Hepatocellular Carcinoma (HCC) is a major form of liver cancer and a leading cause of cancer-related death worldwide. New insights into HCC pathobiology and mechanism of drug actions are urgently ...needed to improve patient outcomes. HCC undergoes metabolic reprogramming of glucose metabolism from respiration to aerobic glycolysis, a phenomenon known as the 'Warburg Effect' that supports rapid cancer cell growth, survival, and invasion. mTOR is known to promote Warburg Effect, but the underlying mechanism(s) remains poorly defined. The aim of this study is to understand the mechanism(s) and significance of mTOR regulation of aerobic glycolysis in HCC.
We profiled mTORC1-dependent long non-coding RNAs (lncRNAs) by RNA-seq of HCC cells treated with rapamycin. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were used to explore the transcriptional regulation of
by mTORC1. U-
C-glucose labeling and metabolomic analysis, extracellular acidification Rate (ECAR) by Seahorse XF Analyzer, and glucose uptake assay were used to investigate the role of mTOR-NEAT1-NONO signaling in the regulation of aerobic glycolysis. RNA immunoprecipitation (RIP) and NONO-binding motif scanning were performed to identify the regulatory mechanism of pre-mRNA splicing by mTOR-NEAT1. Myristoylated AKT1 (mAKT1)/NRAS
-driven HCC model developed by hydrodynamic transfection (HDT) was employed to explore the significance of mTOR-NEAT1 signaling in HCC tumorigenesis and mTOR-targeted therapy.
mTOR regulates lncRNA transcriptome in HCC and that NEAT1 is a major mTOR transcriptional target. Interestingly, although both NEAT1_1 and NEAT1_2 are down-regulated in HCC, only NEAT1_2 is significantly correlated with poor overall survival of HCC patients. NEAT1_2 is the organizer of nuclear paraspeckles that sequester the RNA-binding proteins NONO and SFPQ. We show that upon oncogenic activation, mTORC1 suppresses NEAT1_2 expression and paraspeckle biogenesis, liberating NONO/SFPQ, which in turn, binds to U5 within the spliceosome, stimulating mRNA splicing and expression of key glycolytic enzymes. This series of actions lead to enhanced glucose transport, aerobic glycolytic flux, lactate production, and HCC growth both
and
. Furthermore, the paraspeckle-mediated mechanism is important for the anticancer action of US FDA-approved drugs rapamycin/temsirolimus.
These findings reveal a molecular mechanism by which mTOR promotes the 'Warburg Effect', which is important for the metabolism and development of HCC, and anticancer response of mTOR-targeted therapy.
•AR is an oncogenic driver of hepatocellular carcinoma.•AR-targeted therapy is limited by feedback activation of AKT-mTOR pathway.•Co-targeting of mTORC1 and AR may be an effective approach to HCC ...treatment.
Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and a leading cause of cancer deaths worldwide. HCC is a male-dominant cancer with a male:female ratio of up to 7:1. The androgen receptor (AR) is the male hormone receptor known as a major oncogenic driver of prostate cancer. Although AR has been linked to the sexual dimorphism of HCC, clinical trials with AR-targeted agents failed to generate survival benefits. Recent studies provide new insights into the role of AR in liver tumorigenesis and therapeutic responses. Herein, we review current understanding of AR signaling in HCC and feedback mechanisms that limit response to AR blockade. New AR-targeting strategies that might improve outcomes in HCC therapies are also discussed.
Abstract Objectives Many studies have shown that insomnia is a common problem among university students, but there are wide variations in the prevalence of insomnia. In this systematic review, we ...aimed to explore the prevalence of insomnia among university students using scientific and conclusive methods. Study design A systematic review is designed to analyze the studies reporting on prevalence of insomnia among university students. Methods Systemic searches were conducted in PubMed, BioMed Central, EBSCO, ScienceDirect, Ovid LWW and Medline databases between January 2000 and July 2014, The Meta analyst software was used to calculate the prevalence rate of each study, the pooled means of prevalence rates and 95% CIs across studies were then calculated and presented. Results Seven articles that met the inclusion and exclusion criteria were selected. The overall sample size in the current review was 16,478, with a minimum of 219 and a maximum of 10,322. The prevalence rates of the seven studies ranged between 9.4% (95%CI 8.8–10.0%) and 38.2% (95% CI 35.4–41.1%). Overall, the total students studied with a weighted mean prevalence of 18.5% (95% CI 11.2–28.8%), considerably higher than rates of 7.4% (95% CI 5.8–9.0%) reported in general population. Conclusions This review emphasized that insomnia prevalence in university students is considerably higher than that in general population, suggested that more attention should be paid to insomnia in university students.
