bluuebunny/crossref_metadata_2025 huggingface dataset:
Walk the Line: The Role of Ubiquitin in Regulating Transcription in Myocytes
Authors: Suryadevara Vidyani , Willis Monte S.
Published: August 2019

The ubiquitin-proteasome offers novel targets for potential therapies with their specific activities and tissue localization. Recently, the expansion of our understanding of how ubiquitin ligases (E3s) specifically regulate transcription has demonstrated their roles in skeletal muscle, complementing their roles in protein quality control and protein degradation. This review focuses on skeletal muscle E3s that regulate transcription factors critical to myogenesis and the maintenance of skeletal muscle wasting diseases.
Apolipoprotein E2 Genotype Is Associated with a 2-Fold Increase in the Incidence of Type 2 Diabetes Mellitus: Results from a Long-Term Observational Study
Authors: Santos-Ferreira Cátia , Baptista Rui , Oliveira-Santos Manuel , Costa Regina , Pereira Moura José , Gonçalves Lino
Published: August 2019

Background. The apolipoprotein E (APOE) polymorphisms are associated with cardiovascular (CV) disease, but its interaction with type 2 diabetes mellitus (T2DM) long-term incidence is unknown. We investigated the association between APOE genotype and long-term (i) CV events and (ii) T2DM incidence in a Southern European primary prevention cohort. Methods. We assessed individual APOE genotypes in a total of 436 patients followed at a lipid clinic, with a 15-year median follow-up time. We collected data on major CV events (CV death, myocardial infarction, and stroke) and T2DM development. Results. No differences were found regarding major CV event incidence among the different APOE genotypes. However, after excluding 39 patients with a prior history of T2DM, APOE2 carriers displayed a higher incidence of T2DM during follow-up (42.2%) than APOE3 (27.1%) and APOE4 (28.7%) carriers. The age-, sex-, triglycerides-, and statin usage-adjusted OR for T2DM incidence in APOE2 carriers was 1.8 (95%CI 1.1-2.9, p=0.03), compared with wild-type APOE3. To address the role of statins as a confounder, we analyzed T2DM incidence in statin-treated patients. Statin-treated APOE2 carriers also had a higher T2DM incidence (57.9%), in comparison with APOE3 homozygotes (31.6%) and APOE4 carriers (32.5%). After adjustment for confounding, APOE2 carriers on statins displayed a similar twofold increase in T2DM risk compared to APOE3 homozygotes (OR 2.1, 95%CI 1.1-4.0, p=0.03). Conclusion. Our findings suggest a twofold increase in T2DM incidence in APOE2 carriers. This may prompt for a specific glucose dysmetabolism follow-up that might be tailored on the APOE genotype.
D2D Big Data Privacy‐Preserving Framework Based on (a, k)‐Anonymity Model
Authors: Wang Jie , Li Hongtao , Guo Feng , Zhang Wenyin , Cui Yifeng
Published: August 2019

As a novel and promising technology for 5G networks, device‐to‐device (D2D) communication has garnered a significant amount of research interest because of the advantages of rapid sharing and high accuracy on deliveries as well as its variety of applications and services. Big data technology offers unprecedented opportunities and poses a daunting challenge to D2D communication and sharing, where the data often contain private information concerning users or organizations and thus are at risk of being leaked. Privacy preservation is necessary for D2D services but has not been extensively studied. In this paper, we propose an (a, k)‐anonymity privacy‐preserving framework for D2D big data deployed on MapReduce. Firstly, we provide a framework for the D2D big data sharing and analyze the threat model. Then, we propose an (a, k)‐anonymity privacy‐preserving framework for D2D big data deployed on MapReduce. In our privacy‐preserving framework, we adopt (a, k)‐anonymity as privacy‐preserving model for D2D big data and use the distributed MapReduce to classify and group data for massive datasets. The results of experiments and theoretical analysis show that our privacy‐preserving algorithm deployed on MapReduce is effective for D2D big data privacy protection with less information loss and computing time.
Nonlinear/Linear Switched Control of Inverted Pendulum System: Stability Analysis and Real‐Time Implementation
Authors: Tiga Amira , Ghorbel Chekib , Benhadj Braiek Naceur
Published: August 2019

This paper treats the problems of stability analysis and control synthesis of the switched inverted pendulum system with nonlinear/linear controllers. The proposed control strategy consists of switching between backstepping and linear state feedback controllers on swing‐up and stabilization zones, respectively. First, the backstepping controller is implemented to guarantee the rapid convergence of the pendulum to the desired rod angle from the vertical position. Next, the state feedback is employed to stabilize and maintain the system on the upright position inherently unstable. Based on the quadratic Lyapunov approach, the switching between the two zones is analyzed in order to determine a sufficient domain in which the stability of the desired equilibrium point is justified. A real‐time experimentation shows a reduction of 84% of the samples below the classical scheme when using only the backstepping control in the entire operating region. Furthermore, the reduction percentage has become 92% in comparison with the composite linear/linear controller.
Multimodal Green Logistics Network Design of Urban Agglomeration with Stochastic Demand
Authors: Jiang Jiehui , Zhang Dezhi , Li Shuangyan , Liu Yajie
Published: August 2019

