A series of N-trinitromethyl-substituted polynitro-pyrazoles: high-energy-density materials with positive oxygen balances.

An N-trinitromethyl strategy was employed for the synthesis of polynitro-pyrazole based high-energy-density compounds with great potential as energetic materials. The new compounds were characterized by 1H and 13C NMR, IR spectroscopy, elemental analysis, differential scanning calorimetry, and single-crystal X-ray diffraction. Compound 10 exhibits high energetic properties, has a positive oxygen balance (OB) of +2.1%, and an excellent specific impulse (272.4 s), making it a potential high-energy dense oxidizer to replace AP in solid rocket propellants. The nitration of 7 with HNO3/H2SO4 yielded the green primary explosive 12, which showed higher density, higher performance, better oxygen balance and lower sensitivities to those of currently used diazodinitrophenol. Compound 13 is a nitrogen and oxygen rich secondary explosive with a high OB (+5.0%), comparable energy (D = 9030 m s-1; P = 35.6 GPa; η = 1.03) to HMX, and much lower mechanical sensitivity (IS = 12 J, FS = 240 N).

Irreversible Electroporation Mediates Glioma Apoptosis via Upregulation of AP-1 and Bim: Transcriptome Evidence.

The heat-sink effect and thermal damage of conventional thermal ablative technologies can be minimized by irreversible electroporation (IRE), which results in clear ablative boundaries and conservation of blood vessels, facilitating maximal safe surgical resection for glioblastoma. Although much comparative data about the death forms in IRE have been published, the comprehensive genetic regulatory mechanism for apoptosis, among other forms of regulatory cell death (RCD), remains elusive. We investigated the electric field intensity threshold for apoptosis/necrosis (YO-PRO-1/PI co-staining) of the U251 human malignant glioma cell line with stepwise increased uniform field intensity. Time course samples (0-6 h) of apoptosis induction and sham treatment were collected for transcriptome sequencing. Sequencing showed that transcription factor AP-1 and its target gene Bim (Bcl2l11), related to the signaling pathway, played a major role in the apoptosis of glioma after IRE. The sequencing results were confirmed by qPCR and Western blot. We also found that the transcription changes also implicated three other forms of RCD: autophagy, necroptosis, and immunogenic cell death (ICD), in addition to apoptosis. These together imply that IRE possibly mediates apoptosis by the AP-1-Bim pathway, causes mixed RCD simultaneously, and has the potential to aid in the generation of a systemic antitumor immune response.

Lethal Electric Field Thresholds for Cerebral Cells With Irreversible Electroporation and H-FIRE Protocols: An In Vitro Three-Dimensional Cell Model Study.

The lethal electric field (LEF) thresholds for three typical cerebral cells, including a malignant glioblastoma (GBM) cell line and two cell lines from the healthy blood-brain barrier (BBB), treated by irreversible electroporation (IRE) or high-frequency irreversible electroporation (H-FIRE) protocols were investigated in an in vitro three-dimensional (3D) cell model. A conventional IRE protocol (90 pulses, 1 Hz, and 100-µs pulse duration) and three novel H-FIRE protocols (1-3-1, 0.5-1-0.5, and 1-1-1) were used to treat the cerebral cells in both 3D single-cell and two-cell models. The electrical conductivity of the 3D cell model under different electric field strengths were characterized with the method of electrochemical impedance spectroscopy (EIS). Based on EIS, a numerical electrothermal model of electroporation was built for the determination of the LEF threshold with different protocols and temperature monitoring. Cell viability was assessed by fluorescence staining 6 h after the treatment. The results showed no thermal lethal effect on cells when these protocols were used. The LEF threshold for GBM cells was significantly lower than that of the healthy BBB cells. These results suggest the possibility of selective ablation of human cerebral GBM by IRE and H-FIRE treatments with no injury or reversible injury to healthy cells, and the potential use of IRE or H-FIRE for transient disruption of the BBB to allow chemotherapy to reach the tumor.

Treatment Planning Optimization in Irreversible Electroporation for Complete Ablation of Variously Sized Cervical Tumors: A Numerical Study.

