Evaluation of an EZH2 inhibitor in patient-derived orthotopic xenograft models of pediatric brain tumors alone and in combination with chemo- and radiation therapies.

Brain tumors are the leading cause of cancer-related death in children. Tazemetostat is an FDA-approved enhancer of zeste homolog (EZH2) inhibitor. To determine its role in difficult-to-treat pediatric brain tumors, we examined EZH2 levels in a panel of 22 PDOX models and confirmed EZH2 mRNA over-expression in 9 GBM (34.6 ± 12.7-fold) and 11 medulloblastoma models (6.2 ± 1.7 in group 3, 6.0 ± 2.4 in group 4) accompanied by elevated H3K27me3 expression. Therapeutic efficacy was evaluated in 4 models (1 GBM, 2 medulloblastomas and 1 ATRT) via systematically administered tazemetostat (250 and 400 mg/kg, gavaged, twice daily) alone and in combination with cisplatin (5 mg/kg, i.p., twice) and/or radiation (2 Gy/day × 5 days). Compared with the untreated controls, tazemetostat significantly (Pcorrected < 0.05) prolonged survival times in IC-L1115ATRT (101% at 400 mg/kg) and IC-2305GBM (32% at 250 mg/kg, 45% at 400 mg/kg) in a dose-dependent manner. The addition of tazemetostat with radiation was evaluated in 3 models, with only one [IC-1078MB (group 4)] showing a substantial, though not statistically significant, prolongation in survival compared to radiation treatment alone. Combining tazemetostat (250 mg/kg) with cisplatin was not superior to cisplatin alone in any model. Analysis of in vivo drug resistance detected predominance of EZH2-negative cells in the remnant PDOX tumors accompanied by decreased H3K27me2 and H3K27me3 expressions. These data supported the use of tazemetostat in a subset of pediatric brain tumors and suggests that EZH2-negative tumor cells may have caused therapy resistance and should be prioritized for the search of new therapeutic targets.

Mechanisms Underlying the Antidepressant Effect of Acupuncture via the CaMK Signaling Pathway.

The CaMK pathway has been proven to play an important role in regulating cognitive function and emotional response. Acupuncture through the CaMK pathway improves depression-like behavior and the molecular mechanism related to its antidepressant remains to be explored. In this study, we aimed to determine whether the ability of acupuncture at Baihui (GV20) and Shenting (GV24) points to treat depression is related to the regulation of key proteins in the CaMK pathway. A rat model of depression was induced by chronic unpredicted mild stress (CUMS). Model rats in the electroacupuncture group were subjected to acupuncture at the Baihui (GV20) and Shenting (GV24) acupoints once a day for 20 min. Model rats in the fluoxetine group were gavaged with fluoxetine (1.8 mg/kg). Immunohistochemistry and Western blotting assays were used to evaluate immunoreactivity for and the protein expression levels of CaMKII, CaMKIV, and CaM. The results showed that electroacupuncture had a significant effect in rats with depression. Electroacupuncture and fluoxetine regulated the expression of key proteins in the CaMK signaling pathway, which is related to depression, in the hippocampi of rats. This indicates that acupuncture at Baihui (GV20) and Shenting (GV24) may alleviate depressive symptoms and reduce work- and life-related burdens and stress by regulating the CaMK signaling pathway.

Improvement of cerebral ischemia/reperfusion injury by daucosterol palmitate-induced neuronal apoptosis inhibition via PI3K/Akt/mTOR signaling pathway.

Traditional Chinese medicine has growing importance in the treatment of ischemia stroke due to its abundance and low drug resistance. In this study, we aim to investigate the therapeutic potential of daucosterol palmitate against ischemia stroke, as well as its neuro-protective mechanism. The dose-response effects of daucosterol palmitate in the protection from brain damage were evaluated in a cerebral ischemia/reperfusion (I/R) rat model. The correlation of neuro-protective effects of daucosterol palmitate with apoptosis inhibition was examined and the possible signaling targets were identified. Our findings revealed that daucosterol palmitate treatment after 2 h' ischemia significantly lowered brain damage, and neuronal cell apoptosis caused by I/R injury in a dose-response mode (20, 40 and 80 mg/kg). Western blot analysis indicated that daucosterol palmitate could reverse the effects of I/R injury on protein expression of PI3K and mTOR, and phosphorylation of Akt. Contrarily, inactivation of PI3K using wortmannin dramatically antagonized the effect of daucosterol palmitate for I/R injury. With these findings, it supports the application potential of daucosterol palmitate in the treatment of ischemia stroke. Besides, the PI3K/Akt/mTOR pathway might be potential cellular targets for daucosterol palmitate.

CuS@MOF-Based Well-Designed Quercetin Delivery System for Chemo-Photothermal Therapy.