This study investigates a multimodal green logistics network design problem of urban agglomeration with stochastic demand, in which different logistics authorities among the different cities jointly optimize the logistics node configurations and uniform carbon taxes over logistics transport modes to maximize the total social welfare of urban agglomeration and consider logistics users’ choice behaviors. The users’ choice behaviors are captured by a logit-based stochastic equilibrium model. To describe the game behaviors of logistics authorities in urban agglomeration, the problem is formulated as two nonlinear bilevel programming models, namely, independent and centralized decision models. Next, a quantum-behaved particle swarm optimization (QPSO) embedded with a Method of Successive Averages (MSA) is presented to solve the proposed models. Simulation results show that to achieve the overall optimization layout of the green logistics network in urban agglomeration the logistics authorities should adopt centralized decisions, construct a multimode logistics network, and make a reasonable carbon tax.
Hydrochloric Acid Leaching Study of Rare Earth Elements from Moroccan Phosphate
Authors: Amine Marouane , Asafar Fatima , Bilali Latifa , Nadifiyine Mehdi
Published: August 2019

As part of the valorization of the Moroccan phosphate rock by extraction of rare earths, different experiments on natural Moroccan phosphate from the Gantour Basin (basin of phosphate in the Youssoufia area) were done in the REMATOP laboratory. The response surface methodology was used to study the effects of the influence of different parameters (acid concentration, solid/liquid ratio, duration of the reaction, stirring speed, and temperature) on the progress of the phosphate rock’s dissolution process to determine the optimal parameters for the extraction of rare earths. The analyses were made at the same time on the mineral matrix and the solutions resulting from the attack of this matrix by different concentrations of hydrochloric acid. The rare earth analyses done by the ICP-MS technique have shown an overall amount of rare earths (ΣREs) of 228.408 ppm with the existence of yttrium as the major element.
Effect of Early and Late Interventions with Dietary Oils on Vascular and Neural Complications in a Type 2 Diabetic Rat Model
Authors: Coppey Lawrence , Davidson Eric , Shevalye Hanna , Obrosov Alexander , Yorek Mark
Published: August 2019

Aims. Determine the effect of dietary oils enriched in different mono- or polyunsaturated fatty acids, i.e., olive oil (18 : 1, oleic acid), safflower oil (18 : 2 n-6, linoleic acid), flaxseed oil (18 : 3 n-3, alpha linolenic acid), evening primrose oil (18 : 3 n-6, gamma linolenic acid), or menhaden oil (20:5/22 : 6 n-3 eicosapentaenoic/docosahexaenoic acids), on vascular and neural complications in high-fat-fed low-dose streptozotocin-treated Sprague-Dawley rats, an animal model for late-stage type 2 diabetes. Materials and Methods. Rats were fed a high-fat diet (45% kcal as fat primarily derived from lard) for 8 weeks and then treated with a low dose of streptozotocin (30 mg/kg) in order to induce hyperglycemia. After an additional 8 (early intervention) or 20 (late intervention) weeks, the different groups of rats were fed diets with 1/2 of the kcal of fat derived from lard replaced by the different dietary oils. In addition, a control group fed a standard diet (4.25% kcal as fat) and a diabetic group maintained on the high-fat diet were maintained. The treatment period was approximately 16 weeks. The endpoints evaluated included vascular reactivity of epineurial arterioles, motor and sensory nerve conduction velocity, thermal and corneal sensitivity, and innervation of sensory nerves in the cornea and skin. Results. Our findings show that menhaden and flaxseed oil provided the greatest benefit for correcting peripheral nerve damage caused by diabetes, whereas enriching the high-fat diet with menhaden oil provided the most benefit to acetylcholine-mediated vascular relaxation of epineurial arterioles of the sciatic nerve. Enriching the diets with fatty acids derived from the other oils provided none to partial improvements. Conclusions. These studies imply that long-chain n-6 and n-3 polyunsaturated fatty acids could be an effective treatment for diabetic peripheral neuropathy with n-3 polyunsaturated fatty acids derived from fish oil being the most effective.
Different Mechanistic Association of Myopia with Rhegmatogenous Retinal Detachment between Young and Elderly Patients
Authors: Kim Min Seok , Park Sang Jun , Park Kyu Hyung , Woo Se Joon
Published: August 2019

Objectives. To investigate the mechanism of rhegmatogenous retinal detachment (RRD) in young and elderly Korean patients based on the results of axial length distribution. Subjects/Methods. We retrospectively reviewed the medical records of 1599 patients with RRD who had bilateral axial length data examined at one center between 2003 and 2018. Axial lengths were measured using ultrasound or IOLMaster500. The frequency of RRD and axial length distribution according to age groups were investigated. Results. Patients with RRD displayed a bimodal distribution across ages with two age groups showing the highest peak at 55–59 years and a second peak at 25–29 years of age. The mean axial length was significantly longer in patients younger than 50 years old than that in patients ≥ 50 years old (26.18 ± 1.86 mm vs. 24.55 ± 1.67 mm, respectively, p < 0.001). The percentage of patients with high myopia (axial length ≥ 26 mm) in patients < 50 years old was higher than that in those ≥ 50 years old (51.9% vs. 15.0%, respectively, p < 0.001; odds ratio, 6.11; 95% confidence interval, 4.83 to 7.74). Conclusions. We found a difference in the prevalence of myopia between young and elderly patients with RRD, which corresponds to a bimodal distribution of RRD incidence in East Asian countries. Our data indicate that myopia or high myopia-induced early vitreous detachment appears to be a major mechanism of occurrence of RRD in young East Asian patients, while senile vitreous liquefaction and detachment is the main mechanism of RRD in elderly patients.
Abnormal Detection of Wind Turbine Based on SCADA Data Mining
Authors: Tao Liang , Siqi Qian , Zhang Yingjuan , Shi Huan
Published: August 2019

