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Organic phosphorus is an important source of eutrophication. In this study, to understand the mechanism of organophosphorus photodegradation, humic acid-Fe3+ (HA-Fe3+) complexes were prepared as a sensitizer, and glyphosate (GP) was used as a substrate for photodegradation. The effects of the initial GP concentration, HA concentration, Fe3+ concentration and microbial factors on photodegradation were investigated. The initial concentrations of GP, HA and Fe3+ could significantly affect the degradation rate of GP. Phosphate is the main product of GP photodegradation. Based on the identification of the active species in the reaction process, t-butanol was found to have the most significant inhibitory effect on the degradation. The reaction rate after t-butanol treatment was reduced from 0.017 to 0.003. This confirmed that OH was the main oxidant in the system, which was also demonstrated by EPR spectroscopy. A possible mechanism of GP photodegradation sensitized by HA-Fe3+ complexes was revealed for the first time. The HA-Fe3+ complexes in the reaction system were photodegraded and oxidized to finally produce OH, which promotes GP photodegradation. This study facilitates understanding the phosphorus cycle in a water environment and provides a scientific basis for the restoration of eutrophic lakes.

AIM To evaluate the safety and efficacy of sorafenib plus transarterial chemoembolization (TACE) treatment for intermediate hepatocellular carcinoma (HCC). METHODS Sixty-seven patients with intermediate-stage [Barcelona Clinic liver cancer stage B (BCLC-B)] HCC who were treated with sorafenib plus TACE or TACE alone between 2009 and 2011 were included in the study. Follow-up was until 2014 or patient death. Two groups were defined in the experiment: The experimental group, treated with sorafenib plus TACE, and the control group, treated with standard TACE alone. RESULTS The Kaplan-Meier survival analysis showed that the median overall survival (mOS) of the experimental group was 35.2 mo, while that of the control group was 22.0 mo (P < 0.05). Sorafenib plus TACE showed higher incidence rates of rash, hand-foot syndrome (HFS), and hypertension (P < 0.05) than TACE treatment alone. CONCLUSION Sorafenib plus TACE treatment for BCLC-B HCC significantly prolonged the mOS of patients compared to TACE treatment alone. The most common toxicities with sorafenib were rash (31.6%), HFS (39.5%) and hypertension (31.6%), but there were no intolerable adverse events. The Cox multivariate analysis showed that the survival of patients with BCLC-B HCC depended on the Child-Pugh classification, tumor diameter, and treatment with sorafenib plus TACE compared to TACE alone.

A new fast static security analysis algorithm, based on the interval analysis theory and probability theory, is proposed to improve the efficiency and accuracy of security analysis during power network interaction. In this paper, the characteristics of network interaction and uncertainty in the interaction process are illustrated firstly. After that the dimension reduction technique is employed in DC interval load flow calculation to determine the branch power flow efficiently. Then active power related contingency screening index is proposed, based on the DC interval analysis and the probability theory, which facilitates the screening of serious contingencies during the interactive process and improves the accuracy of contingency screening. Finally, cumulated and Gram-Charlier series expansion based AC probabilistic power flow is carried out for different operating scenarios during interactive time process. JS 1018-bus example system is introduced to validate the proposed method. Compared with traditional static security analysis, the proposed method can provide more efficient and accurate results for real time system operation.

WAMS(Wide-area Measurement System) is one of the most potentially effective techniques to damp inter-area low frequency oscillations in power systems. This paper studies the data corruption phenomenon which is ubiquitous in WAMS and establishes the unified model of time-delay and data-loss. Then DTA(Damping Torque Analysis) index considering time-delay and data-loss is deduced based on the previous model and applied to WADC(Wide-area Damping Controller) parameter tuning combining with the phase compensation method. Firstly simulations are carried out in 2A4M(2Area 4Machine) Kundur system and HDPG(Huadong Power Grid) with different timelays and data-loss ratios to show their impacts on small disturbance stability. Then DTA index is applied to PSS(Power System Stabilizer) parameter tuning and results show that it can effectively inhibit inter-area oscillations. With time-delay and data-loss ratio increasing, the superiority is getting more prominent.