We present a StyleGAN2‐based deep learning approach for 3D shape generation, called SDF‐StyleGAN, with the aim of reducing visual and geometric dissimilarity between generated shapes and a shape ...collection. We extend StyleGAN2 to 3D generation and utilize the implicit signed distance function (SDF) as the 3D shape representation, and introduce two novel global and local shape discriminators that distinguish real and fake SDF values and gradients to significantly improve shape geometry and visual quality. We further complement the evaluation metrics of 3D generative models with the shading‐image‐based Fréchet inception distance (FID) scores to better assess visual quality and shape distribution of the generated shapes. Experiments on shape generation demonstrate the superior performance of SDF‐StyleGAN over the state‐of‐the‐art. We further demonstrate the efficacy of SDF‐StyleGAN in various tasks based on GAN inversion, including shape reconstruction, shape completion from partial point clouds, single‐view image‐based shape generation, and shape style editing. Extensive ablation studies justify the efficacy of our framework design. Our code and trained models are available at https://github.com/Zhengxinyang/SDF‐StyleGAN.
The midline pattern of sternal ossification characteristic of the Cretaceous enantiornithine birds is unique among the Ornithodira, the group containing birds, nonavian dinosaurs and pterosaurs. This ...has been suggested to indicate that Enantiornithes is not the sister group of Ornithuromorpha, the clade that includes living birds and their close relatives, which would imply rampant convergence in many nonsternal features between enantiornithines and ornithuromorphs. However, detailed comparisons reveal greater similarity between neornithine (i.e. crown group bird) and enantiornithine modes of sternal ossification than previously recognized. Furthermore, a new subadult enantiornithine specimen demonstrates that sternal ossification followed a more typically ornithodiran pattern in basal members of the clade. This new specimen, referable to the Pengornithidae, indicates that the unique ossification pattern observed in other juvenile enantiornithines is derived within Enantiornithes. A similar but clearly distinct pattern appears to have evolved in parallel in the ornithuromorph lineage. The atypical mode of sternal ossification in some derived enantiornithines should be regarded as an autapomorphic condition rather than an indication that enantiornithines are not close relatives of ornithuromorphs. Based on what is known about molecular mechanisms for morphogenesis and the possible selective advantages, the parallel shifts to midline ossification that took place in derived enantiornithines and living neognathous birds appear to have been related to the development of a large ventral keel, which is only present in ornithuromorphs and enantiornithines. Midline ossification can serve to medially reinforce the sternum at a relatively early ontogenetic stage, which would have been especially beneficial during the protracted development of the superprecocial Cretaceous enantiornithines.
