Search

Figure S6: IL-18 promotes proliferation and invasion of PC cells via the NF-κB pathway.

Purpose: We sought to find new immune-based treatments for pancreatic cancer.Experimental Design: We detected IL18 expression in plasma and specimens from patients with pancreatic cancer. We then investigated whether IL18 had a therapeutic effect for pancreatic cancer in vitro and in vivo and any underlying mechanisms.Results: Higher plasma IL18 was associated with longer overall survival (OS), but higher IL18 in pancreatic cancer tissues was associated with shorter OS and increased invasion and metastasis. Recombinant IL18 alone had no antitumor effect in the syngeneic mice with orthotopically transplanted tumors and promoted tumors in immunocompromised mice; it also facilitated immune responses in vitro and in vivo by augmenting the activity of cytotoxic T cells and NK cells in peripheral blood and lymph nodes. However, IL18 promoted the proliferation and invasion of pancreatic cancer cells, in vitro and in vivo, through the NF-κB pathway. Nevertheless, by coadministrating IL18 with BAY11-7082, an NF-κB inhibitor, we were able to prevent the procancerous effects of IL18 and prolong the survival time of the mice.Conclusions: IL18 has both cancer-promoting and cancer-suppressing functions. Although its single-agent treatment has no therapeutic effect on pancreatic cancer, when combined with the NF-κB pathway inhibitor, IL18 improved survival in a murine pancreatic cancer model. Our study implies the possibility of a combinational immunotherapy that uses IL18 and targets NF-κB pathway. Clin Cancer Res; 22(23); 5939–50. ©2016 AACR.

Supplemental Material and Methods

AJCC TNM stage and WHO grade (G) are two widely used staging systems to guide clinical management for pancreatic neuroendocrine neoplasms (panNENs), based on clinical staging and pathological grading information, respectively. We proposed to integrate TNM stage and G grade into one staging system (TNMG) and to evaluate its clinical application as a prognostic indicator for panNENs. Accordingly, 5254 patients diagnosed with panNENs were used to evaluate and to validate the applicability of TNMG to panNENs. The predictive accuracy of TNMG system was compared with that of each separate staging/grading system. We found that TNM stage and G grade were independent risk factors for survival in both the Surveillance, Epidemiology, and End Result (SEER) and multicenter series. The interaction effect between TNM stage and G grade was significant. Twelve subgroups combining the TNM stage and G grade were proposed in the TNMG stage, which were classified into five stages TNMG. According to the TNMG staging classification in the SEER series, the estimated median survival for stages I, II, III, IV, and V were 203, 174, 112, 61, and 8 months, respectively. The predictive accuracy of TNMG stage was higher than that of TNM stage and G grade used independently. The TNMG stage classification was more accurate in predicting panNEN patient's prognosis than either the TNM stage or G grade.

The nearest level modulation (NLM) based submodule capacitor voltage measuring technology for a modular multilevel converter (MMC) with reduced sensors can effectively reduce the costs of the data acquisition system of MMC and simplify the operation system. One of the technical challenges of this submodule capacitor voltage measuring technology is to reduce the measurement errors of submodule capacitor voltage. This paper proposes an improved submodule capacitor voltage measuring algorithm to overcome this challenge. In the proposed algorithm, by keeping the operation states of submodules unchanged during the continuous control period, the probability of obtaining the actual capacitor voltage is increased, and then the number of corrections of observed capacitor voltage is significantly increased. Thus, the proposed algorithm can effectively reduce the measuring errors. More significantly, the proposed algorithm can also improve the measurement accuracy even in the capacitance deviation situation. Finally, both simulation and experimental results are provided to verify the feasibility and effectiveness of the proposed voltage measuring algorithm.

Several natural products have been demonstrated to both enhance the anti-tumor efficacy and alleviate the side effects of conventional chemotherapy drugs. Rhein, a main constituent of the Chinese herb rhubarb, has been shown to induce apoptosis in various cancer types. However, the exact pharmacological mechanisms controlling the influence of Rhein on chemotherapy drug effects in pancreatic cancer (PC) remain largely undefined. In this study, we found that Rhein inhibited the growth and proliferation of PC cells through G1 phase cell cycle arrest. Moreover, Rhein induced caspase-dependent mitochondrial apoptosis of PC cells through inactivation of the PI3K/AKT pathway. Combination treatment of Rhein and oxaliplatin synergistically enhanced apoptosis of PC cells through increased generation of intracellular reactive oxygen species (ROS) and inactivation of the PI3K/AKT pathway. Pre-treatment with the ROS scavenger N-acetyl-L-cysteine attenuated the combined treatment-induced apoptosis and restored the level of phosphorylated AKT, indicating that ROS is an upstream regulator of the PI3K/AKT pathway. The combination therapy also exhibited stronger anti-tumor effects compared with single drug treatments in vivo. Taken together, these data demonstrate that Rhein can induce apoptosis and enhance the oxaliplatin sensitivity of PC cells, suggesting that Rhein may be an effective strategy to overcome drug resistance in the chemotherapeutic treatment of PC.

