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| 2. |
- Sanjiv, Kumar, et al.
(författare)
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MTH1 Inhibitor TH1579 Induces Oxidative DNA Damage and Mitotic Arrest in Acute Myeloid Leukemia
- 2021
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Ingår i: Cancer Research. - : American Association For Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 81:22, s. 5733-5744
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Tidskriftsartikel (refereegranskat)abstract
- Acute myeloid leukemia (AML) is an aggressive hematologic malignancy, exhibiting high levels of reactive oxygen species (ROS). ROS levels have been suggested to drive leukemogenesis and is thus a potential novel target for treating AML. MTH1 prevents incorporation of oxidized nucleotides into the DNA to maintain genome integrity and is upregulated in many cancers. Here we demonstrate that hematologic cancers are highly sensitive to MTH1 inhibitor TH1579 (karonudib). A functional precision medicine ex vivo screen in primary AML bone marrow samples demonstrated a broad response profile of TH1579, independent of the genomic alteration of AML, resembling the response profile of the standard-of-care treatments cytarabine and doxorubicin. Furthermore, TH1579 killed primary human AML blast cells (CD45+) as well as chemotherapy resistance leukemic stem cells (CD45+Lin−CD34+CD38−), which are often responsible for AML progression. TH1579 killed AML cells by causing mitotic arrest, elevating intracellular ROS levels, and enhancing oxidative DNA damage. TH1579 showed a significant therapeutic window, was well tolerated in animals, and could be combined with standard-of-care treatments to further improve efficacy. TH1579 significantly improved survival in two different AML disease models in vivo. In conclusion, the preclinical data presented here support that TH1579 is a promising novel anticancer agent for AML, providing a rationale to investigate the clinical usefulness of TH1579 in AML in an ongoing clinical phase I trial.
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| 3. |
- von Haartman, Martin, et al.
(författare)
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Random telegraph signal noise in SiGe heterojunction bipolar transistors
- 2002
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Ingår i: Journal of Applied Physics. - : AIP Publishing. - 0021-8979 .- 1089-7550. ; 92:8, s. 4414-4421
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Tidskriftsartikel (refereegranskat)abstract
- In this work, random telegraph signal (RTS) noise in SiGe heterojunction bipolar transistors (HBTs) was characterized both as a function of bias voltage and temperature. The RTS amplitudes were found to scale with the total base current, and the characteristic times in the higher and lower RTS state were found to decrease rapidly with bias voltage, approximately as 1/exp(qV(BE)/kT) or stronger. The RTS amplitudes were explained by a model based on voltage barrier height fluctuations across the base-emitter junction induced by trapped carriers in the space charge region. It was shown that the relative RTS amplitudes DeltaI(B)/I-B decrease exponentially with temperature in this model, which also was verified by measurements. The trapping/detrapping mechanism was suggested to be electron and hole capture, where the hole capture process occurs by tunneling. The characteristic times in both the lower and higher RTS state were in some cases found to decrease exponentially with temperature, characteristic for a thermally activated process, and in some cases found to be only weakly temperature dependent. The former behavior was explained by a multiphonon process with thermally activated capture cross sections, and an activation energy of 0.39 eV was extracted. RTS amplitudes proportional to the nonideal base current component or weaker were also found, originating from traps at the Si/SiO2 interface at the emitter periphery. The trapped carriers affect the recombination rate in the base-emitter space charge region, probably by changing the number of carriers. In this case, DeltaI(B)/I-B only showed a weak temperature dependence, which correlates well with this model. Characteristic times that decreased exponentially with temperature were observed, originating from a multiphonon process in the SiO2 with an activation energy for the capture cross section of 0.29 eV.
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| 4. |
- Borné, Yan, et al.
(författare)
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Cadmium, Carotid Atherosclerosis, and Incidence of Ischemic Stroke.
