PSMD10/gankyrin induces autophagy to promote tumor progression through cytoplasmic interaction with ATG7 and nuclear transactivation of ATG7 expression.

Although autophagy is most critical for survival of cancer cells, especially in fast-growing tumors, the mechanism remains to be fully characterized. Herein we report that PSMD10/gankyrin promotes autophagy in hepatocellular carcinoma (HCC) in response to starvation or stress through 2 complementary routes. PSMD10 was physically associated with ATG7 in the cytoplasm, and this association was enhanced by initial nutrient deprivation. Subsequently, PSMD10 translocated into the nucleus and bound cooperatively with nuclear HSF1 (heat shock transcription factor 1) onto the ATG7 promoter, upregulated ATG7 expression in the advanced stage of starvation. Intriguingly, the type of PSMD10-mediated autophagy was independent of the proteasome system, although PSMD10 has been believed to be an indispensable chaperone for assembly of the 26S proteasome. A significant correlation between PSMD10 expression and ATG7 levels was detected in human HCC biopsies, and the combination of these 2 parameters is a powerful predictor of poor prognosis. The median survival of sorafenib-treated HCC patients with high expression of PSMD10 was much shorter than those with low expression of PSMD10. Furthermore, PSMD10 augmented autophagic flux to resist sorafenib or conventional chemotherapy, and inhibition of autophagy suppressed PSMD10-mediated resistance. We conclude that these results present a novel mechanism involving modulation of ATG7 by PSMD10 in sustaining autophagy, promoting HCC cell survival against starvation or chemotherapy. Targeting of PSMD10 might therefore be an attractive strategy in HCC treatment by suppressing autophagy and inducing HCC cell sensitivity to drugs

GWAS Identifies Novel Susceptibility Loci on 6p21.32 and 21q21.3 for Hepatocellular Carcinoma in Chronic Hepatitis B Virus Carriers

Genome-wide association studies (GWAS) have recently identified KIF1B as susceptibility locus for hepatitis B virus (HBV)–related hepatocellular carcinoma (HCC). To further identify novel susceptibility loci associated with HBV–related HCC and replicate the previously reported association, we performed a large three-stage GWAS in the Han Chinese population. 523,663 autosomal SNPs in 1,538 HBV–positive HCC patients and 1,465 chronic HBV carriers were genotyped for the discovery stage. Top candidate SNPs were genotyped in the initial validation samples of 2,112 HBV–positive HCC cases and 2,208 HBV carriers and then in the second validation samples of 1,021 cases and 1,491 HBV carriers. We discovered two novel associations at rs9272105 (HLA-DQA1/DRB1) on 6p21.32 (OR = 1.30, P = 1.13×$10^{−19}$) and rs455804 (GRIK1) on 21q21.3 (OR = 0.84, P = 1.86×$10^{−8}$), which were further replicated in the fourth independent sample of 1,298 cases and 1,026 controls (rs9272105: OR = 1.25, P = 1.71×$10^{−4}$; rs455804: OR = 0.84, P = 6.92×$10^{−3}$). We also revealed the associations of HLA-DRB1*0405 and 0901*0602, which could partially account for the association at rs9272105. The association at rs455804 implicates GRIK1 as a novel susceptibility gene for HBV–related HCC, suggesting the involvement of glutamate signaling in the development of HBV–related HCC

Study on the Evolution of a Flooded Tailings Pond and Its Post-Failure Effects

In order to avoid the risk of tailing pond failures and to minimize the post-failure losses, it is necessary to analyze the current operation status of tailings ponds, to explore the evolution law of their failure process, to grasp their post-failure impact range, and to propose corresponding effective prevention and control measures. Based on a tailings pond in China, this paper establishes a 1:200 scale indoor model to explore the evolution law of post-failure tailings discharge in a tailings pond under flooded roof conditions; secondly, the finite element difference method and smooth particle fluid dynamics are combined to compare and analyze the post-failure impact area and to delineate the risk prevention and control area. The results of the study show that, during the dam break, the lower tailing sand in the breach is the first to slip, and after forming a steep can, the upper tailing sand in the steep can is pulled to slip, so that the erosion trench mainly develops vertically first, and then laterally. The velocity of the discharged tailing sand will quickly reach its peak value in a short period of time and then decrease to the creeping stage; the front edge of the sand flow is the first to stop moving, and the trailing edge of the tailing sand accumulation depth continues to increase until the end of the dam failure, at which point the initial bottom dam area of the discharge tailing sand flow velocity is the largest. The further the tailings are released from the initial dam, the smaller the accumulation depth and the larger the particle size, and the larger the elevation of the foundation in the same section, the smaller the accumulation depth and the larger the particle size; further, the presence of blocking materials will increase the local tailings accumulation depth. Based on the maximum flow velocity of the discharged tailings and the accumulation depth, the risk area downstream of the tailings pond is divided, so that relocation measures can be formulated. The test results can provide an important reference for the operation and management of similar tailings ponds

Direct Access of the Chiral Quinolinyl Core of Cinchona Alkaloids via a Brønsted Acid and Chiral Amine Co-catalyzed Chemo- and Enantioselective α‑Alkylation of Quinolinylmethanols with Enals

A strategy for the facile construction of the chiral quinolinylmethanolic structure, a core featured in cinchona alkaloids, is reported. A new reactivity is harnessed by TfOH-promoted chemoselective activation of α-C–H over O–H bond in quinolinylmethanols. The new reactivity is successfully engineered with an iminium catalysis in a synergistic manner to create a powerful conjugate addition–cyclization cascade process for synthesis of chiral quinoline derived γ-butyrolactones in good yields and with good to excellent enantioselectivities. The method enables the first total synthesis of natural product broussonetine in three steps

High-resolution relaxometry-based calibrated fMRI in murine brain: Metabolic differences between awake and anesthetized states

International audienceFunctional magnetic resonance imaging (fMRI) techniques using the blood-oxygen level-dependent (BOLD) signal have shown great potential as clinical biomarkers of disease. Thus, using these techniques in preclinical rodent models is an urgent need. Calibrated fMRI is a promising technique that can provide high-resolution mapping of cerebral oxygen metabolism (CMR O2 ). However, calibrated fMRI is difficult to use in rodent models for several reasons: rodents are anesthetized, stimulation-induced changes are small, and gas challenges induce noisy CMR O2 predictions. We used, in mice, a relaxometry-based calibrated fMRI method which uses cerebral blood flow (CBF) and the BOLD-sensitive magnetic relaxation component, R 2 0 , the same parameter derived in the deoxyhemoglobin-dilution model of calibrated fMRI. This method does not use any gas challenges, which we tested on mice in both awake and anesthetized states. As anesthesia induces a whole-brain change, our protocol allowed us to overcome the former limitations of rodent studies using calibrated fMRI. We revealed 1.5-2 times higher CMR O2 , dependent upon brain region, in the awake state versus the anesthetized state. Our results agree with alternative measurements of whole-brain CMR O2 in the same mice and previous human anesthesia studies. The use of calibrated fMRI in rodents has much potential for preclinical fMRI