Laparoscopic duodenum-preserving total pancreatic head resection (LDPPHRt) is used for treating benign or low-grade malignant tumors of the pancreatic head. However, preservation of the duodenum and biliary tract integrity remains challenging. We present a new approach for LDPPHRt and evaluate its feasibility and safety.From April 2020 to December 2020, 30 patients successfully underwent LDPPHRt using the intracapsular approach in our center. Their medical records were reviewed for relevant clinical characteristics, pathologic findings, postoperative complications, and survival.The median diameter of the lesions was 3.6 cm (range, 2.0-5.5 cm). The median operative time was 234.7 min (range, 195-310 min). The median blood loss was 66.7 ml (range, 20-250 ml). The morbidity rate was 26.7%, including POPF, hemorrhage, lymphatic leakage, wound infection, pulmonary infection, and delayed gastric emptying. Five patients developed pancreatic fistula type A, and two patients had type B, classified according to the International Study Group on Pancreatic Fistula. No biliary tract injury or duodenal leakage was observed. The median postoperative hospital stay was 11.5 days (range, 6-25), and the operative mortality rate was 0%.The intracapsular approach is a feasible and safe surgical procedure in LDPPHRt for patients with benign or low-grade malignant tumors, especially those without severe pancreatic head fibrosis or peripancreatic adhesions.

Poetry composition is an ecologically valid approach for investigating creative processes. However, little is known about how the brain creates poetry and about the role of knowledge during poetry composition. Here, we identified patterns of task-based functional connectivity during poetry composition by experts and novices under two experimental conditions (familiar vs unfamiliar themes) and one control condition. Poetry composition was related to large-scale network connectivity between the language network (LN) and the right executive control network (RECN), precuneus, and higher visual network. Under familiar themes, poetry composition recruited more functional connections between the RECN and default mode network, whereas using unfamiliar themes elicited more functional connections between sensorimotor and visual networks. Moreover, the strength of LN-RECN is positively correlated with originality in the familiar condition, while negatively correlated with originality in the unfamiliar condition. These results reveal the brain connectivity patterns and highlight the importance of knowledge underlying poetry composition.

An autonomous optimal trajectory planning method based on the deep deterministic policy gradient (DDPG) algorithm of reinforcement learning (RL) for hypersonic vehicles (HV) is proposed in this paper. First, the trajectory planning problem is converted into a Markov Decision Process (MDP), and the amplitude of the bank angle is designated as the control input. The reward function of the MDP is set to minimize the trajectory terminal position errors with satisfying hard constraints. The deep neural network (DNN) is used to approximate the policy function and action-value function in the DDPG framework. The Actor network then computes the control input directly according to flight states. Using a limited exploration strategy, the optimal policy network would be considered fully trained when the reward value reached maximum convergence. Simulation results show that the policy network trained using a DDPG algorithm accomplishes 3-dimensional (3D) trajectory planning during the HV glide phase with high terminal precision and stable convergence. Additionally, the single step calculation time of the policy network occurs in near real time, which suggests great potential as an autonomous online trajectory planner. Monte Carlo experiments prove the strong robustness of the implementation of an autonomous trajectory planner under aerodynamic disturbances.

In the convex optimization problem for entry trajectory planning, the middle variables as new controls are defined to reduce the difficulty of convexification of original problem. Because of some reasons, the discontinuous or non-smooth of profiles of commands appear when solving commands using middle variables. For handling the phenomenon, a solution method of guidance commands via low-pass filter is proposed in this paper. Firstly, a discretized convex trajectory planning problem is formulated. Secondly, the solution errors of commands are defined. On the discretization points with high error, the proposed method is performed to smooth the abnormal commands by commands updating equations. On the other discretization points with low error, the method is not necessary. Finally, the method is inserted into a sequential iteration algorithm to solve the original non-convex entry trajectory planning problem. In numerical simulation, the effectiveness of the proposed method is verified, and the influence of filter coefficients on convergence and accuracy is discussed.

