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Background: Hepatocellular carcinoma (HCC) is an aggressive malignant disease with poor prognosis. Recent advances suggest the existence of cancer stem cells (CSCs) within liver cancer, which are considered to be responsible for tumor relapse, metastasis, and chemoresistance. However, novel therapeutic approaches for eradicating CSCs are yet to be established. Here, we aimed to identify the role of glutaminase 1 (GLS1) in stemness, and the feasibility that GLS1 serves as a therapeutic target for elimination CSCs as well as the possible mechanism. Methods: Publicly-available data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) was mined to unearth the association between GLS1 and stemness phenotype. Using big data, human tissues and multiple cell lines, we gained a general picture of GLS1 expression in HCC progression. We generated stable cell lines by lentiviral-mediated overexpression or CRISPR/Cas9-based knockout. Sphere formation assays and colony formation assays were employed to analyze the relationship between GLS1 and stemness. A series of bioinformatics analyses and molecular experiments including qRT-PCR, immunoblotting, flow cytometry, and immunofluorescence were employed to investigate the role of GLS1 in regulating stemness in vitro and in vivo. Findings: We observed GLS1 (both KGA and GAC isoform) is highly expressed in HCC, and that high expression of GAC predicts a poor prognosis. GLS1 is exclusively expressed in the mitochondrial matrix. Upregulation of GLS1 is positively associated with advanced clinicopathological features and stemness phenotype. Targeting GLS1 reduced the expression of stemness-related genes and suppressed CSC properties in vitro. We further found GLS1 regulates stemness properties via ROS/Wnt/β-catenin signaling and that GLS1 knockout inhibits tumorigenicity in vivo. Interpretation: Targeting GLS1 attenuates stemness properties in HCC by increasing ROS accumulation and suppressing Wnt/β-catenin pathway, which implied that GLS1 could serve as a therapeutic target for elimination of CSCs. Keywords: Glutaminase 1, Glutamine metabolism, Cancer stem cell, Stemness, Wnt/β-catenin signaling pathway, Hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death worldwide, because recurrence often occurs in most HCC patients undergoing hepatectomy. It is necessary to identify patients with high risk for recurrence and adopt effective therapies. An obstacle to monitor patients at high risk for poor prognosis has been the lack of useful predictive biomarkers. Fortunately, recent progress in system biology allows to screen the biomarkers for HCC prognosis in a high-throughput manner. In this study, we performed systematic Kaplan-Meier survival analysis of the whole mRNA transcriptomics based on the Cancer Genome Atlas project (TCGA) and developed a three-gene prognostic signature composing of three genes UPB1, SOCS2 and RTN3. The model was validated in two independent microarray data sets retrieved from Gene Expression Omnibus (GEO) and the expression pattern of these three predictive genes in HCC was confirmed by western blot and immunohistochemistry with our HCC samples. In conclusion, our results showed that this three-gene signature has prognostic value for HCC patients.

With the aim of maximally reducing imaging dose while meeting requirements for adaptive radiation therapy (ART), we propose in this paper a new cone beam CT (CBCT) acquisition and reconstruction method that delivers images with a low noise level inside a region of interest (ROI) and a relatively high noise level outside the ROI. The acquired projection images include two groups: densely sampled projections at a low exposure with a large field of view (FOV) and sparsely sampled projections at a high exposure with a small FOV corresponding to the ROI. A new algorithm combining the conventional filtered back-projection algorithm and the tight-frame iterative reconstruction algorithm is also designed to reconstruct the CBCT based on these projection data. We have validated our method on a simulated head-and-neck (HN) patient case, a semi-real experiment conducted on a HN cancer patient under a full-fan scan mode, as well as a Catphan phantom under a half-fan scan mode. Relative root-mean-square errors (RRMSEs) of less than 3% for the entire image and ~1% within the ROI compared to the ground truth have been observed. These numbers demonstrate the ability of our proposed method to reconstruct high-quality images inside the ROI. As for the part outside ROI, although the images are relatively noisy, it can still provide sufficient information for radiation dose calculations in ART. Dose distributions calculated on our CBCT image and on a standard CBCT image are in agreement, with a mean relative difference of 0.082% inside the ROI and 0.038% outside the ROI. Compared with the standard clinical CBCT scheme, an imaging dose reduction of approximately 3–6 times inside the ROI was achieved, as well as an 8 times outside the ROI. Regarding computational efficiency, it takes 1–3 min to reconstruct a CBCT image depending on the number of projections used. These results indicate that the proposed method has the potential for application in ART. [ABSTRACT FROM AUTHOR]

