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Transarterial chemoembolization (TACE) is the first-line treatment for unresectable intermediate-stage hepatocellular carcinoma (HCC). It is of high clinical significance to explore the synergistic effect of TACE with antiangiogenic inhibitors and the molecular mechanisms involved. This study determined that glucose, but not other analyzed nutrients, offered significant protection against cell death induced by sorafenib, as indicated by glucose deprivation sensitizing cells to sorafenib-induced cell death. Next, this synergistic effect was found to be specific to sorafenib, not to lenvatinib or the chemotherapeutic drugs cisplatin and doxorubicin. Mechanistically, sorafenib-induced mitophagy, as indicated by PINK1 accumulation, increased the phospho-poly-ubiquitination modification, accelerated mitochondrial membrane protein and mitochondrial DNA degradation, and increased the amount of mitochondrion-localized mKeima-Red engulfed by lysosomes. Among several E3 ubiquitin ligases tested, SIAH1 was found to be essential for inducing mitophagy; that is, SIAH1 silencing markedly repressed mitophagy and sensitized cells to sorafenib-induced death. Notably, the combined treatment of glucose restriction and sorafenib abolished ATP generation and mitophagy, which led to a high cell death rate. Oligomycin and antimycin, inhibitors of electron transport chain complexes, mimicked the synergistic effect of sorafenib with glucose restriction to promote cell death mediated via mitophagy inhibition. Finally, inhibition of the glucose transporter by canagliflozin (a clinically available drug used for type-II diabetes) effectively synergized with sorafenib to induce HCC cell death in vitro and to inhibit xenograft tumor growth in vivo. This study demonstrates that simultaneous treatment with sorafenib and glucose restriction is an effective approach to treat HCC, suggesting a promising combination strategy such as transarterial sorafenib-embolization (TASE) for the treatment of unresectable HCC.

In this paper, uniaxial compression tests were carried out on a series of composite rock specimens with different dip angles, which were made from two types of rock-like material with different strength. The acoustic emission technique was used to monitor the acoustic signal characteristics of composite rock specimens during the entire loading process. At the same time, an optical non-contact 3D digital image correlation technique was used to study the evolution of axial strain field and the maximal strain field before and after the peak strength at different stress levels during the loading process. The effect of bedding plane inclination on the deformation and strength during uniaxial loading was analyzed. The methods of solving the elastic constants of hard and weak rock were described. The damage evolution process, deformation and failure mechanism, and failure mode during uniaxial loading were fully determined. The experimental results show that the $$\theta = 0{^{\circ }}$$ – $$45{^{\circ }}$$ specimens had obvious plastic deformation during loading, and the brittleness of the $$\theta = 60{^{\circ }}$$ – $$90{^{\circ }}$$ specimens gradually increased during the loading process. When the anisotropic angle $$\theta $$ increased from $$0{^{\circ }}$$ to $$90{^{\circ }}$$ , the peak strength, peak strain, and apparent elastic modulus all decreased initially and then increased. The failure mode of the composite rock specimen during uniaxial loading can be divided into three categories: tensile fracture across the discontinuities ( $$\theta = 0{^{\circ }}$$ – $$30{^{\circ }})$$ , sliding failure along the discontinuities ( $$\theta = 45{^{\circ }}$$ – $$75{^{\circ }})$$ , and tensile-split along the discontinuities ( $$\theta = 90{^{\circ }})$$ . The axial strain of the weak and hard rock layers in the composite rock specimen during the loading process was significantly different from that of the $$\theta = 0{^{\circ }}$$ – $$45{^{\circ }}$$ specimens and was almost the same as that of the $$\theta = 60{^{\circ }}$$ – $$90{^{\circ }}$$ specimens. As for the strain localization highlighted in the maximum principal strain field, the $$\theta = 0{^{\circ }}$$ – $$30{^{\circ }}$$ specimens appeared in the rock matrix approximately parallel to the loading direction, while in the $$\theta = 45{^{\circ }}$$ – $$90{^{\circ }}$$ specimens it appeared at the hard and weak rock layer interface.