In light of the challenges associated with pancreaticoduodenectomy (PD) and recent key improvements, this bibliometric analysis aimed to analyze the 100 top-cited (T100) articles related to PD surgery to widen the awareness of relevant research on this procedure.The term "pancreaticoduodenectomy" was used to retrieve articles from the Web of Science Core Collection database. The 100 most cited manuscripts in the English language were identified and further analyzed by their countries of origin, publication journals, authors, and themes.A thorough literature search was performed on the Web of Science until April 2020. The total number of citations for the T100 articles ranged from 227 to 3029. The T100 articles came from 18 different countries, with the USA accounting for the plurality (n = 72). Professor J.L. Cameron from Johns Hopkins Medicine USA published the most articles (n = 22), including one as the first author and two as a co-author. Furthermore, Johns Hopkins Medicine, USA, published the most articles on PD surgery (n = 24), with a total citation count of 14,151. The journal Annals of Surgery published 40 of the T100 articles, with 15,847 citations and an average citation count of 396. Among the T100 articles, the citation frequency following the year of publication showed a parabolic trend, with citations peaking in the 9th year following publication.Our study identified and analyzed the T100 articles in PD surgery. The USA was the dominant country regarding articles, researchers, and institutions. The citations of the articles peaked in the 9th year after publication.

As common submodule (SM) capacitor voltage measuring method of modular multilevel converter(MMC) requiring large number of voltage sensors, submodule voltage measuring technique based on observation is then introduced to reduce voltage sensors. However, observed submodule capacitor voltage has a strong dependence on the parameters, which will reduce the robustness of MMC control system. In this paper, a deadbeat control method for MMC with reduced sensors is proposed to enhance the robustness, which is just uses the arm bridge current and the load current reference value as the control input to improve the robustness of the operation performance. Simulation and experimental results have proven the effectiveness of the proposed control method.

In contrast to the steady increase in survival observed for most cancer types, advances have been slow for pancreatic cancers. Current chemotherapy has limited benefits for patients with pancreatic cancer. Therefore, there is an urgent need for effective pancreatic cancer treatment strategies. At present, targeting the autophagic pathway is regarded as a promising new strategy for cancer treatment. Danthron (1,8-dihydroxyanthrquinone), a component from Rheum palmatum L. (polygonaceae), has several biological activities. However, the inhibition of autophagy by danthron has never been recognized, previously.Here we find that danthron may prevent autophagy, inhibit proliferation and induce apoptosis in pancreatic cancer cells in vitro. Autophagy induced by doxorubicin plays a protective role in pancreatic cancer cells and inhibition of autophagy by chloroquine or silencing autophagy protein 5 (Atg5) may chemosensitize pancreatic cancer cell lines to doxorubicin. Similarly, inhibition of autophagy by danthron also enhances toxicity of doxorubicin to pancreatic cancer cells. These results indicate that danthron has an anticancer effect and can sensitize the chemotherapeutic effect of doxorubicin on pancreatic cancer cells. These findings also suggest that inhibition of autophagy may be an effective way to promote the chemotherapy of pancreatic cancer.

Background:There is no widely-accepted staging system for pancreatic neuroendocrine tumors (pNETs). The aim of this study was to validate the American Joint Committee on Cancer (AJCC) 8th edition staging system for well-differentiated (G1/G2) pNETs.Methods:A multicenter dataset (n=1086) was used to evaluate the application of the AJCC 7th and 8th, the European Neuroendocrine Tumor Society (ENETS), and the modified ENETS (mENETS) staging systems for well-differentiated pNETs.Results:The proportion of patients with stage III tumors was extremely low (1.1%) according to the AJCC 7th staging system. For the ENETS staging system, patients with stage IIIA disease had worse estimated mean survival than patients with stage IIIB disease (78.9 vs. 107.3 months). When comparing with patients in stage I, the AJCC 7th, ENETS, and mENETS staging systems showed good performance in discriminating between stages; however, there was no significant difference in some stages when the reference was defined as the earlier stage. When the reference was defined as stage I or the earlier stage, there was a significant inter-stage difference in the AJCC 8th staging system.Conclusions:The AJCC 8th staging system is more suitable for pNETs than other TNM staging systems and may be adopted in clinical practice.

