m6A is the most common form of mRNA modification. However, little is known about its role in clear cell renal cell carcinoma (ccRCC). This study aims to identify gene signatures and prognostic values of m6A regulators in ccRCC. In this study, a total of 528 ccRCC patients from TCGA database with sequencing and CNV data were included. Survival analysis was performed using log-rank tests and Cox regression model. The association between alteration of m6A regulators and clinicopathological characteristics was examined using chi-square test. The results showed that alteration of m6A regulators was associated with pathologic stage. Patients with any CNVs of the regulatory genes had worse OS and DFS than those with diploid genes. Moreover, deletion of m6A “writer” genes was an independent risk factor for OS, and copy number gain of “eraser” genes could magnify the effect in a synergistic way. Additionally, low expression of the writer gene METTL3 was related to activations of adipogenesis and mTOR pathways. Thus, we for the first time determined genetic alterations of m6A regulators in ccRCC and found a significant relationship between the alterations and worse clinical characteristics. The findings provide us clues to understand epigenetic modification of RNA in ccRCC.

This study examines key elements of glutamatergic transmission within sensory ganglia of the rat. We show that the soma of primary sensory neurons release glutamate when depolarized. Using acute dissociated mixed neuronal/glia cultures of dorsal root ganglia (DRG) or trigeminal ganglia and a colorimetric assay, we show that when glutamate uptake by satellite glial cells (SGCs) is inhibited, KCl stimulation leads to simultaneous increase of glutamate in the culture medium. With calcium imaging we see that the soma of primary sensory neurons and SGCs respond to AMPA, NMDA, kainate and mGluR agonists, and selective antagonists block this response. Using whole cell patch-clamp technique, inward currents were recorded from small diameter (<30 µm) DRG neurons from intact DRGs (ex-vivo whole ganglion preparation) in response to local application of the above glutamate receptor agonists. Following a chronic constriction injury (CCI) of either the inferior orbital nerve or the sciatic nerve, glutamate expression increases in the trigeminal ganglia and DRG respectively. This increase occurs in neurons of all diameters and is present in the somata of neurons with injured axons as well as in somata of neighboring uninjured neurons. These data provides additional evidence that glutamate can be released within the sensory ganglion, and that the somata of primary sensory neurons as well as SGCs express functional glutamate receptors at their surface. These findings, together with our previous gene knockdown data, suggest that glutamatergic transmission within the ganglion could impact nociceptive threshold.

CS055 (Chidamide/HBI-8000) is a novel benzamide-type HDACi (histone deacetylase inhibitor), which has entered Phase I clinical trials in the U.S. and Phase II/III in China. In the present study, we investigated the effects of CS055 on proliferation, differentiation and apoptosis in human leukaemia cell lines and primary myeloid leukaemia cells. The results showed that at low concentrations (<1 μM), CS055 induced G1 arrest. At moderate concentrations (0.5 μM-2 μM), CS055 induced differentiation, as determined by the increased expression of the myeloid differentiation marker CD11b. At relatively high concentrations (2 μM-4 μM), CS055 potently induced caspase-dependent apoptosis. Co-treatment with the ROS (reactive oxygen species) scavengers N-acetyl-L-cysteine or Tiron blocked CS055-induced cell differentiation and apoptosis, suggesting an essential role for ROS in these effects. Cytochrome c release and ROS-mediated mitochondrial dysfunction are involved in CS055-induced apoptosis of leukaemia. In addition to cell lines, CS055 also exhibits therapeutic effects in human primary leukaemia cells. Moreover, daily oral CS055 treatment of nude mice bearing HL60 cell xenografts suppressed tumour growth, induced tumour cell apoptosis and prolonged the survival of tumour-bearing mice. In conclusion, our findings demonstrate that CS055 is a novel HDACi with potential chemotherapeutic value in several haematological malignancies, especially leukaemia.

The findings show that open tension-free mesh-plug hernia repair, TAPP, and TEP are safe and effective for patients with primary unilateral inguinal hernia. Both TAPP and TEP are superior to open repair in terms of less postoperative pain and faster recovery time. The authors therefore recommend laparoscopic repair techniques as the preferable choice of surgical procedure. However, they think open repair will remain a practical solution in China because of its lower cost, short learning period, and need for no special equipment.

Tetrandrine, a bisbenzylisoquinoline alkaloid component of broadly used traditional Chinese medicine, has antitumor effects against some cancers. In our study, we investigated the effects of tetrandrine on the human hepatocellular carcinoma (HCC) in vitro and in vivo. The results showed that tetrandrine effectively induced apoptosis of liver cancer cell in a dose-and time-dependent manner accompanied by alteration of cell morphology, chromatin fragmentation and caspase activation. Tetrandrine treatment also induced intracellular accumulation of reactive oxygen species (ROS), and ROS scavengers (LNAC and GSH) completely blocked the effects of tetrandrine-induced apoptosis, suggesting that the generation of ROS plays an important role in tetrandrine-induced apoptosis. Although the activities of JNK and ERK were inhibited significantly by tetrandrine treatment, JNK and ERK are not involved in the tetrandrine-induced apoptosis. In contrast, Akt activity was found to be closely related to tetrandrine-induced apoptosis. The data demonstrated that Akt activity inhibitor LY294002 synergistically promoted tetrandrine-induced apoptosis of HCC, whereas ectopic expression of Akt contrastly abrogated partial of the tetrandrine-induced apoptosis. These data suggest that Akt signal is the downstream event of ROS generation in the tetrandrine-induced HCC cell apoptosis. Moreover, the results of xenograft in nude mice were consistent with that of the in vitro studies. Therefore, our data suggest that tetrandrine may be a promising agent for the treatment of HCC as a regulator of ROS/Akt pathway.

No abstract

Background: Tetrandrine exhibits antitumor effects and causes liver cancer apoptosis. Results: Tetrandrine induced hepatocellular carcinoma autophagy via ATG7 and ROS/ERK in vitro, in vivo, and in Caenorhabditis elegans muscle cells. Conclusion: Tetrandrine is a potent autophagy agonist. Significance: Tetrandrine may be a promising clinical chemotherapeutic agent for human hepatocellular carcinoma.

No abstract