Rhizosphere carbon sequestration plays a crucial role in soil carbon dynamics. Little information is available on the dynamics of rhizosphere soil labile organic carbon fractions compared with bulk soil at different citrus stand age. Two replicate sites of three stand ages (10-, 20-, and 30-year) of citrus in the Three Gorges Reservoir area of China were studied. The results showed that rhizosphere soil organic carbon has an increases of 18.76 % under 20-year stand and 11.09 % under 30-year stand compared with bulk soil (P

Radiation-induced pulmonary fibrosis (RIPF) is a debilitating side effect that occurs in up to 30% of thoracic irradiations in breast and lung cancer patients. RIPF remains a major limiting factor to dose escalation and an obstacle to applying more promising new treatments for cancer cure. Limited treatment options are available to mitigate RIPF once it occurs, but recently, mesenchymal stem cells (MSCs) and a drug treatment stimulating endogenous stem cells (GM-CSF) have been investigated for their potential in preventing this disease onset. In a pre-clinical rat model, we contrasted the application of longitudinal computed tomography (CT) imaging and classical histopathology to quantify RIPF and to evaluate the potential of MSCs in mitigating RIPF. Our results on histology demonstrate promises when MSCs are injected endotracheally (but not intravenously). While our CT analysis highlights the potential of GM-CSF treatment. Advantages and limitations of both analytical methods are contrasted in the context of RIPF.

Genetic structure of 142 parent lines of sorghum [Sorghum bicolor (L.) Moench] was analyzed using model-based approach based on SSR markers. Forty-one selected from 103 SSR markers were used to analyze the parent lines, which generated 189 alleles revealed by each marker ranging from 2 to 11 with an average of 4.6 per marker. The polymorphic information content (PIC) value was 0.543 with a range of 0.089 to 0.850. All the parent lines were assigned to 7 subgroups, named Kafir, Kaoliang, Feterita, Shallu, Hegari, Milo and Durra. Parent lines without clear pedigree record were clustered into their corresponding groups, and genetic components of each line were estimated by Q-values. Information of this study would be useful for breeders to conclude their genetic background and select appropriate parents for germplasm improvement and hybrid breeding, and thus improve the efficiency of breeding programs.

Ni-free Ti-based shape memory alloys (SMAs) are increasingly recognized as promising functional materials for medical applications. The mechanical properties of these metastable Ti-based SMAs are sensitive to aging and thermomechanical treatment. Effects of severe plastic deformation (SPD)-equal channel angular pressing (ECAP) and aging on superelastic behavior of Ni-free Ti-based SMAs, Ti-9.8Mo-3.9Nb-2V-3.1Al wt.% (TMNVA) and Ti-25at.%Nb, have been investigated. The results show that the yielding strength of TMNVA alloy increases sharply with the number of ECAP processes—to greater than 1,400 MPa after two passes ECAP—but elongation of TMNVA alloy decreases severely and the plasticity is lost completely after two passes ECAP. Both ECAP process and flash annealing treatment have weak contribution to the superelastic recoverable strains of Ti-Mo-based alloy. For Ti-25at.%Nb alloy, after one pass ECAP process at 400 °C, the yielding stress increases obviously, and the recovery strain increases a little. With the further increase in the number of ECAP processes, the yielding stress and the recovery strain change little. Aging treatment at low temperature after ECAP process is in favor of superelasticity of Ti-25at.%Nb alloy. An almost completely recoverable strain of 1.5% is obtained in Ti-25at.%Nb alloy after two passes ECAP and aging at 300 °C for 1 h. The mechanisms of the effects of SPD and aging are also discussed.