BackgroundPancreatic cancer is one of the most lethal human cancers.N6-methyladenosine (m6A), a common eukaryotic mRNA modification, plays critical roles in both physiological and pathological processes. However, its role in pancreatic cancer remains elusive.MethodsLC/MS was used to profile m6A levels in pancreatic cancer and normal tissues. Bioinformatics analysis, real-time PCR, immunohistochemistry, and western blotting were used to identify the role of m6A regulators in pancreatic cancer. The biological effects of methyltransferase-like 14 (METTL14), an mRNA methylase, were investigated using in vitro and in vivo models. MeRIP-Seq and RNA-Seq were used to assess the downstream targets of METTL14.ResultsWe found that the m6A levels were elevated in approximately 70% of the pancreatic cancer samples. Furthermore, we demonstrated that METTL14 is the major enzyme that modulates m6A methylation (frequency and site of methylation). METTL14 overexpression markedly promoted pancreatic cancer cell proliferation and migration both in vitro and in vivo,via direct targeting of the downstreamPERPmRNA (p53 effector related to PMP-22) in an m6A-dependent manner. Methylation of the target adenosine lead to increasedPERPmRNA turnover, thus decreasing PERP (mRNA and protein) levels in pancreatic cancer cells.ConclusionsOur data suggest that the upregulation of METTL14 leads to the decrease of PERP levels via m6A modification, promoting the growth and metastasis of pancreatic cancer; therefore METTL14 is a potential therapeutic target for its treatment.

Additional file 6: Table S1. Association between clinicopathological features and m6A mRNA levels.

The lysosome is emerging as a central regulator of the autophagic process, which plays a critical role in tumor growth and chemoresistance. Alantolactone, which is a natural compound produced by Inula helenium, has been shown to induce apoptosis in numerous cancer types. However, the mechanism by which alantolactone regulates apoptosis is still poorly understood. In this work, we observed that alantolactone caused the accumulation of autophagosomes due to impaired autophagic degradation and substantially inhibited the activity and expression of CTSB/CTSD proteins that when depleted caused lysosomal dysfunction. Furthermore, we found that alantolactone inhibited the proliferation of pancreatic cancer cells in vitro and in vivo and enhanced the chemosensitivity of pancreatic cancer cells to oxaliplatin. In addition, a reduction in TFEB levels was a critical event in the apoptosis and cell death caused by alantolactone. Our data demonstrated that alantolactone, which impaired autophagic degradation, was a pharmacological inhibitor of autophagy in pancreatic cancer cells and markedly enhanced the chemosensitivity of pancreatic cancer cells to oxaliplatin.

In order to improve the penetration performance of hypersonic glide vehicles, a lateral pendulum maneuvering strategy is proposed. A single radar trajectory tracking model is established and EKF is used to estimate the entire trajectory parameters. Based on the analysis of the composition of the defense system and the intercepting mechanism, the pendulum maneuvering trajectory is designed, and the influencing factors of the gliding penetration performance are analyzed. Then, an integrated index of penetration performance consists of the hit point prediction error, intercepting velocity, overload and the energy consumption caused by maneuver is constructed. Furthermore, a maneuvering strategy is proposed that the first maneuver is performed to enlarge prediction error of hitting point when the vehicle entrances the radar coverage, and the second one is carried out in the intercept zone to increase the maneuvering overload. The two maneuvers are the combat of the glider to the early warning system and the intercept system respectively, which can effectively enhance the penetration performance with less energy consumption.

Pancreatic cancer (PC) is highly resistant to current therapies; thus, there is an urgent need to develop new treatment strategies. The proteasome is crucially important for proteostasis, which is involved in cell proliferation and survival, making it an attractive therapeutic target in cancer. However, recent studies have indicated that bortezomib, a highly selective proteasome inhibitor, has limited effects in solid tumors including PC. Thus, more mechanistic insights into chemo-sensitization strategies for bortezomib are urgently needed. Herein, we demonstrate that bortezomib induced apoptosis and autophagy via a mechanism involving endoplasmic reticulum (ER) stress in PC cells. Additionally, bortezomib treatment led to increased levels of intracellular reactive oxygen species (ROS), which play critical roles in bortezomib-induced ER stress and apoptosis. Moreover, autophagy functions as a compensatory mechanism to eliminate bortezomib-induced ROS and resists ER stress-mediated apoptosis. Additionally, the Nrf2-mediated antioxidative response, which works against with bortezomib-induced autophagy, also protected cells against bortezomib-induced ROS production. Finally, the dual inhibition of autophagy and Nrf2 signaling cooperatively enhanced bortezomib-induced apoptosis by elevating ROS levels and ER stress. Together, these data demonstrate that activation of autophagy and the Nrf2 antioxidant system, which lowers intracellular ROS, are mechanistically how PC cells overcome bortezomib treatment. In summary, combining proteasome inhibitors with drugs targeting autophagy and Nrf2 signaling could be a promising therapeutic approach for PC treatment.