Irreversible electroporation (IRE), a relatively new energy-based tumor ablation technology, has shown itself in the last decade to be able to safely ablate tumors with favorable clinical outcomes, yet little work has been done on optimizing the IRE protocol to variously sized tumors. Incomplete tumor ablation has been shown to be the main reason leading to the local recurrence and thus treatment failure. The goal of this study was to develop a general optimization approach to optimize the IRE protocol for cervical tumors in different sizes, while minimizing the damage to normal tissues. This kind of approach can lay a foundation for future personalized treatment of IRE. First, a statistical IRE cervical tumor death model was built using previous data in our group. Then, a multi-objective optimization problem model was built, in which the decision variables are five IRE-setting parameters, namely, the pulse strength (U), the length of active tip (H), the number of pulses delivered in one round between a pair of electrodes (A), the distance between electrodes (D), and the number of electrodes (N). The domains of the decision variables were determined based on the clinical experience. Finally, the problem model was solved by using nondominated sorting genetic algorithms II (NSGA-II) algorithm to give respective optimal protocol for three sizes of cervical tumors. Every protocol was assessed by the evaluation criterion established in the study to show the efficacy in a more straightforward way. The results of the study demonstrate this approach can theoretically provide the optimal IRE protocol for different sizes of tumors and may be generalizable to other types, sizes, and locations of tumors.

An in vivo study of a custom-made high-frequency irreversible electroporation generator on different tissues for clinically relevant ablation zones.

PURPOSE: To examine the ablation zone, muscle contractions, and temperature increases in both rabbit liver and kidney models in vivo for a custom-made high-frequency irreversible electroporation (H-FIRE) generator. MATERIALS AND METHODS: A total of 18 New Zealand white rabbits were used to investigate five H-FIRE protocols (n = 3 for each protocol) and an IRE protocol (n = 3) for the performance of the designed H-FIRE device in both liver and kidney tissues. The ablation zone was determined by using histological analysis 72 h after treatment. The extent of muscle contractions and temperature change during the application of pulse energy were measured by a commercial accelerometer attached to animals and fiber optic temperature probe inserted into organs with IRE electrodes, respectively. RESULTS: All H-FIRE protocols were able to generate visible ablation zones without muscle contractions, for both liver and kidney tissues. The area of ablation zone generated in H-FIRE pulse protocols (e.g., 0.3-1 µs, 2000 V, and 90-195 bursts) appears similar to that of IRE protocol (100 µs, 1000 V, and 90 pulses) in both liver and kidney tissues. No significant temperature increase was noticed except for the protocol with the highest pulse energy (e.g., 1 µs, 2000 V, and 180 bursts). CONCLUSION: Our work serves to complement the current H-FIRE pulse waveforms, which can be optimized to significantly improve the quality of ablation zone in terms of precision for liver and kidney tumors in clinical setting.

CoPd Nanoalloys with Metal-Organic Framework as Template for Both N-Doped Carbon and Cobalt Precursor: Efficient and Robust Catalysts for Hydrogenation Reactions.

In this work, a series of metal-organic framework (MOF)-derived CoPd nanoalloys have been prepared. The nanocatalysts exhibited excellent activities in the hydrogenation of nitroarenes and alkenes in green solvent (ethanol/water) under mild conditions (H2 balloon, room temperature). Using ZIF-67 as template for both carbon matrix and cobalt precursor coating with a mesoporous SiO2 layer, the catalyst CoPd/NC@SiO2 was smoothly constructed. Catalytic results revealed a synergistic effect between Co and Pd components in the hydrogenation process due to the enhanced electron density. The mesoporous SiO2 shell effectively prevented the sintering of hollow carbon and metal NPs at high temperature, furnishing the well-dispersed nanoalloy catalysts and better catalytic performance. Moreover, the catalyst was durable and showed negligible activity decay in recycling and scale-up experiments, providing a mild and highly efficient way to access amines and arenes.

Tumor Ablation Enhancement by Combining Radiofrequency Ablation and Irreversible Electroporation: An In Vitro 3D Tumor Study.

We hypothesized and demonstrated for the first time that significant tumor ablation enhancement can be achieved by combining radiofrequency ablation (RFA) and irreversible electroporation (IRE) using a 3D cervical cancer cell model. Three RFA (43, 50, and 60 °C for 2 min) and IRE protocols (350, 700, and 1050 V/cm) were used to study the combining effect in the 3D tumor cell model. The in vitro experiment showed that both RFA enhanced IRE and IRE enhanced RFA can lead to a significant increase in the size of the ablation zone compared to IRE and RFA alone. It was also noted that the sequence of applying ablation energy (RFA â†’ RE or IRE â†’ RFA) affected the efficacy of tumor ablation enhancement. The electrical conductivity of 3D tumor was found to be increased after preliminary RFA or IRE treatment. This increase in tumor conductivity may explain the enhancement of tumor ablation. Another explanation might be that there is repeat injury to the transitional zone of the first treatment by the second one. The promising results achieved in the study can provide us useful clues about the treatment of large tumors abutting large vessels or bile ducts.