Scutellarin is an active flavone from Erigeron breviscapine (vant) Hand Mass. This study aimed to investigate the potential role of scutellarin in migration and invasion of human hepatocellular carcinoma (HCC) cells and its possible mechanism. In comparison with the vehicle-treated controls, treatment with scutellarin (50 mg/kg/day) for 35 days significantly mitigated the lung and intrahepatic metastasis of HCC tumors in vivo. Scutellarin treatment significantly reduced HepG2 cell viability in a dose-dependent manner, and inhibited migration and invasion of HCC cells in vitro. Scutellarin treatment significantly reduced STAT3 and Girders of actin filaments (Girdin) expression, STAT3 and Akt phosphorylation in HCC cells. Introduction of STAT3 overexpression restored the scutellarin-downregulated Girdin expression, Akt activation, migration and invasion of HCC cells. Furthermore, induction of Girdin overexpression completely abrogated the inhibition of scutellarin on the Akt phosphorylation, migration and invasion of HCC cells. Scutellarin can inhibit HCC cell metastasis in vivo, and migration and invasion in vitro by down-regulating the STAT3/Girdin/Akt signaling.

Introduction: cfDNA (circulating cell-free DNA), short DNA fragments shredded from dying normal and tumor cells, has been proved capable of serving as molecular biomarkers for clinical decision making, including but not limit to tumor diagnosis, treatment and monitoring. Urine, by its non-invasive nature and unique biological characteristics, is far superior comparing to other liquid biopsy specimens, such as blood and cerebrospinal fluid, and has broad clinical implications for genitourinary cancers. The challenge for urine cfDNA test, is the instability of cfDNA, caused by nuclease, high content of urea, and contamination from genomic DNA released from nucleated cells and microbials in urine. Here, we have developed a robust and user friendly urine preservative collection Kit to maintain integrity of cfDNA in urine and to facilitate transportation of urinary samples to clinical laboratory. Methods: Urine samples from 5 donors collected using the developed urine collection kit were tested after incubation under 4°C and 37°C, mimicking extreme storage or transporting environments, and were compared to untreated urine and treated urine by another commercial preserve buffer. cfDNA was extracted after incubation of 0, 4, 7 days and then quantified by ddPCR with 3 markers: EGFR as an endogenous DNA marker, PSA (synthetic oligos containing intron-deleted sequence, pre-incubation spike-in) as an exogenous DNA marker, ARv7 (synthetic oligos containing intron-deleted sequence, post-incubation spike-in) as an inner control for the extraction and detection assays. Results While untreated urine showed significant decrease after incubation under 37°C, cfDNA derived from urine stored in developed urine collection tubes remained stable till day 7. There is no significant change on normalized copies of EGFR and PSA in the treated urine samples under 4°C for up to 7 days. Conclusion: the developed Urine Collection Kit demonstrated great urine cfDNA preserving capacity under different temperatures for at least 7 days, on par with commercially available preserve buffer and even outperforming it under certain circumstances. The developed kit provides an easy-to-use solution of obtaining stable urine cfDNA for clinical use. Citation Format: Zheng Li, Haoran Tang, Tiantian Zhang, Chunxiao Liu, Shengnan Zhu, Ying Zhang, Binggang Xiang, Zhixin Zhao. Development and validation of urine cfDNA preservative kit for detection of genomic alterations in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2236.

© 2016 IEEE. Electron and X-ray interactions with matter can be recorded as digital images, which are signal acquisition mechanisms often used to investigate materials microstructure. Recently, the ability to quickly acquire large datasets at high resolution has created new challenges in areas that rely upon image-based information. The proposed analysis schemes employ Convolutional Neural Networks as the core algorithm in the reconnaissance of expected events from data gathered in two regimes: experimentally and by simulation. At the interface of physical and digital datasets, we propose classification schemes that exploit complex geometrical structure from scientific images through different machine learning packages, such as MatConvNet and TensorFlow. Our results show correct classification rates over 90% considering thousands of samples from four image modalities: cryo-electron microscopy, X-ray diffraction, X-ray scattering and X-ray microtomography. Our main contributions are: (a) developing algorithms designed for data that stem from physical experiments; (b) building new software to constrain parameter space, particularly given new hardware; and (c) testing different CNN models for classification of scientific images.

