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Background: Recently, one of the specific BH3-mimetics, Venetoclax has been approved by FDA providing new options for newly diagnosed AML patient especially who are unfitted to receive conventional chemotherapy. Though the clinical success of venetoclax has been achieved in clinical outcomes such as complete remission (CR) and overall survival. Acquired resistance to ABT-199 which is induced by the regulation of apoptosis pathway is still an important clinical problem. To this end, the attempt to combine drugs which can reverse the compensatory regulation is urgent. Methods: In three AML cell lines (KG-1, Kasumi-1 and THP-1), the anti-AML effects of the combination of and metformin or the two drugs used alone were compared. CCK8 was used to evaluate the cell viability, and flow cytometry was used to estimate the rate of apoptosis, Western blot method was performed to detect apoptosis-related protein levels. In mice experiments, female BALB/c-nu nude mice were subcutaneously injected with THP-1 cells for subcutaneous tumor formation, and the combined effect of ABT-199 and metformin was tested. The evaluation indicators were tumor size, tumor weight, and Ki67 staining. Mouse body weight and HE staining were detected to evaluate liver damage and adverse drug reactions. Results: Both in vitro and in vivo experiments showed that compared with metformin or ABT-199 alone, the combined use of the two drugs exerts a synergistic effect on promoting apoptosis, thereby producing a strong anti-leukemia effect. Furthermore, after a short incubation time, ABT-199 swiftly increased the expression level of the anti-apoptotic protein Mcl-1, while the combined use of metformin and ABT-199 significantly reduced the level of Mcl-1. Notably, Metformin significantly downregulates the level of Mcl-1 protein by inhibiting its protein production. To less extent, metformin can also downregulate the expression of another anti-apoptotic protein, BCL-xl. Conclusion:Metformin downregulates the expression of anti-apoptotic proteins Mcl-1 and Bcl-xl by inhibiting protein production, and shows a synergistic anti-tumor effect with ABT-199 in acute myeloid leukemia.

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A novel PVDF dielectric nanocomposite was achieved by controlling phase morphology and incorporating conductive fillers simultaneously, and the mechanical, thermal, dielectric properties of the resultant dielectric nanocomposites were investigated. Mechanical analysis showed that incorporation of modified MWCNTs (MWCNTs-COOH) in the PVDF nanocomposites resulted in significant improvements on the tensile strength (T s ) and elasticity modulus (E m ). When the filler content was 12 wt%, the T s of MWCNTs-COOH/PVDF could reach 64.6 MPa. XRD test showed that the addition of MWCNTs-COOH and MWCNTs promoted the formation of β-phase of PVDF. DMA analysis showed that the glass-transition temperature of the PVDF nanocomposites slightly increases on loading of original MWCNTs and this effect was more pronounced on loading MWCNTs-COOH. The dielectric property analysis showed that the original MWCNTs were more likely to form local conductive networks in the PVDF matrix, promoting the electron displacement polarization, and improving the dielectric constant. When the contents of MWCNTs was 12 wt%, the percolation threshold was obtained and the dielectric constant (ε 0 ) reached 286, which was 36 times of pure PVDF. Our work provides a simple way to fabricate polymer blends with excellent dielectric performances, good mechanical properties as well as good processing capability but low cost.

Pain is a multidimensional process, which can be modulated by emotions; however, the mechanisms underlying this modulation are unknown. We used pictures with different emotional valence (negative, positive, and neutral) as primes and applied electrical painful stimuli as targets to healthy participants. We assessed pain intensity and unpleasantness ratings and recorded electroencephalograms (EEGs). We found that pain unpleasantness and not pain intensity ratings were modulated by emotion, with increased ratings for negative and decreased ratings for positive pictures. We also found two consecutive gamma band oscillations (GBOs) related to pain processing from time frequency analyses of the EEG signals. The early GBO had a cortical distribution contralateral to the painful stimulus and its amplitude was positively correlated with intensity and unpleasantness ratings, but not with prime valence. The late GBO had a centroparietal distribution and its amplitude was larger for negative compared to neutral and positive pictures. The emotional modulation effect (negative vs. positive) of the late GBO amplitude was positively correlated with pain unpleasantness. The early GBO might reflect the overall pain perception, possibly involving the thalamocortical circuit, while the late GBO might be related to the affective dimension of pain and top-down-related processes.

Chemically reduced graphene (C- rGO) nanosheets were first prepared from graphene oxide (GO), and then the polypropylene (PP) composites synergistically reinforced–toughened by styrene–butadiene rubber (SBR), and C- rGO nanosheets were fabricated via melt blending. The mechanical properties of PP can be considerably improved by synergistically filling with C- rGO nanosheets and SBR, especially for the notched Izod impact strength (IS). The results from the X-ray diffraction, polarizing optical micrographs, scanning electron microscope, differential scanning calorimetric, dynamic mechanical analysis, and thermogravimetric analysis measurements reveal that: (1) the β-phase crystal structure of the PP is formed when the C- rGO and SBR are synergistically filled with PP and its formation plays a role for the enhancement of the impact strength for PP/SBR/C- rGO composites; (2) the dispersion of the C- rGO and SBR in the PP/SBR/C- rGO composites is homogeneous, indicating that synergistic incorporating method decreases the aggregation of nanosheets and thus increases the sites for dissipation of shock for impact energy in the PP/SBR/C- rGO composites; and (3) the thermal analysis shows high thermal stability for the PP/SBR/C- rGO composites.

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