Mongolia has the highest incidence of hepatocellular carcinoma (HCC) in the world, but its causative factors and underlying tumor biology remain unknown. Here, we describe molecular characteristics of HCC from 76 Mongolian patients by whole-exome and transcriptome sequencing. We present a comprehensive analysis of mutational signatures, driver genes, and molecular subtypes of Mongolian HCC compared to 373 HCC patients of different races and ethnicities and diverse etiologies. Mongolian HCC consists of prognostic molecular subtypes similar to those found in patients from other areas of Asia, Europe, and North America, as well as other unique subtypes, suggesting the presence of distinct etiologies linked to Mongolian patients. In addition to common driver mutations (TP53, CTNNB1) frequently found in pan-cancer analysis, Mongolian HCC exhibits unique drivers (most notably GTF2IRD2B, PNRC2, and SPTA1), the latter of which is associated with hepatitis D viral infection. These results suggest the existence of new molecular mechanisms at play in Mongolian hepatocarcinogenesis.

Three-dimensional (3D) printing is an attractive technology in dentistry. Acrylic-based 3D printed resin parts have to undergo postcuring processes to enhance their mechanical and biological properties, such as UV-light and thermal polymerization. However, no previous studies have revealed how the postcuring temperature influences the biocompatibility of the produced parts. Therefore, we postprocessed 3D printed denture teeth resin under different postcuring temperatures (40, 60 and 80 °C) for different periods (15, 30, 60, 90 and 120 min), and evaluated their flexural properties, Vickers hardness, cell cytotoxicity, cell viability, and protein adsorption. In addition, confocal laser scanning was used to assess the condition of human gingival fibroblasts. It was found that increasing the postcuring temperature significantly improved the flexural strength and cell viability. The flexural strength and cell viability were 147.48 ± 5.82 MPa (mean ± standard deviation) and 89.51 ± 7.09%, respectively, in the group cured at 80 °C for 120 min, which were higher than the values in the 40 and 60 °C groups. The cell cytotoxicity increased in the 40 °C groups and for longer cultivation time. Confocal laser scanning revealed identifiable differences in the morphology of fibroblasts. This study has confirmed that the postcuring temperature influences the final mechanical and biological properties of 3D printed resin.

Several studies have sought systematically to identify protein subcellular locations, but an even larger task is to map which of these proteins conditionally relocates in disease (the mislocalizome). Here, we report an integrative computational framework for mapping conditional location and mislocation of proteins on a proteome-wide scale, called a conditional location predictor (CoLP). Using CoLP, we mapped the locations of over 10,000 proteins in normal human brain and in glioma. The prediction showed 0.9 accuracy using 100 location tests of 20 randomly selected proteins. Of the 10,000 proteins, over 150 have a strong likelihood of mislocation under glioma, which is striking considering that few mislocation events have been identified in this disease previously. Using immunofluorescence and Western blotting in both primary cells and tissues, we successfully experimentally confirmed 15 mislocations. The most common type of mislocation occurs between the endoplasmic reticulum and the nucleus; for example, for RNF138, TLX3, and NFRKB. In particular, we found that the gene for the mislocating protein GFRA4 had a nonsynonymous point mutation in exon 2. Moreover, redirection of GFRA4 to its normal location, the plasma membrane, led to marked reductions in phospho-STAT3 and proliferation of glioma cells. This framework has the potential to track changes in protein location in many human diseases.

Alcohol is a neurotoxic agent, since long-term heavy ingestion of alcohol can cause various neural diseases including fetal alcohol syndrome, cerebellar degeneracy and alcoholic dementia. However, the molecular mechanisms of alcohol-induced neurotoxicity are still poorly understood despite numerous studies. Thus, we hypothesized that activated microglial cells with elevated AGE-albumin levels play an important role in promoting alcohol-induced neurodegeneration. Our results revealed that microglial activation and neuronal damage were found in the hippocampus and entorhinal cortex following alcohol treatment in a rat model. Increased AGE-albumin synthesis and secretion were also observed in activated microglial cells after alcohol exposure. The expressed levels of receptor for AGE (RAGE)-positive neurons and RAGE-dependent neuronal death were markedly elevated by AGE-albumin through the mitogen activated protein kinase pathway. Treatment with soluble RAGE or AGE inhibitors significantly diminished neuronal damage in the animal model. Furthermore, the levels of activated microglial cells, AGE-albumin and neuronal loss were significantly elevated in human brains from alcoholic indivisuals compared to normal controls. Taken together, our data suggest that increased AGE-albumin from activated microglial cells induces neuronal death, and that efficient regulation of its synthesis and secretion is a therapeutic target for preventing alcohol-induced neurodegeneration.

Advanced glycation end products (AGEs) are known to play an important role in the pathogenesis of neurodegenerative diseases, including Parkinson’s disease (PD), by inducing protein aggregation and cross-link, formation of Lewy body, and neuronal death. In this study, we observed that AGE-albumin, the most abundant AGE product in the human PD brain, is synthesized in activated microglial cells and accumulates in the extracellular space. AGE-albumin synthesis in human-activated microglial cells is distinctly inhibited by ascorbic acid and cytochalasin treatment. Accumulated AGE-albumin upregulates the receptor to AGE, leading to apoptosis of human primary dopamine (DA) neurons. In animal experiments, we observed reduced DA neuronal cell death by treatment with soluble receptor to AGE. Our study provides evidence that activated microglial cells are one of the main contributors in AGE-albumin accumulation, deleterious to DA neurons in human and animal PD brains. Finally, activated microglial AGE-albumin could be used as a diagnostic and therapeutic biomarker with high sensitivity for neurodegenerative disorders, including PD.