The aim of the study was to test whether calcium citrate combined with rhBMP-2 was able to enhance bone regeneration compared with a matrix containing only rhBMP-2. In each of experimental mice, one cylinder of calcium citrate–rhBMP-2 or rhBMP-2 alone was implanted into the thigh muscle pouches of the mouse. The following two treatment modalities were randomly allocated: (1) empty control with rhBMP-2 alone in a gelatin matrix and (2) a gelatin matrix including both calcium citrate and BMP-2. After several weeks, bone granules were obtained by histological analysis. Histomorphometric analysis showed the greatest amount of newly formed bone was observed in the group that contained 10.0 mg calcium citrate with 2.0 mg rhBMP-2 (p

To ascertain the effects of erlotinib on CYP3A, to investigate the amplitude and kinetics of erlotinib-mediated inhibition of seven major CYP isoforms in human liver microsomes (HLMs) for evaluating the magnitude of erlotinib in drug-drug interaction in vivo.The activities of 7 major CYP isoforms (CYP1A2, CYP2A6, CYP3A, CYP2C9, CYP2D6, CYP2C8, and CYP2E1) were assessed in HLMs using HPLC or UFLC analysis. A two-step incubation method was used to examine the time-dependent inhibition of erlotinib on CYP3A.The activity of CYP2C8 was inhibited with an IC(50) value of 6.17±2.0 μmol/L. Erlotinib stimulated the midazolam 1'-hydroxy reaction, but inhibited the formation of 6β-hydroxytestosterone and oxidized nifedipine. Inhibition of CYP3A by erlotinib was substrate-dependent: the IC(50) values for inhibiting testosterone 6β-hydroxylation and nifedipine metabolism were 31.3±8.0 and 20.5±5.3 μmol/L, respectively. Erlotinib also exhibited the time-dependent inhibition on CYP3A, regardless of the probe substrate used: the value of K(I) and k(inact) were 6.3 μmol/L and 0.035 min(-1) for midazolam; 9.0 μmol/L and 0.045 min(-1) for testosterone; and 10.1 μmol/L and 0.058 min(-1) for nifedipine.The inhibition of CYP3A by erlotinib was substrate-dependent, while its time-dependent inhibition on CYP3A was substrate-independent. The time-dependent inhibition of CYP3A may be a possible cause of drug-drug interaction, suggesting that attention should be paid to the evaluation of erlotinib's safety, especially in the context of combination therapy.

Effects of specific interleukin-1β-converting enzyme inhibitor on ischemic acute renal failure in murine models

\( BMO \) and \( VMO \) spaces consist of all those locally integrable functions on the open unit ball such that their mean oscillations on any Bergman ball are, respectively, bounded and vanishing to zero as the Bergman ball approaches the boundary of the unit ball. The harmonic (or analytic) versions of the \( BMO \) and \( VMO \) spaces are the Bloch space and the little Bloch space, respectively. The study of these spaces plays an important role in modern analysis, especially in the the area of operator theory and holomorphic spaces. In this paper, we characterize systematically the multipliers of \( BMO \)and \( VMO \) spaces.

We study Clifford valuedBMO in Bergman metrics. We prove that aBMO function can be decomposed into a “bad” function that is bounded in terms of Carleson measure norm and a “good” function that is in the Sobolev type space. Applications to Hankel operators and bilinear forms are also included.

Sodium selenite administered to normal and hepatoma (HA)-bearing mice sc (2 mg/kg) or ip (1 mg/kg) led to a significant increase in cyclic AMP (cAMP) level and a decrease in cAMP phosphodiesterase (PDE) activity in HA cells. In contrast, in tumor host liver and normal liver the cAMP level was reduced, and the PDE activity was slightly elevated, whereas the cAMP adenylate cyclase (AC) was little affected by Na2SeO3, if at all. These results imply that selenite-induced changes in PDE activity play a decisive role in regulating intracellular cAMP level. Kinetic studies revealed that there were different forms of PDE. TheK m value of PDE isozymes in normal liver and host liver were identical, but differed from those of HA. It seems likely that the selective responsiveness of PDE to selenite may be related to the difference in PDE isozyme patterns. Addition of DBcAMP to the culture medium resulted in an inhibition of(3)H-thymidine incorporation into hepatoma cells, indicating that the inhibition of HA cell proliferation was cAMP-mediated. Thus, selenium has been shown to exert a selective effect on cAMP metabolism of hepatoma cells, which may account for its inhibitory effects on cancer cells.