BackgroundDespite the high cure rate of T cell acute lymphoblastic leukemia (T-ALL), drug resistance to chemotherapy remains a significant clinical problem. Bone marrow mesenchymal stem cells (MSCs) protect leukemic cells from chemotherapy, but the underlying mechanisms are poorly understood. In this study, we aimed to uncover the mechanism of MSC-induced chemoresistance in T-ALL cells, thus providing a promising clinical therapy target.MethodsCell viability was determined using the viability assay kit CCK-8. The mitochondrial ROS levels were detected using the fluorescent probe MitoSOX™ Red, and fluorescence intensity was measured by flow cytometry. In vitro, MSCs and Jurkat cells were cocultured. MSCs were labeled with green fluorescent protein (GFP), and Jurkat cells were labeled with the mitochondria-specific dye MitoTracker Red. Bidirectional mitochondrial transfer was detected by flow cytometry and confocal microscopy. The mechanism of mitochondria transfer was analyzed by inhibitor assays. Transcripts related to Jurkat cell/MSC adhesion in the coculture system were assessed by qRT-PCR. After treatment with a neutralizing antibody against a key adhesion molecule, mitochondria transfer from Jurkat cells to MSCs was again detected by flow cytometry and confocal microscopy. Finally, we verified our findings using human primary T-ALL cells cocultured with MSCs.ResultsChemotherapeutic drugs caused intracellular oxidative stress in Jurkat cells. Jurkat cells transfer mitochondria to MSCs but receive few mitochondria from MSCs, resulting in chemoresistance. This process of mitochondria transfer is mediated by tunneling nanotubes, which are protrusions that extend from the cell membrane. Moreover, we found that most Jurkat cells adhered to MSCs in the coculture system, which was mediated by the adhesion molecule ICAM-1. Treatment with a neutralizing antibody against ICAM-1 led to a decreased number of adhering Jurkat cells, decreased mitochondria transfer, and increased chemotherapy-induced cell death.ConclusionsWe show evidence that mitochondria transfer from Jurkat cells to MSCs, which is mediated by cell adhesion, may be a potential therapeutic target for T-ALL treatment.Electronic supplementary materialThe online version of this article (10.1186/s13045-018-0554-z) contains supplementary material, which is available to authorized users.
Ultra-wide-bandgap gallium oxide (Ga2O3) devices have recently emerged as promising candidates for power electronics; however, the low thermal conductivity (kT) of Ga2O3 causes serious concerns about their electrothermal ruggedness. This work presents the first experimental demonstrations of largearea Ga2O3 Schottky barrier diodes (SBDs) packaged in the bottom-side-cooling and double-side-cooling configurations, and for the first time, characterizes the surge current capabilities of these packaged Ga2O3 SBDs. Contrary to popular belief, Ga2O3 SBDs with proper packaging show high surge current capabilities. The double-side-cooled Ga2O3 SBDs with a 3×3 mm 2 Schottky contact area can sustain a peak surge current over 60 A, with a ratio between the peak surge current and the rated current superior to that of similarly-rated commercial SiC SBDs. The key enabling mechanisms for this high surge current are the small temperature dependence of on-resistance, which strongly reduces the thermal runaway, and the double-side-cooled packaging, in which the heat is extracted directly from the Schottky junction and does need to go through the low-kT bulk Ga2O3 chip. These results remove some crucial concerns regarding the electrothermal ruggedness of Ga2O3 power devices and manifest the significance of their die-level thermal management. 1
This work presents the temperature-dependent forward conduction and reverse blocking characteristics of a high-voltage vertical Ga2O3 power rectifier from 300 K to 600 K. Vertical β-Ga2O3 Schottky barrier diodes (SBDs) were fabricated with a bevel-field-plated edge termination, where a beveled sidewall was implemented in both the mesa and the field plate oxide. The Schottky barrier height was found to increase from 1.2 eV to 1.3 eV as the temperature increases from 300 K to 600 K, indicating the existence of barrier height inhomogeneity. The net donor concentration in the drift region shows little dependence on the temperature. The reverse leakage current up to 500 V was found to be limited by both the thermionic-field electron injection at the Schottky contact and the electron hopping via the defect states in the depletion region. At 300–500 K, the leakage is first limited by the electron injection at low voltages and then by the hopping in depleted Ga2O3 at high voltages. At temperatures above 500 K, the thermionic field emission limits the device leakage over the entire voltage range up to 500 V. Compared to the state-of-the-art SiC and GaN SBDs when blocking a similar voltage, our vertical Ga2O3 SBDs are capable of operating at significantly higher temperatures and show a smaller leakage current increase with temperature. This shows the great potential of Ga2O3 SBDs for high-temperature and high-voltage power applications.
The low thermal conductivity of Ga 2 O 3 has arguably been the most serious concern for Ga 2 O 3 power and RF devices. Despite many simulation studies, there is no experimental report on the thermal resistance of a large-area, packaged Ga 2 O 3 device. This work fills this gap by demonstrating a 15-A double-side packaged Ga 2 O 3 Schottky barrier diode (SBD) and measuring its junctionto-case thermal resistance (R θJC ) in the bottom-side-and junction-side-cooling configurations. The R θJC characterization is based on the transient dual interface method, i.e., JEDEC 51-14 standard. The R θJC of the junction-and bottom-cooled Ga 2 O 3 SBD was measured to be 0.5 K/W and 1.43 K/W, respectively, with the former R θJC lower than that of similarly-rated commercial SiC SBDs. This low R θJC is attributable to the heat extraction directly from the Schottky junction instead of through the Ga 2 O 3 chip. The R θJC lower than that of commercial SiC devices proves the viability of Ga 2 O 3 devices for high-power applications and manifest the significance of proper packaging for their thermal management.
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