In order to reduce the curse of dimensionality of massive data from SCADA (Supervisory Control and Data Acquisition) system and remove data redundancy, the grey correlation algorithm is used to extract the eigenvectors of monitoring data. The eigenvectors are used as input vectors and the monitoring variables related to the unit state as output vectors. The genetic algorithm and cross validation method are used to optimize the parameters of the support vector regression (SVR) model. A high precision prediction is carried out, and a reasonable threshold is set up to alarm the fault. The condition monitoring of the wind turbine is realized. The effectiveness of the method is verified by using the actual fault data of a wind farm.
Birth Outcomes among Diabetic Mothers Who Delivered in Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia
Authors: Eshetu Bajrond , Sintayehu Yitagesu , Mekonnen Bazie , Daba Woreknesh
Published: August 2019

Introduction. Diabetes develops in 4% of all the pregnancies worldwide, and its prevalence ranges from 1 to 14%, and 7% are complicated and results in prenatal morbidity and mortality. The disease affects women and their babies during pregnancy, labor, and delivery. However, little is known about its prevalence, birth outcomes, and associated factors in the study setting. Method. A facility-based retrospective cross-sectional study was done on all deliveries attended from January 1, 2015, to December 31, 2017, to determine the prevalence of diabetes and birth outcome. The mothers who had complete data record were identified and consecutively reviewed. The data were entered in EpiData Version 4.2 and exported to SPSS Version 23.0 for analysis. Results. Of the 14039 women who gave birth during the study period, 2.6% of them had diabetes mellitus, and from reviewed data, 54.6% had gestational diabetes and 45.4% had pregestational diabetes. Out of the diabetic mothers, 57.8% delivered by cesarean section, 39.9% by spontaneous vaginal delivery, and 26% of the pregnancies ended up with pregnancy-induced hypertension. Regarding the fetal outcome, 17.9% were preterm delivery, 17.6% macrocosmic, 9.2% respiratory distress, 10.1% low birth weight, and 65% admitted to neonatal intensive care unit. Class I obesity and history of PIH were associated with adverse maternal outcomes at aOR = 95%CI 3.8 (1.29, 8.319) and aOR = 95%CI 2.1 (1.03, 4.399), respectively. Being a house wife and preterm deliveries were associated with adverse fetal outcomes at aOR = 95%CI 2.117 (1.315, 3.405) and aOR = 95%CI 9.763 (4.560, 20.902), respectively. Conclusion. The prevalence of diabetes mellitus delivered in the hospital was 2.6%. Class I obesity and previous history of pregnancy-induced hypertension were significantly associated with adverse maternal outcomes, whereas preterm delivery and being housewife were associated with adverse fetal outcome.
Human Amnion Epithelial Cell Therapy for Chronic Liver Disease
Authors: Andrewartha Neil , Yeoh George
Published: August 2019

Liver fibrosis is a common consequence of chronic liver disease. Over time, liver fibrosis can develop into liver cirrhosis. Current therapies for liver fibrosis are limited, and liver transplant is the only curative therapy for patients who progress to end-stage disease. A potential approach to treat chronic liver disease with increasing interest is cell-based therapy. Among the multiple cell types which have been proposed for therapeutic uses, human amnion epithelial cells and amniotic fluid-derived mesenchymal cells are promising. These cells are highly abundant, and their use poses no ethical concern. Furthermore, they exert potent anti-inflammatory and antifibrotic effects in animal models of liver injury. This review highlights the therapeutic characteristics and discusses how human amnion epithelial cells can be utilised as a therapeutic tool for chronic liver disease.
Study on Fluid‐Structure Coupling Vibration of Compressor Pipeline
Authors: Wu Jia , Li Chunjie , Zheng Shuiying , Gao Jingheng
Published: August 2019

In practical engineering, pipeline vibration is often not caused by a single factor but by a combination of many factors. A fluid‐structure coupling method is proposed in this paper and used to study the vibration of the compressor pipeline under the interaction of pipeline structure and airflow in it. The method is based on structured grids, so that the displacements of grid nodes can be calculated accurately at each time step. The results of transient calculation show that when the given inlet mass flow rate is constant and there is no other disturbance, the pressure fluctuation and the vibration of pipeline structure will occur by using fluid‐structure coupling, and the vibration frequencies are consistent with the third‐ and fifth‐order structural natural frequencies. Moreover, the higher the pressure in the pipe, the greater the fluid‐structure coupling vibration. In addition, the fluid‐structure coupling vibration not only occurs in the studied pipeline but also propagates to distant downstream pipeline. Comparing the above results with experimental results, it is found that the results of fluid‐structure coupling calculation are in agreement with the actual situation, which shows that the method is reasonable and reliable and can be applied to engineering.
Long-Term Effects of Balance Training on Habitual Physical Activity in Older Adults with Parkinson’s Disease
Authors: Nero Håkan , Franzén Erika , Ståhle Agneta , Benka Wallén Martin , Hagströmer Maria
Published: August 2019