- 2017
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Ingår i: Journal of the American Heart Association. - 2047-9980. ; 6:12
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Tidskriftsartikel (refereegranskat)abstract
- Exposure to cadmium has been associated with carotid plaques, inflammation in carotid plaques, and increased risk of ischemic stroke. This study examined the separate and interacting effects of blood cadmium levels and carotid plaques on the risk of incident ischemic stroke.Cadmium levels were measured in 4156 subjects (39.2% men; mean±SD age 57.3±5.9years) without history of stroke, from the Malmö Diet and Cancer cohort. The right carotid artery was examined using B-mode ultrasound examination at baseline. Incidence of ischemic stroke was monitored over a mean follow-up of 16.7years. Carotid plaque was present in 34.5% of participants. Cadmium was significantly higher in subjects with plaque (mean±SD: 0.53±0.58μg/L versus 0.42±0.49μg/L; P<0.001). A total of 221 subjects had ischemic stroke during the follow-up. Incidence of ischemic stroke was associated both with carotid plaque (hazard ratio 1.44, 95% confidence interval, 1.09-1.90, P=0.009) and cadmium (hazard ratio for quartile [Q] 4 versus Q1-3: 1.95, confidence interval, 1.33-2.85, P=0.001), after adjustment for risk factors. There was a significant interaction between cadmium and plaque with respect to risk of ischemic stroke (P=0.011). Adjusted for risk factors, subjects with plaque and cadmium in Q4 had a hazard ratio of 2.88 (confidence interval, 1.79-4.63) for ischemic stroke, compared with those without plaque and cadmium in Q1 to Q3.Cadmium was associated with incidence of ischemic stroke, both independently and in synergistic interaction with carotid plaques. This supports the hypothesis that cadmium promotes vulnerability of carotid plaques, thereby increasing the risk of rupture and ischemic stroke.
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| 5. |
- Buono, Benedetto, et al.
(författare)
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Current Gain Degradation in 4H-SiC Power BJTs
- 2011
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Ingår i: Materials Science Forum. - : Trans Tech Publications Inc.. - 0255-5476 .- 1662-9752. ; 679-680, s. 702-705
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Tidskriftsartikel (refereegranskat)abstract
- SiC airs are very attractive for high power application, but long term stability is still problematic and it could prohibit commercial production of these devices. The aim of this paper is to investigate the current gain degradation in BJTs with no significant degradation of the on-resistance. Electrical measurements and simulations have been used to characterize the behavior of the BJT during the stress test. Current gain degradation occurs, the gain drops from 58 before stress to 43 after 40 hours, and, moreover, the knee current shows fluctuations in its value during the first 20 hours. Current gain degradation has been attributed to increased interface traps or reduced lifetime in the base-emitter region or small stacking faults in the base-emitter region, while fluctuations of the knee current might be due to stacking faults in the collector region.
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| 6. |
- Buono, Benedetto, et al.
(författare)
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Influence of Emitter Width and Emitter-Base Distance on the Current Gain in 4H-SiC Power BJTs
- 2010
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Ingår i: IEEE Transactions on Electron Devices. - 0018-9383 .- 1557-9646. ; 57:10, s. 2664-2670
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Tidskriftsartikel (refereegranskat)abstract
- The influence of the emitter-base geometry on the current gain has been investigated by means of measurements and simulations. Particular attention has been placed on the emitter width and on the distance between the emitter edge and the base contact. When the emitter width is decreased from 40 to 8 mu m, the current gain is reduced by 20%, whereas when the distance between the base contact and the emitter edge is decreased from 5 to 2 mu m, the current gain is reduced by 10%. Simulations have been used to investigate the reasons for the current gain reduction. The reduction of the emitter width induces two mechanisms of current gain reduction: earlier forward biasing of the base-collector junction and higher recombination in the emitter region. Both mechanisms result from the higher current density flowing under the emitter region. Placing the base contact very close to the emitter edge increases the base current by increasing the gradient of the electron concentration toward the base contact. The effect of increasing the base doping in the extrinsic region has been simulated, and the results demonstrate that the current gain can be improved if a high doping concentration in the range of 5 x 10(18) cm(-3) is used.
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| 7. |
- Buono, Benedetto, et al.
(författare)
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Investigation of Current Gain Degradation in 4H-SiC Power BJTs
- 2012
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Ingår i: Materials Science Forum. - 0255-5476 .- 1662-9752. ; 717-720, s. 1131-1134
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Tidskriftsartikel (refereegranskat)abstract
- The current gain degradation of 4H-SiC BJTs with no significant drift of the on-resistance is investigated. Electrical stress on devices with different emitter widths suggests that the device design can influence the degradation behavior. Analysis of the base current extrapolated from the Gummel plot indicates that the reduction of the carrier lifetime in the base region could be the cause for the degradation of the gain. However, analysis of the base current of the base-emitter diode shows that the degradation of the passivation layer could also influence the reduction of the current gain.
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| 8. |
- Buono, Benedetto, et al.