Invadopodium formation is a crucial early event of invasion and metastasis of hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying regulation of invadopodia remain elusive. This study aimed to investigate the potential role of discs large homolog 5 (Dlg5) in invadopodium formation and function in HCC. We found that Dlg5 expression was significantly lower in human HCC tissues and cell lines than adjacent nontumor tissues and liver cells. Lower Dlg5 expression was associated with advanced stages of HCC, and poor overall and disease-free survival of HCC patients. Dlg5-silencing promoted epithelial-mesenchymal transition, invadopodium formation, gelatin degradation function, and invadopodium-associated invasion of HepG2 cells. In contrast, Dlg5 overexpression inhibited epithelial-mesenchymal transition, functional invadopodium formation, and invasion of SK-Hep1 cells. Both Girdin and Tks5, but not the Tks5 nonphosphorylatable mutant, were responsible for the enhanced invadopodium formation and invasion of Dlg5-silenced HepG2 cells. Furthermore, Dlg5 interacted with Girdin and interfered with the interaction of Girdin and Tks5. Dlg5 silencing promoted Girdin and Tks5 phosphorylation, which was abrogated by Girdin silencing and rescued by inducing shRNA-resistant Girdin expression. Moreover, Dlg5 overexpression significantly inhibited HCC intrahepatic and lung metastasis in vivo. Taken together, our data indicate that Dlg5 acts as a novel regulator of invadopodium-associated invasion via Girdin and by interfering with the interaction between Girdin and Tks5, which might be important for Tks5 phosphorylation in HCC cells. Conceivably, Dlg5 may act as a new biomarker for prognosis of HCC patients.

Lysyl oxidase (LOX) remodels the tumour microenvironment by cross-linking the extracellular matrix. LOX overexpression is associated with poor cancer outcomes. We find that LOX regulates the epidermal growth factor receptor (EGFR) to drive tumour progression. LOX regulates EGFR by suppressing TGFβ1 signalling through the secreted protease HTRA1. This increases the expression of Matrilin2 (MATN2), an EGF-like domain containing protein that traps EGFR at the cell surface to facilitate its activation by EGF. A novel pharmacological inhibitor of LOX, CCT365623, disrupts EGFR cell surface retention in vitro and delays the growth of primary tumour cells in vivo. In addition to its role in controlling primary tumour growth, LOX expression is also implicated in the processes of cancer cell invasion, and thereby the process of metastasis. Notably, we find that when LOX is depleted or inhibited, cancer cells are no longer able to sence a chemo-attractive gradient, and invade in a directional manner. Importantly, LOX produced by both cancer cells and fibroblasts can mediate this behaviour. Together, we show that LOX regulates EGFR cell surface retention to drive tumour progression. We also find that LOX does not regulate cancer cell invasion per se, but rather that it regulates the directionality of cancer cell migration, and both the cancer and stromal cells appear to contribute to this behaviour. Citation Format: Haoran Tang, Caroline Springer, Richard Marais. Lysyl oxidase regulates cell surface EGFR, and directionality of cancer cell invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5166.