Postmenopausal osteoporosis (PMO) is a risk factor for periodontitis, and current therapeutics against PMO prevent the aggravated alveolar bone loss of periodontitis in estrogen-deficient women. Gut ...microbiota is recognized as a promising therapeutic target for PMO. Berberine extracted from Chinese medicinal plants has shown its effectiveness in the treatment of metabolic diseases such as obesity and diabetes via regulating gut microbiota. Here, we hypothesize that berberine ameliorates periodontal bone loss by improving the intestinal barriers by regulating gut microbiota under an estrogen-deficient condition. Experimental periodontitis was established in ovariectomized (OVX) rats, and the OVX-periodontitis rats were treated with berberine for 7 wk before sacrifice for analyses. Micro–computed tomography and histologic analyses showed that berberine treatment significantly reduced alveolar bone loss and improved bone metabolism of OVX-periodontitis rats as compared with the vehicle-treated OVX-periodontitis rats. In parallel, berberine-treated OVX-periodontitis rats harbored a higher abundance of butyrate-producing gut microbiota with elevated butyrate generation, as demonstrated by 16S rRNA sequencing and high-performance liquid chromatography analysis. Berberine-treated OVX-periodontitis rats consistently showed improved intestinal barrier integrity and decreased intestinal paracellular permeability with a lower level of serum endotoxin. In parallel, IL-17A-related immune responses were attenuated in berberine-treated OVX-periodontitis rats with a lower serum level of proinflammatory cytokines and reduced IL-17A+ cells in alveolar bone as compared with vehicle-treated OVX-periodontitis rats. Our data indicate that gut microbiota is a potential target for the treatment of estrogen deficiency–aggravated periodontal bone loss, and berberine represents a promising adjuvant therapeutic by modulating gut microbiota.
A facile method for solid-solution treatment of 6061 Al alloys by using electropulse, namely electropulsing solution treatment (EPST) is explored in this study. Compared with the conventional ...solution treatment (CST), the EPST tremendously improves the dissolution rate. The dissolution process completes in 15s. The EBSD analysis shows that the recrystallized grain sizes of EPST samples are finer and more uniform than the CST samples. The XRD analysis indicates higher supersaturation degree is achieved by EPST. Higher supersaturation degree leads to the formation of denser precipitation in the aging process. As a result, the EPST-aged samples get a 6.8% increase in tensile strength and a 7.2% increase in Vickers hardness compared with the CST-aged samples.
Rapamycin and its analogs (rapalogs) are the first generation of mTOR inhibitors, which have the same molecular scaffold, but different physiochemical properties. Rapalogs are being tested in a wide ...spectrum of human tumors as both monotherapy and a component of combination therapy. Among them, temsirolimus and everolimus have been approved for the treatment of breast and renal cancer. However, objective response rates with rapalogs in clinical trials are modest and variable. Identification of biomarkers predicting response to rapalogs, and discovery of drug combinations with improved efficacy and tolerated toxicity are critical to moving this class of targeted therapeutics forward. This review focuses on the aberrations in the PI3K/mTOR pathway in human tumor cells or tissues as predictive biomarkers for rapalog efficacy. Recent results of combinational therapy using rapalogs and other anticancer drugs are documented. With the rapid development of next-generation genomic sequencing and precision medicine, rapalogs will provide greater benefits to cancer patients.
Nutrients are not only organic compounds fueling bioenergetics and biosynthesis, but also key chemical signals controlling growth and metabolism. Nutrients enormously impact the production of ...reactive oxygen species (ROS), which play essential roles in normal physiology and diseases. How nutrient signaling is integrated with redox regulation is an interesting, but not fully understood, question. Herein, we report that superoxide dismutase 1 (SOD1) is a conserved component of the mechanistic target of rapamycin complex 1 (mTORC1) nutrient signaling. mTORC1 regulates SOD1 activity through reversible phosphorylation at S39 in yeast and T40 in humans in response to nutrients, which moderates ROS level and prevents oxidative DNA damage. We further show that SOD1 activation enhances cancer cell survival and tumor formation in the ischemic tumor microenvironment and protects against the chemotherapeutic agent cisplatin. Collectively, these findings identify a conserved mechanism by which eukaryotes dynamically regulate redox homeostasis in response to changing nutrient conditions.
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•SOD1 is a conserved effector of mTORC1 signaling in eukaryotic cells•Nutrients restrain SOD1 through mTORC1-dependent phosphorylation to promote growth•Starvation stimulates SOD1 activity to prevent oxidative damage and enhance survival•SOD1 enhances cancer cell survival and chemoresistance in ischemic microenvironment
Tsang et al. show that SOD1 phosphorylation by mTOR provides a dynamic mechanism for eukaryotic cells to respond to changing nutrient conditions. It permits rapid growth in rich nutrients, while it confers resistance to oxidative stress during starvation. This mechanism contributes to cancer cell survival and chemoresistance in the ischemic microenvironment.
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