Quercetin (QT) is one promising candidate for the treatment of various cancers with virtually no toxic side effects. However, its anticancer effect is severely restricted by its poor bioavailability, low water solubility, and chemical instability in the neutral and alkaline medium. Herein, zeolitic imidazolate framework-8 (ZIF-8) is first reported as the multifunctional nanoplatform to the codelivery of quercetin as an anticancer agent and CuS nanoparticles as a photothermal therapy (PTT) agent for synergistic combination of chemotherapy and PTT as well as overcoming the drawbacks of quercetin. Moreover, folic acid-bovine serum albumin (FA-BSA) conjugates are applied to stabilize the CuS@ZIF-8-QT to promote the bioavailability of quercetin and realize active-targeting drug delivery. Near-infrared (NIR) fluorescent imaging demonstrated the highly increased drug accumulations of FA-BSA/CuS@ZIF-8-QT in tumors, resulting from efficient internalization via FA-receptors-mediated endocytosis. The results of in vivo and in vitro anticancer experiments demonstrate that quercetin and PTT agent can work together efficiently under NIR irradiation, thus remarkably improving the anticancer effect. Therefore, our newly designed FA-BSA/CuS@ZIF-8-QT multifunctional drug delivery system might be a promising nanoplatform for cancer treatment.

mTOR ATP-competitive inhibitor INK128 inhibits neuroblastoma growth via blocking mTORC signaling.

High-risk neuroblastoma often develops resistance to high-dose chemotherapy. The mTOR signaling cascade is frequently deregulated in human cancers and targeting mTOR signaling sensitizes many cancer types to chemotherapy. Here, using a panel of neuroblastoma cell lines, we found that the mTOR inhibitor INK128 showed inhibitory effects on both anchorage-dependent and independent growth of neuroblastoma cells and significantly enhanced the cytotoxic effects of doxorubicin (Dox) on these cell lines. Treatment of neuroblastoma cells with INK128 blocked the activation of downstream mTOR signaling and enhanced Dox-induced apoptosis. Moreover, INK128 was able to overcome the established chemoresistance in the LA-N-6 cell line. Using an orthotopic neuroblastoma mouse model, we found that INK128 significantly inhibited tumor growth in vivo. In conclusion, we have shown that INK128-mediated mTOR inhibition possessed substantial antitumor activity and could significantly increase the sensitivity of neuroblastoma cells to Dox therapy. Taken together, our results indicate that using INK128 can provide additional efficacy to current chemotherapeutic regimens and represent a new paradigm in restoring drug sensitivity in neuroblastoma.

[Research on the methods for electroencephalogram feature extraction based on blind source separation].

In the present investigation, we studied four methods of blind source separation/independent component analysis (BSS/ICA), AMUSE, SOBI, JADE, and FastICA. We did the feature extraction of electroencephalogram (EEG) signals of brain computer interface (BCI) for classifying spontaneous mental activities, which contained four mental tasks including imagination of left hand, right hand, foot and tongue movement. Different methods of extract physiological components were studied and achieved good performance. Then, three combined methods of SOBI and FastICA for extraction of EEG features of motor imagery were proposed. The results showed that combining of SOBI and ICA could not only reduce various artifacts and noise but also localize useful source and improve accuracy of BCI. It would improve further study of physiological mechanisms of motor imagery.

[Spatial discharge characteristics and total load control of non-point source pollutants based on the catchment scale].

Agricultural non-point source pollution is one of the major causes of water quality deterioration. Based on the analysis of the spatial discharge characteristics and intensity of major pollutants from the agricultural pollution source, the establishment of spatial management subzones for controlling agricultural non-point pollution and a design of a plan for total load control of pollutants from each subzone is an important way to improve the efficiency of control measures. In this paper the Four Lake basin in Hubei Province is adopted as the research case region and a systematic research of the control countermeasures of agricultural non-point pollution based on the catchment scale is carried out. The results shows that in the Four Lake basin, the COD, total nitrogen, total phosphorus and ammonia nitrogen load of the water environment are mainly caused by agricultural non-point pollution. These four kinds of non-point source pollutants respectively account for 67.6%, 82.2%, 84.7% and 50.9% of the total pollutant discharge amount in the basin. The analysis of the spatial discharge characteristics of non-point source pollutants in the Four Lake basin shows that the major contributor source regions of non-point source pollutant in the basin are the four counties, including Honghu, Jianli, Qianjiang and Shayang where the aquatic and livestock production are relatively developed. According to the spatial discharge characteristics of the pollutants and the evaluation of the discharge intensity of pollutants, the Four Lake basin is divided into three agricultural non-point pollution management subzones, which including Changhu upstream aquatic and livestock production pollution control subzone, Four-lake trunk canal rural non-point source pollution control subzone and Honghu aquatic production pollution control subzone. Specific pollution control measures are put forward for each subzone. With a comprehensive consideration of the water quality amelioration and the allowable discharge of pollutants, a total load control solution is designed for the three non-point pollution management subzones, so as to fulfill the requirements of all indices of the monitoring sites and the requirements for the allowable discharge of pollutants of the water. Among the major pollutants, the major COD reduction area includes the Four-lake trunk canal subzone and the Honghu Lake subzone, which respectively account for 43% and 42% of the total COD reduction amount; the major ammonia nitrogen reduction area includes the Four-lake trunk canal subzone, accounting for 66% of the total ammonia nitrogen reduction amount; the major total nitrogen reduction area covers the Four-lake trunk canal subzone and the Honghu Lake subzone, accounting for 42% and 31% of the total nitrogen reduction amount in the basin respectively; the major total phosphorus reduction area is the Four-lake trunk canal subzone, accounting for 53% of the total phosphorus reduction amount in the basin.