As modular multilevel converter(MMC) requires a large number of sensors to measure capacitor voltages, reducing the number of sensors for MMC has become an emerging topic. One of the technical challenges for reduced-voltage-sensor-based MMC operated with NLM is to eliminate the overvoltage that occurred on submodules. In order to solve this problem, a capacitor overvoltage elimination strategy for reduced-voltage-sensor-based MMC is proposed in this paper. The overvoltage elimination is consists of pre-measurement and in-process measurement of capacitor voltage, which is to obtain the actual value of submodule capacitor voltage so that to sort submodule capacitor voltages in the correct sequence. In this way, the submodules with excessively high voltage or with overvoltage trends can be selected for discharging until their voltages reach the normal level. Therefore, the overvoltage that occurred on submodules can be eliminated. A 31-level single-phase MMC simulation model is performed in MATLAB/SIMULINK, and a 9-level one is constructed in an experimental laboratory. Both the simulation and experimental results verify the effectiveness of the proposal even in the situation of capacitance parameter deviation.

A rapid entry trajectory planning algorithm for hypersonic glide vehicles is presented in this paper, and the avoidance of no-fly zones with large cross-range is achieved. The highly-constrained entry trajectory generation mission is accomplished using an adjustable angle of attack and bank, instead of a nominal angle of attack and reversal logic of bank angle. In this way, the maneuvering capability of the vehicle is greatly improved. Moreover, as no reversal of bank angle exists in the whole flight, the control command is easier to follow. Firstly, longitudinal entry corridor with an adjustable angle of attack is built up. The drag acceleration profile is represented as five piecewise affine functions of the energy, which are adjusted to meet the requirements of the trajectory length and lateral maneuvering capability. Secondly, based on the quasi-equilibrium glide condition (QEGC), the maximum and minimum boundary of the lateral lift-to-drag corridor corresponding to the current drag acceleration profile is approximated, and the lateral profile is represented as an interpolation result of the boundaries. Finally, the parameters of longitudinal and lateral profile are found by the Newton iteration scheme with the help of a reduced order system. A combined proportional integral derivative (PID) tracker is also designed to follow the drag and heading angle profile. The approach is tested using the Common Aero Vehicle model. Simulation results demonstrate that the generated entry trajectories can avoid no-fly zone with a large cross-range and achieve the terminal conditions while satisfying all the complex path constraints.

An entry trajectory planning algorithm that generates flyable trajectories satisfying multiple no-fly zones and other path and terminal constraints is presented. The algorithm divides the entry trajectory into initial and glide phases. In the initial phase, the maximum value of heating rate is controlled accurately as the altitude of the quasi-equilibrium glide condition (QEGC) transition point is adjusted with a nominal angle of attack and a parameterized bank angle. In the glide phase, a geometry based planning algorithm that relies on the center positions and radius of the multiple no-fly zones, is proposed to calculate the waypoints of the virtual flight path. The magnitude and reversal point of the bank angle in each sub-phase are searched based on a reduced-order lateral system with the predictor-corrector method. The altitude is designed as an analytical function of energy, and the QEGC is employed to analytically solve the remaining state variables. Finally, a linear quadratic regulator is used to test the realization of the 3D trajectory. The algorithm is tested using the common aero vehicle-H model. The results demonstrate that the algorithm can rapidly generate the entry trajectory with multiple no-fly zone constraints and achieve complex flight missions satisfying all flight constraints.

Landing footprint is critical in generating feasible entry trajectories for hypersonic glide vehicles. In this paper, a new landing footprint generation algorithm that considers multiple uncertainty effects is proposed, based on the improved 3D acceleration profile planning method. First, a new entry corridor with uncertainty effects is derived, in which the angle of attack profile is adjustable at any time during the entire flight. Second, the longitudinal drag profile is designed as the interpolation results of the upper and lower fitting safe boundaries. The corresponding lateral lift-to-drag corridor is obtained using the quasi-equilibrium glide condition. A combined Proportion Integration Differentiation (PID) tracker is used to follow the planned profiles in the longitudinal and lateral corridors, and the feasible entry trajectories are completed. Finally, feasible footprint is generated by repeatedly computing the reachable boundaries for all the profiles in the new safe corridor, as well as the analytical calculation of the maximum range point. The approach is tested using the Common Aero Vehicle-H model. Simulation results demonstrate that the proposed algorithm can rapidly generate a feasible footprint of entry for vehicles while satisfying all the path and terminal constraints.