The HiBalance program is a progressive and highly challenging balance training intervention incorporating Parkinson’s disease (PD) specific balance components. The program improves balance and gait and increases the amount of ambulation in short-term, in older adults with PD. Yet, potential short- and long-term effects on habitual physical activity and sedentary behavior are currently unidentified. The aim of this study was to conduct preplanned secondary analyses of short- and long-term effects of the HiBalance program on objectively measured amount and bouts of brisk walking, sedentary behavior, and total physical activity in older adults with PD. Further, our aim was to investigate demographic, intervention-related, disease-related, and function-related factors potentially related to a difference in activity after intervention. A total of 100 older adults with mild-moderate PD were recruited. The intervention group participated in the HiBalance program, and the control received care as usual and was offered the HiBalance program after study termination. Physical activity data were collected using accelerometers at baseline, after intervention and after 6 and 12 months. A multilevel model was utilized to investigate the postintervention and long-term (6 and 12 months) effects on total physical activity, amount and bouts of brisk walking (i.e., moderate intensity physical activity), and sedentary behavior. Between-group difference for the main outcome brisk walking was at postintervention: Δ −10, CI −23.78 to 3.69 min/day (p<0.05); 6 months: Δ −10, CI −23.89 to 3.89 min/day (p<0.05); and 12 months: Δ −4, CI −16.81 to 8.81 min/day (p=0.43). Being part of the intervention group as well as finishing training during spring/summer showed an independent association to increased brisk walking after the intervention period. In conclusion, the HiBalance program increases the physical activity on moderate intensity after intervention and at 6 months but not at 12 months, independently of improved balance. Season seems to influence the effect on the physical activity.
L1 Input‐Output Finite‐Time Control of Positive Switched Nonlinear Systems
Authors: Liu Leipo , Cao Xiangyang , Fan Bo , Fu Zhumu
Published: August 2019

In this paper, the problem of L1 input‐output finite‐time control of positive switched nonlinear systems with time‐varying and distributed delays is investigated. Nonlinear functions considered in this paper are located in a sector field. Firstly, the proof of the positivity of switched positive nonlinear systems with time‐varying and distributed delays is given, and the concept of L1 input‐output finite‐time stability (L1 IO‐FTS) is firstly introduced. Then, by constructing multiple co‐positive‐type nonlinear Lyapunov functions and using the average dwell time (ADT) approach, a state feedback controller is designed and sufficient conditions are derived to guarantee the corresponding closed‐loop system is L1 IO‐FTS. Such conditions can be easily solved by linear programming. Finally, a numerical example is provided to demonstrate the effectiveness of the proposed method.
Transcriptome Analysis of Low-Temperature-Induced Breaking of Garlic Aerial Bulb Dormancy
Authors: Dong Yuhui , Guan Mengjiao , Wang Lixia , Yuan Lei , Sun Xiudong , Liu Shiqi
Published: August 2019

The long history of asexual reproduction of garlic using garlic cloves has resulted in virus accumulation and genetic depression. Propagation of garlic seedlings by tissue culture can both eliminate viruses and improve breeding efficiency. Aerial bulbs are the first-choice materials for breeding virus-free garlic seedlings under external conditions, but they show dormancy just like garlic bulbs. However, low temperatures can quickly break dormancy. In this research, we used a high-throughput sequencing method to sequence aerial bulbs during dormancy and after low-temperature-induced breaking of dormancy to screen out the key differentially expressed genes (DEGs) associated with low temperature and to provide a theoretical basis for exploring the molecular mechanism of low-temperature-induced breaking of aerial bulb dormancy. The high-throughput transcriptome sequencing results showed that 6,675 DEGs were upregulated and 36,596 DEGs were downregulated in the aerial bulbs given low-temperature treatment. Then, 19,507 DEGs were assigned KEGG annotations, among which most DEGs were annotated to the metabolism pathway (11,817 genes, accounting for 60.58%), followed by the genetic information processing pathway (4,521 genes, accounting for 23.18%). The DEGs were mostly concentrated in pathways such as protein processing in the endoplasmic reticulum, plant-pathogen interaction, plant hormone signal transduction, and ribosome biogenesis in eukaryotes, with significant enrichment. The key DEGs related to calcium signaling, hormonal signaling, and transcription factors were screened out, including CaM, CDPK, and CML in accessory pathways of calcium signaling; GA20ox, GAI1, and GA2ox in accessory pathways of hormonal signaling; and transcription factor genes such as MYB, AP2/ERF, bHLH, MADS, and bZIP. qRT-PCR verification results were consistent with the sequencing results, indicating that the transcriptome sequencing data were accurate and reliable. Our results provide a theoretical basis for breaking the dormancy of aerial bulbs with low-temperature treatment to produce virus-free seedlings and increase the output and quality of garlic.
Abstract 1007: Reactive oxygen species are essential for neurotensin receptors to regulate EGFR and HER2 transactivation
Authors: Moody Terry W. , Lee Lingaku , Jensen Robert T.
Published: August 2019