(författare)
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Modeling and Characterization of Current Gain Versus Temperature in 4H-SiC Power BJTs
- 2010
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Ingår i: IEEE Transactions on Electron Devices. - : Institute of Electrical and Electronics Engineers (IEEE). - 0018-9383 .- 1557-9646. ; 57:3, s. 704-711
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Tidskriftsartikel (refereegranskat)abstract
- Accurate physical modeling has been developed to describe the current gain of silicon carbide (SiC) power bipolar junction transistors (BJTs), and the results have been compared with measurements. Interface traps between SiC and SiO2 have been used to model the surface recombination by changing the trap profile, capture cross section, and concentration. The best agreement with measurement is obtained using one single energy level at 1 eV above the valence band, a capture cross section of 1 x 10(-15) cm(2), and a trap concentration of 2 x 10(12) cm(-2). Simulations have been performed at different temperatures to validate the model and characterize the temperature behavior of SiC BJTs. An analysis of the carrier concentration at different collector currents has been performed in order to describe the mechanisms of the current gain fall-off at a high collector current both at room temperature and high temperatures. At room temperature, high injection in the base ( which has a doping concentration of 3 x 10(17) cm(-3)) and forward biasing of the base-collector junction occur simultaneously, causing an abrupt drop of the current gain. At higher temperatures, high injection in the base is alleviated by the higher ionization degree of the aluminum dopants, and then forward biasing of the base-collector junction is the acting mechanism for the current gain fall-off. Forward biasing of the base-collector junction can also explain the reduction of the knee current with increasing temperature by means of the negative temperature dependence of the mobility.
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| 9. |
- Buono, Benedetto, et al.
(författare)
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Modeling and Characterization of the ON-Resistance in 4H-SiC Power BJTs
- 2011
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Ingår i: IEEE Transactions on Electron Devices. - 0018-9383 .- 1557-9646. ; 58:7, s. 2081-2087
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Tidskriftsartikel (refereegranskat)abstract
- The ON-resistance of silicon carbide bipolar transistors is characterized and simulated. Output characteristics are compared at different base currents and different temperatures in order to validate the physical model parameters. A good agreement is obtained, and the key factors, which limit the improvement of R-ON, are identified. Surface recombination and material quality play an important role in improving device performances, but the device design is also crucial. Based on simulation results, a design that can enhance the conductivity modulation in the lowly doped drift region is proposed. By increasing the base doping in the extrinsic region, it is possible to meet the requirements of having low voltage drop, high current density, and satisfactory forced current gain. According to simulation results, if the doping is 5 x 10(18) cm(-3), it is possible to conduct 200 A/cm(2) at V-CE = 1 V by having a forced current gain of about 8, which represents a large improvement, compared with the simulated value of only one in the standard design.
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| 10. |
- Buono, Benedetto
(författare)
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Simulation and Characterization of Silicon Carbide Power Bipolar Junction Transistors
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The superior characteristics of silicon carbide, compared with silicon, have suggested considering this material for the next generation of power semiconductor devices. Among the different power switches, the bipolar junction transistor (BJT) can provide a very low forward voltage drop, a high current capability and a fast switching speed. However, in order to compete on the market, it is crucial to a have high current gain and a breakdown voltage close to ideal. Moreover, the absence of conductivity modulation and long-term stability has to be solved. In this thesis, these topics are investigated comparing simulations and measurements. Initially, an efficient etched JTE has been simulated and fabricated. In agreement with the simulations, the fabricated diodes exhibit the highest BV of around 4.3 kV when a two-zone JTE is implemented. Furthermore, the simulations and measurements demonstrate a good agreement between the electric field distribution inside the device and the optical luminescence measured at breakdown. Additionally, an accurate model to simulate the forward characteristics of 4H-SiC BJTs is presented. In order to validate the model, the simulated current gains are compared with measurements at different temperatures and different base-emitter geometries. Moreover, the simulations and measurements of the on-resistance are compared at different base currents and different temperatures. This comparison, coupled with a detailed analysis of the carrier concentration inside the BJT, indicates that internal forward biasing of the base-collector junction limits the BJT to operate at high current density and low forward voltage drop simultaneously. In agreement with the measurements, a design with a highly-doped extrinsic base is proposed to alleviate this problem. In addition to the static characteristics, the comparison of measured and simulated switching waveforms demonstrates that the SiC BJT can provide fast switching speed when it acts as a unipolar device. This is crucial to have low power losses during transient. Finally, the long-term stability is investigated. It is observed that the electrical stress of the base-emitter diode produces current gain degradation; however, the degradation mechanisms are still unclear. In fact, the analysis of the measured Gummel plot suggests that the reduction of the carrier lifetime in the base-emitter region might be only one of the causes of this degradation. In addition, the current gain degradation due to ionizing radiation is investigated comparing the simulations and measurements. The simulations suggest that the creation of positive charge in the passivation layer can increase the base current; this increase is also observed in the electrical measurements.
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