// Xiuhui Shi 1, * , Hang Zhang 1, * , Min Wang 1, * , Xiaodong Xu 1 , Yan Zhao 1 , Ruizhi He 1 , Min Zhang 1 , Min Zhou 1 , Xu Li 1 , Feng Peng 1 , Chengjian Shi 1 , Ming Shen 1 , Xin Wang 1 , Xingjun Guo 1 and Renyi Qin 1 1 Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China * These authors have contributed equally to this study Correspondence to: Renyi Qin, email: ryqin@tjh.tjmu.edu.cn Xingjun Guo, email: xjguo@tjh.tjmu.edu.cn Keywords: long noncoding RNA, AFAP1-AS1, cholangiocarcinoma, proliferation, metastasis Received: February 07, 2017 Accepted: March 15, 2017 Published: April 06, 2017 ABSTRACT We investigated the role of actin filament associated protein 1 antisense RNA1 (AFAP1-AS1) lncRNA in promoting cholangiocarcinoma (CCA). qRT-PCR analysis of patient samples showed that AFAP1-AS1 expression was higher in CCA tumors than matched adjacent non-tumor tissue. AFAP1-AS1 levels were also higher in CCA cell lines (HuCCT1 and TFK-1) than a normal biliary epithelium cell line (HIBEpic). AFAP1-AS1 knockdown in CCA cell lines using shAFAP1-AS1 reduced cell proliferation and colony formation in CCK-8 and colony formation assays, respectively. Cell cycle analysis demonstrated that AFAP1-AS1 knockdown resulted in G0/G1 cell cycle arrest and inhibition of S-G2/M transition compared to the controls. CCA cells transfected with shAFAP1-AS1 also exhibited reduced metastasis and invasiveness in Transwell and wound healing assays. This was further confirmed in xenograft experiments with nude mice using CCA cells transfected with shAFAP1-AS1 or control shRNA. AFAP1-AS1 knockdown cells produced smaller tumors, demonstrating that AFAP1-AS1 promotes tumor growth in vivo . AFAP1-AS1 knockdown also increased expression of actin filament associated protein 1 (AFAP1) and reduced cell stress filament integrity, as determined from western blot and immunofluorescence assays, respectively. These findings indicate that AFAP1-AS1 exerts oncogenic effects in CCA. We postulate that AFAP1-AS1 is a potentially useful diagnostic and prognostic biomarker and therapeutic target for CCA.

Purpose: We sought to find new immune-based treatments for pancreatic cancer. Experimental Design: We detected IL18 expression in plasma and specimens from patients with pancreatic cancer. We then investigated whether IL18 had a therapeutic effect for pancreatic cancer in vitro and in vivo and any underlying mechanisms. Results: Higher plasma IL18 was associated with longer overall survival (OS), but higher IL18 in pancreatic cancer tissues was associated with shorter OS and increased invasion and metastasis. Recombinant IL18 alone had no antitumor effect in the syngeneic mice with orthotopically transplanted tumors and promoted tumors in immunocompromised mice; it also facilitated immune responses in vitro and in vivo by augmenting the activity of cytotoxic T cells and NK cells in peripheral blood and lymph nodes. However, IL18 promoted the proliferation and invasion of pancreatic cancer cells, in vitro and in vivo, through the NF-κB pathway. Nevertheless, by coadministrating IL18 with BAY11-7082, an NF-κB inhibitor, we were able to prevent the procancerous effects of IL18 and prolong the survival time of the mice. Conclusions: IL18 has both cancer-promoting and cancer-suppressing functions. Although its single-agent treatment has no therapeutic effect on pancreatic cancer, when combined with the NF-κB pathway inhibitor, IL18 improved survival in a murine pancreatic cancer model. Our study implies the possibility of a combinational immunotherapy that uses IL18 and targets NF-κB pathway. Clin Cancer Res; 22(23); 5939–50. ©2016 AACR.