Neurotensin (NTS) is a 13 amino acid peptide which is present in many lung cancer cell lines (Moody et al., Life Sci 1985; 36: 1727). High expression of the NTS receptor 1 (R1) is associated with poor survival of non-small cell lung cancer (NSCLC) patients (Alfano et al., Clin Cancer Res 2010; 16: 4401). NTS stimulates but the NTSR1 antagonist SR48692 inhibits the proliferation of NSCLC cells (Moody et al., Life Sci 2014; 100: 25). NTSR1 regulates NSCLC proliferation by transactivation of the EGFR. The cellular signaling mechanisms of the NTSR1 were investigated using NSCLC cells. Using NCI-H838 or A549 cells, addition of NTS or NTS(8-13) but not NTS(1-8) increased tyrosine phosphorylation of P-EGFR, P-HER2 and P-ERK 4-, 3- and 2-fold, respectively. The increase in EGFR and HER2 transactivation caused by NTS addition to NSCLC cells was blocked by SR48692, gefitinib (EGFR tyrosine kinase inhibitor (TKI)), lapatinib (EGFR and HER2 TKI), N-acetyl cysteine ((NAC) is an antioxidant), tiron (reactive oxygen species (ROS) scavenger) or diphenyleneiodonium (DPI is an inhibitor of NOX and DUOX enzymes). NTS increased ROS in NSCLC cells which was inhibited by NAC, tiron or DPI. NTS or NTS(8-13) stimulate NSCLC colony growth but SR48692, gefitinib, lapatinib or DPI inhibit growth. The results indicate that the NTSR1 regulates in a ROS-dependent manner the formation of EGFR homodimers or EGFR-HER2 heterodimers in NSCLC cells.

Citation Format: Terry W. Moody, Lingaku Lee, Robert T. Jensen. Reactive oxygen species are essential for neurotensin receptors to regulate EGFR and HER2 transactivation [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 1007.
Abstract 1029: Metastatic cancer cells activate endothelial RhoA-ROCK pathway for trans-endothelial migration
Authors: Sajib Md Sanaullah , Zahra Fatema Tuz , Park Jee Hyun , Tullar Paul , Srivastava Sanjay K. , Bickel Ulrich , Mikelis Constantinos M
Published: August 2019

Metastasis is the process through which tumor cells disseminate from the primary tumor and colonize in distant parts of the body. Two of the steps in the metastatic process are the trans-migration of cancer cells through the endothelial lining of blood and lymphatic vessels, during entrance (intravasation) and exit (extravasation) from the vascular system. We and others have shown that the endothelial RhoA pathway plays important role in endothelial permeability. Translating these findings in the metastasis context we aim to explore the role of endothelial RhoA signaling pathway on cancer cell trans-endothelial migration and metastasis. In vitro, we have established a quantifiable, highly reproducible, transwell-based, two-cell co-culture model of trans-endothelial migration, where fluorescently-labeled cancer cells transmigrate through an endothelial monolayer. Pharmacological and molecular biology approaches were incorporated to dissect the role of endothelial RhoA signaling pathway. Primary and immortalized endothelial cells were used and cancer cells of both mouse and human origin were tested. In all cases, conditioned media from the cancer cells activated endothelial RhoA. Blockade of the RhoA pathway inhibited cancer cell trans-endothelial migration. In vivo, syngeneic and human cancer cell lines were tested in tail-vein and intra-cardiac models of experimental metastasis. We observed decreased lung metastatic nodules in endothelial-specific RhoA-deficient mice, compared to the littermate controls. Treatment with a clinically-relevant inhibitor of the RhoA pathway, Fasudil, also decreased the metastatic colonization of both human and cancer cells. The above findings demonstrate that the endothelial RhoA pathway has a pivotal role on cancer cell trans-endothelial migration.

Citation Format: Md Sanaullah Sajib, Fatema Tuz Zahra, Jee Hyun Park, Paul Tullar, Sanjay K. Srivastava, Ulrich Bickel, Constantinos M Mikelis. Metastatic cancer cells activate endothelial RhoA-ROCK pathway for trans-endothelial migration [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 1029.
Abstract 1033: Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer
Authors: Arner Emily N. , Cruz Victoria H. , Du Wenting , Brekken Rolf
Published: August 2019

Pancreatic ductal adenocarcinoma (PDA) is characterized by an activating mutation in KRAS. Direct inhibition of KRAS through pharmacological means remains a challenge; however, targeting key KRAS effectors has therapeutic potential. We investigated the contribution of TANK-binding kinase 1 (TBK1), a critical downstream effector of mutant active KRAS, to PDA progression. We report that higher levels of TBK1 mRNA are associated with poorer overall survival in human PDA patients and that TBK1 supports the growth and metastasis of KRAS-mutant PDA by driving an epithelial plasticity program in tumor cells that enhances invasive and metastatic capacity. Further, we identify that the receptor tyrosine kinase Axl induces TBK1 activity in a Ras-RalB-dependent manner. These findings demonstrate that TBK1 is central to an Axl-driven epithelial-mesenchymal transition in KRAS-mutant PDA and suggest that interruption of the Axl-TBK1 signaling cascade above or below KRAS has potential therapeutic efficacy in this recalcitrant disease.