Purpose: Lysyl oxidase (LOX) increases extracellular matrix stiffness by cross-linking collagen. A stiffer matrix drives integrin activation, and therefore LOX is believed to promote cancer cell invasion through enhanced integrin signaling. However increased matrix stiffness does not necessarily lead to a more permissive environment for invasion. Fibrillar collagen matrix orientation, density and porosity also determine how well cells can invade. Assays based on collagen gel-covered transwell systems have previously been used to show that LOX is required for invasion. These systems are driven by a chemoattractant gradient, and thus a role for LOX in chemotaxis could not be excluded. In this study we aimed to clarify whether LOX was required for matrix invasion or chemotaxis. Experimental procedures: To set up a 3D invasion assay that was not driven by a chemoattractant gradient, spheroids from multiple LOX expressing cancer cell lines were embedded into a thick 3D collagen gel. Cells were then allowed to randomly invade into the surrounding collagen. Alternatively, cancer cells were allowed to invade a fibroblast-modified 3D collagen gel in an organotypic assay. In this assay the invasion was driven by a strong chemoattractant gradient through a dense collagen gel, with cancer cells cultured atop the collagen gel at the air-medium interface. A Dunn chemotaxis chamber or a transwell tissue culture insert was used to investigate chemotaxis towards serum or EGF. Small interfering RNA (siRNA) or short hairpin RNA (shRNA) specific to human LOX was used to deplete LOX expression in the cancer cells, to test potential LOX functions in the above assays. Results: LOX depletion in parental MDA-MB-231 cells, MDA-MB-231 brain or bone metastatic sub-population cells, U87 and U118 cells did not impact 3D collagen gel invasion. LOX inhibition by BAPN also did not impact collagen gel invasion in MDA-MB-231, LN229, U87, U118 and U138 cells. The data indicated that LOX was not required for invasion through a thick 3D collagen gel in vitro. However, in the chemotactic-driven organotypic assay, loss of LOX in MDA-MB-231 cells completely abolished invasion. When the chemotactic potential towards serum and EGF of LOX depleted MDA-MB-231 and U87 cells was tested using Dunn chemotaxis chambers, we observed strong chemotactic defects in both cell lines. The chemotactic defects of these cells were also observed when a transwell based chemotaxis assay was used. Random cell migration of MDA-MB-231 and U87 cells were otherwise not affected by LOX depletion. Conclusions: LOX is not required for collagen matrix invasion per se. Instead LOX is important for cells to sense chemoattractants and to maintain directional cell migration. The molecular mechanisms underlying these observations are now the subject of further investigation. Citation Format: Haoran Tang, Nathalie Dhomen, Richard Marais. Lysyl oxidase is required for chemotaxis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 905. doi:10.1158/1538-7445.AM2017-905

Acral melanoma is a rare subtype of melanoma found on the non-hair bearing surfaces of the skin. It is associated with a worse prognosis than cutaneous melanoma, with higher proportions of patients developing metastatic disease. Combination treatments targeting the MAP kinase (MAPK) pathway and immune checkpoint inhibitors have improved overall survival in patients with stage IV disease. However, resistance to both modalities remains a challenge. This is exemplified by our comprehensive analysis of a patient presenting with acral melanoma that developed resistance to both immune and targeted therapy. The patient developed metastatic disease in multiple sites and we obtained fresh tumour tissue and generated cell lines from a skin metastasis at baseline prior to nivolumab. Following an initial complete response, the patient developed new mediastinal lymph node and brain metastases, which were also resected. On further relapse, the patient commenced dabrafenib with a partial response. Despite ongoing extra-cranial control, the brain lesion progressed and was therefore resected. To investigate resistance to immune therapy, we performed comprehensive genomic analysis and gene expression profiling on the lesions from the three sites, which identified common mutations in all three lesions and a low overall mutational burden consistent with acral melanoma. Heterogeneity of the MHC class I and II restricted antigen profile of the pre-treatment subcutaneous metastasis versus lymph node and brain progressions could not account for the development of resistance to immunotherapy. Gene expression profiling revealed up-regulation of known mechanisms of immune tolerance in both the lymph node and brain metastasis compared to the pre-treatment subcutaneous metastasis. To investigate resistance to targeted therapy, we compared patient-derived cell lines from brain lesions taken pre (DabS) and on progression on dabrafenib (DabR), and showed ongoing sensitivity to dabrafenib despite the patient having progressed in the brain. When cells from the DabR cell line were cultured in cerebrospinal fluid (CSF) in the presence of dabrafenib, we observed a reduction in cell death. Thus, extrinsic factors present in CSF may have resulted in the progression of the brain lesion in this patient. Using a combination of platforms to study patient derived tissues, we show that immune editing through selection of cells with an immune resistant phenotype may have resulted in the resistance of this patient's tumours to immune therapy whilst resistance to MAPK targeted therapy could have been mediated by extrinsic factors in the CSF. Citation Format: Rebecca J. Lee, Maria Romina Girotti, Amaya Viros, Franziska Baenke, Amit Mandal, Garima Khandelwal, John Bridgeman, Elena Galvani, Gabriela Gremel, Milena Kalaitsidou, Garry Ashton, Isabel Peset, Matthew Smith, Jacqueline Swan, Kang Zeng, Haoran Tang, Caron Abbey, Robert Hawkins, Alberto Fusi, Crispin Miller, David Gilham, Nathalie Dhomen, Paul Lorigan, Richard Marais. Mechanisms of resistance to immuno and targeted therapies in acral melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2400.