Pancreatic cancer (PC) is one of the most lethal diseases, and effective treatment of PC patients remains an enormous challenge. Rocaglamide A (Roc-A), a bioactive molecule extracted from the plant Aglaia elliptifolia, has aroused considerable attention as a therapeutic choice for numerous cancer treatments. Nevertheless, the effects and underlying mechanism of Roc-A in PC are still poorly understood. Here, we found that Roc-A inhibited growth and stimulated apoptosis by induction of mitochondria dysfunction in PC. Moreover, Roc-A accelerated autophagosome synthesis and triggered mitophagy involving the PTEN-induced putative kinase 1 (PINK1)/Parkin signal pathway. We also demonstrated that inhibition of autophagy/mitophagy can sensitize PC cells to Roc-A. Finally, Roc-A treatment results in an obvious accumulation of reactive oxygen species (ROS), and pretreatment of cells with the reactive oxygen species scavenger N-acetylcysteine reversed the apoptosis and autophagy/mitophagy induced by Roc-A. Together, our results elucidate the potential mechanisms of action of Roc-A. Our findings indicate Roc-A as a potential therapeutic agent against PC and suggest that combination inhibition of autophagy/mitophagy may be a promising therapeutic strategy in PC.

Modular Multilevel Converter (MMC) has proven to be the most viable and promising candidates for high power applications. However, half bridge submodule, the most commonly used cells in MMC, possess limited two-level output voltage and inability to block dc fault current, consequently restricting the application of MMC in high power situations. A novel structure of submodule with threelevel output voltage and dc fault blocking capability relying on antiparallel insulated-gate bipolar transistors used in MMC is presented in this paper. Compared with other submodules with the same function, the new-model submodule has additional benefits of less diodes and semiconductor switching devices, lower conducting losses, and faster speed of dc fault current blocking. To stabilize the capacitors voltage, a control method based on neighboring number sorting is proposed according to the structure characteristics of this new-model three-level MMC (3LMMC). The feasibility and validity of the proposed converter under the fault condition is demonstrated by simulations in MATLAB/Simulink.

For a disk-type contra-rotating permanent magnet synchronous motor (CR-PMSM), when the dynamic master-slave control method with sliding mode speed control is employed, the robustness of the rotor in the case of large sudden load variation is poor, speed and torque pulsation of slave rotor under the conditions of heave unbalanced load torque are great. Aiming at these problems, an optimized vector control strategy adopting load torque compensation is proposed in the paper. The strategy realizes the torque current control of dual rotor. Meanwhile, two sliding mode observers are applied to observe load torque of dual rotor, and the observed values are made feedforward compensation to the system. The experimental results show that, by adopting the proposed strategy, the robustness of the rotor is improved when sudden load changes are large, and the dual rotor of CR- PMSM could synchronously track for a given speed with no pulsation in the situation of heavy unbalanced load torque.

Sequential convex programming method is one of the potential approaches to make trajectory generation onboard. However, the contradiction between the solution accuracy and the computational efficiency restricts its application. To overcome the difficulty, a novel sequential convex programming method based on customized adaptive mesh refinement is proposed in this paper. The main contribution includes two aspects. Firstly, a customized adaptive mesh refinement method is developed. The mesh points are adjusted adaptively based on the linearization error after each iteration, and thus the number of mesh points is changed. Secondly, an unconventional convergence condition is proposed, which can make the sequential convex programming method converges to a feasible solution of the original problem with fewer iterations. Taking the entry trajectory planning problem as an example, the simulation results show that the proposed method can decrease the number of mesh points while ensuring the feasibility of converged solution. Due to the fewer iterations, the computational time to solve the original problem is decreased. As a result, a good balance between solution accuracy and computational efficiency is achieved.

Background Pancreatic cancer is a highly malignant tumor with a poor prognosis. Chemotherapy such as gemcitabine is still an important treatment. Gemcitabine (Gem) may prolong survival time and delay the development of recurrent disease after complete resection of pancreatic cancer. Currently, some control studies have been performed between certain drugs and gemcitabine monotherapy after pancreatic cancer surgery, but the outcomes were uncertain. Here, we implemented meta-analysis to compare the efficacy between adjuvant treatments and gemcitabine monotherapy in patients with resected pancreatic cancer. Methods PubMed, Embase and the Central Registry of Controlled Trials of the Cochrane Library searches were undertaken to identify randomized controlled trials (RCTs). Date of search ranged from January 1997 to December 2017. The meta-analysis included six RCTs. The major endpoints involved overall survival (OS), disease-free survival/progress free survival/relapse-free survival (DFS/PFS/RFS) and grade 3–4 toxicity. Results Pooled meta-analytic estimates were derived using random-effects model. Subgroup analysis used fixed-effects model. The outcome showed that there was no difference in OS (hazard ratio (HR), 0.87; 95% CI, 0.70–1.07; P = 0.19) and DFS (HR, 0.85; 95% CI, 0.71–1.02; P = 0.08) between the adjuvant treatments group (fluorouracil+folinic acid, S-1, gemcitabine+capecitabine, gemcitabine+erlotinib and gemcitabine+uracil/tegafur) and Gem monotherapy group. However, the subgroup analysis showed that only S-1 chemotherapy, which is an oral fluoropyrimidine agent containing tegafur, gimeracil and oteracil, was significant in OS (HR, 0.59; 95% CI, 0.46–0.74; P