Citation Format: Emily N. Arner, Victoria H. Cruz, Wenting Du, Rolf Brekken. Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic 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 1033.
Abstract 1037: Axl is critical for pancreatic cancer progression and metastasis
Authors: Du Wenting , Huang Huocong , Toombs Jason , Wang Zhaoning , Hosein Abdel , Burton Natalie , Brekken Rolf A.
Published: August 2019

Pancreatic ductal adenocarcinoma (PDAC), a leading cause of cancer-related death in the US, has a high metastatic rate that is associated with persistent immune suppression. Axl, a member of the TAM (Tyro3, Axl, MerTK) receptor tyrosine kinase family, has been identified as a critical factor that drives metastasis and immune suppression in many cancer types. We have shown that pharmacological inhibition of Axl significantly reduces tumor progression and metastasis and improves response to chemotherapy in multiple preclinical PDAC models. Here we demonstrate that Axl-deficient PDAC bearing mice have longer median survival, smaller tumors, fewer metastases and higher sensitivity to chemotherapy (gemcitabine) compared to Axl wild-type (WT) PDAC mice. Furthermore, Axl-deficient PDAC displays a more differentiated histology and has a more inflammatory and active immune microenvironment. Single cell RNA sequencing of PDAC genetically engineered mouse models reveals that Axl is expressed highly in tumor cells that have a mesenchymal-like phenotype and Axl expression correlates with classic markers of mesenchymal tumor cells at the RNA and protein level. To investigate the importance of Axl on tumor cells, CRISPR-Cas9 was used to knockout Axl in PDAC cells. Human and murine Axl-deficient PDAC cells displayed a more differentiated (epithelial) phenotype in vitro including reduced migratory capacity compared to Axl WT parental cells. Orthotopic injection of Axl-deficient murine PDAC cells into Axl WT mice resulted in longer median survival and fewer metastases compared to WT mice injected with WT PDAC cells. However, Axl-deficient mice injected with WT PDAC cell injection showed similar median survival and metastases as WT mice injected with WT PDAC cells. These in vivo results indicate that Axl expression on tumor cells is critical for PDAC progression and metastasis. In vitro experiments using WT and Axl-deficient human PDAC cells show that Axl is required for TGFβ-mediated epithelial to mesenchymal transition, probably through regulating the expression of Smad2 and Smad4. Interesting, Axl depletion has no effect on the mRNA level of Smad2 and Smad4, but does decrease the protein level, indicating that Axl might be involved in post-translational regulation (e.g., protein stability) of canonical TGFβ signaling intermediates. In summary, our study demonstrates that Axl expressed by pancreatic cancer cells is critical to tumor cell plasticity, tumor progression and metastasis.

Citation Format: Wenting Du, Huocong Huang, Jason Toombs, Zhaoning Wang, Abdel Hosein, Natalie Burton, Rolf A. Brekken. Axl is critical for pancreatic cancer progression and metastasis [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 1037.
Abstract 1041: Casein kinase 2 modulates epithelial mesenchymal transition through Helicobacter pylori CagA dependent pathway in gastric cancer cells
Authors: Lee SoDam , Hwang Bo Ram , Yun Jung Chang , Yu Byeong Min , Lee Yong Chan
Published: August 2019

Helicobacter pylori is the most important carcinogen in human gastric cancer. However, the pathogenic molecular mechanism which underlies the carcinogenesis in gastric cancer by H. pylori remains largely unknown. In this study, we understand that molecular biological mechanism related to gastric carcinogenesis by investigating the role of CK2 in EMT. Casein kinase 2 is a serine/threonine protein kinase and consists of two catalytic subunits (α or α’) and regulatory subunits (β). CK2 regulates many substrates and its involved in cell growth, proliferation, survival, angiogenesis, invasion. Epithelial-to-mesenchymal transition (EMT) is involved in many signaling pathways, but the key regulatory kinases in this process have not been clearly identified. In our previous study, we reported the cytotoxin-associated gene A (CagA) protein of H. pylori induces cell migration and invasion through increased CK2α activity in gastric epithelial cells. Although the role of CK2 catalytic subunits has remained largely uncharacterized, several studies have recently focused on regulator subunits in EMT.

Here, we analyzed the expression level of CK2α did not altered, whereas CK2β decreased in CagA-dependent pathway. Moreover, expression of ectopic CK2β was downregulated by CagA. This suggests that CagA negatively regulates the stability of CK2β protein. We examined the level of ubiquitinated CK2β were higher in HP60190 infected cells than in control cells. Thus, CK2β is degraded by the proteasomal machinery following CagA of H. pylori. In addition, CagA binds both CK2α and CK2β, which results in suppression of CK2β binding by infected HP60190, but does not suppress CK2α binding. Furthermore, downregulation of CK2β increased Snail such as CK2 target genes, EMT-related marker in H. pylori-infected gastric cancer cells. Therefore, the role of Snail regulated by CK2β should be considered when developing cancer therapeutic. Overall, CK2 tetramer subunits might control the function of CagA and EMT related genes, thereby regulating CagA-dependent pathology. Taken together, the results of the present study suggest that the CK2 regulatory subunit has diverse effect on CagA-dependent cellular processes. A pharmacological activator or activator of CK2β may have potential as a therapeutic agent for gastric cancer associated with CagA.