This study explored the relationship between the appearance traits and internal components of Cinnamomi Ramulus pieces, so as to provide a reference for the quality evaluation and the formulation of grade standards. This study determined the appearance traits and index component contents of 41 batches of Cinnamomi Ramulus pieces in the core producing areas of Guangxi and Guangdongand established the HPLC characteristic map method. The weight of the pieces, the narrowest diameter, and the widest diameter of the tr ansverse section were used as the indices of appearance traits. The content of index components(cinnamic acid and cinnamalde hyde)was determined by the established content determination method. The chromatographic characteristics were determinedon a Waters XBridge C_(18)(4. 6 mm×250 mm, 5 μm) column with a mobile phase consisting of 0. 1% phosphoric acidacetonitrile and gradient elution at the flow rate of 1 mL ·min~(-1). The column temperature was 30 ℃, and the detection wavelength was 254 nm. Cluster analysis, principal component analysis, and other stoichiometric methods were used to analyze the correlation between theap pearance traits and the index/characteristic components of Cinnamomi Ramulus pieces and compare the qu ality differences of the piecesfrom different batches and plac es. The results showed that the larger weight, the narrowest diameter, andthe widest diameter of the tra nsverse section indicated lowercontent of main indexes/characteristic components, and there was a synergistic decreasing trend amongd ifferent components. The overall quality of Cinnamomi Ramulus pieces in Guangdong Province and Guangxi Province was similar, but there were still differences between different origins and different batches of the same origin. It is scientific and feasible to evaluatethe quality of Cinnamomi Ramulus pieces and establish grading standards based on the appearance traits and index/character istic components. The research provides a more scientific and comprehensive basis for the quality control evaluation and standardformulation of Cinnamomi Ramulus.

The study aims to analyze the mechanisms of Hirudo in promoting blood circulation and removing blood stasis based on network pharmacology. A database of chemical components of Hirudo was established through literature retrieval. The targets were predicted by using the reverse pharmacophore matching method and screened according to the antithrombotic and anticoagulant drug targets approved by FDA in the DrugBank database. Then, the targets were analyzed by KEGG pathway analysis, the protein interactions were analyzed by using BioGrid database, and the active constituents-target-pathway network model of Hirudo was established to study the mechanisms of Hirudo in promoting blood circulation and removing blood stasis. This study collected 49 chemical components of Hirudo, including amino acid, polypeptide, fatty acid ester, alkaloid, glycosides, and steroid. Totally 376 targets were predicted, and 5 critical targets related to the effects of Hirudo in promoting blood circulation and removing blood stasis were screened, including fibrinogen gamma chain, plasminogen, prothrombin, Urokinase-type plasminogen activator and coagulation factor X. The potential regulatory pathways included complement and coagulation cascades, platelet activation, VEGF signaling pathway, focal adhesion. This study reflects the multi-component, multi-target and multi-pathway features of Hirudo, and provides a scientific basis for elucidating the mechanisms of action of Hirudo in promoting blood circulation and removing blood stasis, as well as a reference for the study of mechanisms of traditional Chinese medicine., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

Animal medicine is a unique part of traditional Chinese medicine. They have strong effects, but their effective compounds are not entirely known. The efficiency and safety of animal medicines can't be effectively controlled by current quality assurance system and evaluation method, which has deeply influenced the development of animal medicines. Biological assay does not focus on efficacy of single component, but directly reflects the pharmacodynamics and safety of animal medicines by biological effect. With the development of biotechnology, many new technologies have emerged, such as biochip and high content analysis. Based on the related targets, pathways and key biochemical factors, the field of biological assay has been expanded. With advantages of pharmacology andoverall controllability, as well as the characteristics of in line with the quality control of Chinese Medicine, biological assay will become one of the important development directionsfor quality standardization of animal medicines., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

Objective: To detect the level of fasting plasma homocysteine (Hcy) in patients with oligospermia and/or asthenospermia and to investigate its clinical significance., Methods: Semen quality analyses and fasting plasma Hcy determination were performed for 86 infertility patients (21 with oligospermia, 32 with asthenospermia and 33 with oligo-asthenospermia) and 19 normal fertile volunteers. The results were compared., Results: The level of plasma Hcy was significantly higher in the infertility patients than in the normal controls (P < 0.05) and negatively correlated with sperm concentration (r = -0.433, P < 0.01), the percentage of grade a sperm (r = -0.303, P < 0.05) and the percentage of grade a+b sperm (r = -0.339, P < 0.01)., Conclusion: The increased level of human plasma Hcy directly or indirectly affects spermatogenesis and correlates negatively with oligospermia and/or asthenospermia.

Objective: To identify the brain structural differences of schizophrenia patients and their parents between those with family history and those sporadic cases., Methods: High resolution T1 weighted images were obtained using 3T MR from 10 familial patients and 10 sporadic patients matched with age, sex, years of education and duration of disease. All patients were in their first episode of care. Twenty unaffected parents of the patients (8 for familial cases, 12 for sporadic cases) and 20 normal controls were also examined. The images were preprocessed according to the optimized VBM protocol. Student t test was performed to test the differences of the gray matter density (GMD) of the patients and their parents between the groups with and without family histories, and between the patient groups and the normal controls., Results: Compared with the sporadic group, significant reduce of GMD was observed in bilateral thalamus in both familial schizophrenia patients and their parents. Compared with normal controls, both familial and sporadic schizophrenia patients showed lower GMD in many areas including bilateral insula, right temporal lobe, right occipital lobe, left lenticula, right cerebellum and left rectal gyrus extending to anterior cingulated gyrus. Only familial patients showed lower GMD in the right thalamus. Familial parents also showed lower GMD in several areas including right insula extending to right temporal lobe and right parietal lobule., Conclusion: Familial schizophrenia is associated with genetically related structural abnormalities, especially in the bilateral thalamus. The brain structural differences can explain, at least in part, the symptom differences between familial and sporadic schizophrenia.