse MDR in two types of P-gp overexpressing human cancer cell lines, reflecting a 14% hit rate. Of these inhibitors, all were non-toxic to non-cancerous human cells, and six were not transport substrates of P-gp. Our novel P-gp inhibitors are chemically diverse and are good candidates for lead optimization. Our results demonstrate that the nucleotide binding domains of P-gp are an underused target in the effort to reverse P-gp-mediated multidrug resistance.Competing Interest StatementThe authors have declared no competing interest.