Citation Format: SoDam Lee, Bo Ram Hwang, Jung Chang Yun, Byeong Min Yu, Yong Chan Lee. Casein kinase 2 modulates epithelial mesenchymal transition through Helicobacter pylori CagA dependent pathway in gastric cancer cells [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 1041.
Abstract 1043: TIP60-dependent acetylation of the SPZ1-TWIST complex promotes epithelial-mesenchymal transition & metastasis in liver cancer
Authors: Wang Shen-Nien , Wang Li-Ting , Hsu Shih-Hsien
Published: August 2019

Metastasis is the main cause of cancer mortality. However, the triggering mechanisms and regulation of epithelial–mesenchymal transition (EMT) factors in the commitment of metastasis have not been well characterized. Spermatogenic Zip 1 (SPZ1) acts as a proto-oncogene and an upstream regulator of EMT during tumorigenesis. Here we report that the HIV-1 Tat-interacting protein 60 kDa (Tip60) acetyltransferase mediates acetylation at lysine residues of SPZ1 at positions 369 and 374, and of TWIST1 at positions 73 and 76, which are required for SPZ1–TWIST1 complex formation and cancer cell migration in vitro and in vivo. Ectopic SPZ1 and TWIST1 expression, but not that of TWIST1 alone, enhanced vascular endothelial growth factor (VEGF) expression via the recruitment of bromodomain-containing protein 4 (BRD4), thus enhancing RNA-Pol II-dependent transcription and inducing metastasis. Neutralization of VEGF using humanized monoclonal antibodies such as Avastin, effectively abrogated the EMT and oncogenesis induced by the acetylated SPZ1–TWIST1 complex. Our findings highlight the importance of acetylation signaling in the SPZ1–TWIST1–BRD4 axis in the mediation of EMT and its regulation during tumor initiation and metastasis.

Citation Format: Shen-Nien Wang, Li-Ting Wang, Shih-Hsien Hsu. TIP60-dependent acetylation of the SPZ1-TWIST complex promotes epithelial-mesenchymal transition & metastasis in liver 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 1043.
Abstract 105: MTH1 promotes mitotic progression to avoid oxidative DNA damage in cancer cells
Authors: Sanjiv Kumar , gad Helge , Rudd Sean G. , Mortusewicz Oliver , Stolz Ailine , Amaral Nuno , Brautigham Lars , Pudelko Linda , Kaldéren Christina , Jemth Ann-Sofie , Almlöf Ingrid , Visnes Torkild , Schultz Niklas , Boström Johan , Montano1 José Manuel Calderon , Hagenkort Anna , Groth Petra , Gokturk Camilla , Koolmeister Tobias , Wakchaure Prasad , Homan Evert , Altun Mikael , Ström Cecilia , Scobie Martin , Bastians Holger , Berglund Ulrika Warpman , Helleday Thomas
Published: August 2019

MTH1 prevents incorporation of oxidized deoxynucleoside triphosphates (e.g., 8-oxodGTP) into DNA. Earlier we demonstrated that MTH1 inhibitors TH588 and TH1579 possesses anti-cancer activity in various tumour types, while other structurally distinct MTH1 inhibitors failed to kill cancer cells or elevate the levels of oxidized nucleotides in DNA. In our current study, we found a novel function of MTH1 in mitosis, as it plays an important role in correct spindle assembly in cancer cells and progression through mitosis, and furthermore, we demonstrate MTH1 binds tubulin in vivo. We also observed that structurally distinct MTH1 inhibitors display differential abilities to break the MTH1 tubulin interaction, and also demonstrate that TH588 and TH1579 can directly inhibit tubulin polymerisation in vitro. Consistent with our results, we establish that TH588 and TH1579 kill cancer cells by a mitosis-dependent mechanism and implicate reactive oxygen species (ROS) accumulation and incorporation of oxidised nucleotides into DNA in this process. Furthermore, we found that non-cytotoxic MTH1 inhibitors can become cytotoxic and increase incorporation of oxidised nucleotides into DNA when they are combined with sub-therapeutic concentrations of mitotic inhibitors. In conclusion, MTH1 inhibitors killing cancer cells have a unique and complex mechanism of action: (1) causing a mitotic arrest, induced by targeting MTH1 which is required for mitotic progression, but also through direct inhibition of microtubule polymerisation, in-turn leading to an increase in ROS and likely 8-oxodGTP and (2) MTH1-dependent 8-oxodGTPase inhibitory activity causing incorporation of damaged nucleotides into DNA to kill cancer cells.

Citation Format: Kumar Sanjiv, Helge gad, Sean G. Rudd, Oliver Mortusewicz, Ailine Stolz, Nuno Amaral, Lars Brautigham, Linda Pudelko, Christina Kaldéren, Ann-Sofie Jemth, Ingrid Almlöf, Torkild Visnes, Niklas Schultz, Johan Boström, José Manuel Calderon Montano1, Anna Hagenkort, Petra Groth, Camilla Gokturk, Tobias Koolmeister, Prasad Wakchaure, Evert Homan, Mikael Altun, Cecilia Ström, Martin Scobie, Holger Bastians, Ulrika Warpman Berglund, Thomas Helleday. MTH1 promotes mitotic progression to avoid oxidative DNA damage in cancer cells [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 105.
Abstract 1063: In vivo humanized immuno-oncologymodels for drug discovery
Authors: Cheng Jijun , Zhang Feifei , Long Yuan , Xu Wenhua , Chen Hongkui , Wen Danyi
Published: August 2019

Reliable translational, especially humanized mouse models are critical to evaluate efficacy of immuno-therapeutics. While transgenic humanized mice and human CD34+ HSC-reconstituted mice are often used, their human cellular or molecular immune components are limited or defective. Human peripheral blood monocytic cell (PBMC)-reconstitution in immunocompromised mice, although, is transient and limited in infiltrating xenografts, one can manipulate to delicately reconstitute tumor microenvironment with one type, human T cells, or a few types of human immune cells, dendritic and macrophages, from human PBMC, through either systemic reconstitution or local reconstitution. We found that optimized stable PBMC models, both CDX and PDX, can often meet needs of targeting by many developing IO antibody therapeutics, including bi-specifics, in comparison to other humanized models. In particular, for efficacy study and for the convenience of mouse trials, we arrayed panels of PDX models expressing PD-L1 at different levels, in lung, liver, endometrial and gastric cancers, and panels of MSI-H and/or dMMR positive PDX models in these cancer types. In aiding studies of efficacy and resistance, we establish clinically drug-resistant PDX models, such as those resistant to checkpoint antibody drugs. These models are valuable to evaluate efficacy not only for antibody agents but also for combinational therapies involving biotherapeutics such as oncolytic virus.

Citation Format: Jijun Cheng, Feifei Zhang, Yuan Long, Wenhua Xu, Hongkui Chen, Danyi Wen. In vivo humanized immuno-oncologymodels for drug discovery [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 1063.
Abstract 1068: How humanized mouse models could be useful for immuno-oncology research
Authors: Mirjolet Jean-Francois , Caradec Josselin , Duchamp Oliver , Bichat Francis , France Damien , Mignard Caroline , Viviani Fabrice
Published: August 2019

Immunotherapy is one of the most exiting recent breakthroughs in the field of cancer treatment. Different approaches are developed such as cancer vaccines, adoptive cellular immunotherapy or immune checkpoint blockade, and a number have been regulatory approved or are currently investigated in clinic. Effective immunity against cancer involves complex interaction between the tumor, the host and the environment. The assessment of cancer immunotherapy approaches in preclinical settings requires the use of appropriate animal models that sufficiently reflect the physiological situation in humans and that must be chosen carefully to address specific mechanisms of action. In light of evaluating the therapeutic potential of different immunomodulatory agents in mice xenografted with cancer cell lines or patient-derived xenografts, we developed multiple humanization strategies on different immuno-deficient mouse strains. Either human PBMCs, Hematopoietic Stem Cells (HSCs), or specific human immune cells such as Dendritic Cells (DCs), T cells, subset of T cells (e.g. gamma9 delta2 T cells) and NK cells were used, but also the combinations of immune subpopulations such as the co-transfer of autologous T cells and DCs. We will highlight some results of our therapeutic efficacy investigation and evaluation of novel immuno-oncology therapies eg. adoptive cell therapy, bispecific T-cell engager antibody, and vaccine immunomodulatory agents in such humanized mouse models, assessing survival, tumor growth and effects on tumors and immune cells by flow cytometry and immunohistochemistry analyses. All these different humanized models can permit to evidence significant antitumor efficacy of immunomodulatory agents in vivo and might help improve the success rate in clinical trials.

Citation Format: Jean-Francois Mirjolet, Josselin Caradec, Oliver Duchamp, Francis Bichat, Damien France, Caroline Mignard, Fabrice Viviani. How humanized mouse models could be useful for immuno-oncology research [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 1068.
Abstract 1069: New panel of patient derived lymphoma xenografts (PDX) for preclinical research and immune oncology
Authors: Brzezicha Bernadette , Becker Michael , Stecklum Maria , Conrad Teresia , Janz Martin , Bittner Aitomi , Schmitt Clemens , Keilholz Ulrich , Hoffmann Jens
Published: August 2019

Lymphomas represent a very heterogeneous group of hematologic malignancies and pose an important challenge in the clinical routine. They frequently develop resistance to the treatment with standard-of-care (SoC) drugs and have a high incidence of disease recurrence.

Recent progress in molecular high throughput profiling has helped to identify genetic drivers and genetic subtypes of diffuse large B-cell lymphomas (DLBCL). Further target validation and drug development projects are highly dependent on corresponding preclinical models representing the different clinical subtypes. Therefore, we started to establish and characterize new patient derived xenografts (PDX) of non-Hodgkin (NHL) and Hodgkin lymphomas (HL) for drug development, translational and immune oncology research.

All lymphoma PDX were derived from peripheral blood, lymph node extirpations or core needle biopsies, and were usually transplanted subcutaneously into immunodeficient mice.

For further characterization, established lymphoma PDX models were treated with SoC and investigational drugs. In addition, the growth of lymphoma PDX on humanized mice was evaluated to establish new models for the evaluation of novel immune therapy approaches. To gain a deeper insight in the molecular biology of the lymphoma models, RNA sequencing of all was performed.

More than 20 new PDX models from NHL (including 8 DLBCL) and HL have been successfully established and characterized. Heterogeneous individual responses to the treatments were observed. Explorative analysis of RNA sequencing data confirmed the representation of the clinical lymphoma subgroups in our panel of models. Likewise, genetic subtypes of DLBCL COO classes could be confirmed by PCA and hierarchical clustering methods. Patterns of genetic driver mutations as revealed by recently published large genomic studies were identified.

Our newly and extensively characterized lymphoma PDX model panel allows the evaluation on novel targeted and immune therapies in preclinical phase II trial settings. They provide an exceptional platform for the identification and validation of new targets and allow the preclinical screening of new combinations in translational research projects.

Citation Format: Bernadette Brzezicha, Michael Becker, Maria Stecklum, Teresia Conrad, Martin Janz, Aitomi Bittner, Clemens Schmitt, Ulrich Keilholz, Jens Hoffmann. New panel of patient derived lymphoma xenografts (PDX) for preclinical research and immune oncology [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 1069.