Cholangiocarcinoma (CCA) is a cancer type with high postoperative relapse rates and poor long-term survival largely due to tumor invasion, distant metastasis, and multidrug resistance. Deregulated microRNAs (miRNAs) are implicated in several cancer types including CCA. The specific roles of the miRNA let-7c in cholangiocarcinoma are not known and need to be further elucidated. In our translational study we show that microRNA let-7c expression was significantly downregulated in human cholangiocarcinoma tissues when compared to adjacent tissues of the same patient. Let-7c inhibited the tumorigenic properties of cholangiocarcinoma cells including their self-renewal capacity and sphere formation in vitro and subcutaneous cancer cell growth in vivo. Ectopic let-7c overexpression suppressed migration and invasion capacities of cholangiocarcinoma cell lines in vitro, however, promoted distant invasiveness in vivo. Furthermore, we found that let-7c regulated the aforementioned malignant biological properties, at least in part, through regulation of EZH2 protein expression and through the DVL3/β-catenin axis. The miRNA let-7c thus plays an important dual role in regulating tumorigenic and metastatic abilities of human cholangiocarcinoma through mechanisms involving EZH2 protein and the DVL3/β-catenin axis.

Novel biomarkers for pancreatic adenocarcinoma are urgently needed because of its poor prognosis. Here, by using The Cancer Genome Atlas (TCGA) RNA-seq data, we evaluated the prognostic values of the differentially expressed miRNAs and constructed a five-miRNA signature that could effectively predict patient overall survival (OS). The Kaplan-Meier overall survival curves of two groups based on the five miRNAs were notably different, showing overall survival in 10.2% and 47.8% at five years for patients in high-risk and low-risk groups, respectively. The ROC curve analysis achieved AUC of 0.775, showing good sensitivity and specificity of the five-miRNA signature model in predicting pancreatic adenocarcinoma patient survival risk. The functional enrichment analysis suggested that the target genes of the miRNA signature may be involved in various pathways related to cancer, including PI3K-Akt, TGF-β, and pluripotent stem cell signaling pathways. Finally, we analyzed expression of the five specific miRNAs in the miRNA signature, and validated the reliability of the results in 20 newly diagnosed pancreatic adenocarcinoma patients using qRT-PCR. The expression results of qRT-PCR were consistent with the TCGA results. Taken together, these findings suggested that the five-miRNA signature (hsa-miR-203, hsa-miR-424, hsa-miR-1266 hsa-miR-1293, and hsa-miR-4772) could be used as a prognostic marker for pancreatic adenocarcinoma.

// Xiuhui Shi 1 , Yan Zhao 1 , Ruizhi He 1 , Min Zhou 1 , Shutao Pan 1 , Shuo Yu 1 , Yu Xie 1 , Xu Li 1 , Min Wang 1 , Xingjun Guo 1 and Renyi Qin 1 1 Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Correspondence to: Renyi Qin, email: ryqin@tjh.tjmu.edu.cn Xingjun Guo, email: xjguo@tjh.tjmu.edu.cn Keywords: long noncoding RNA; pancreatic adenocarcinoma; TCGA; ceRNA; prognosis Received: August 23, 2017 Accepted: February 01, 2018 Epub: February 08, 2018 Published: May 11, 2018 ABSTRACT Pancreatic adenocarcinoma (PAAD) is a highly aggressive and metastatic cancer characterized by poor survival rates. Long non-coding RNAs (lncRNAs) play important roles in various biological processes, including cancer and PAAD. To identify the specific lncRNAs associated with PAAD and analyze their function, we constructed a global triple network based on the competitive endogenous RNA (ceRNA) theory and RNA-seq data from The Cancer Genome Atlas. Using 182 PAAD cases, we established a lncRNA–miRNA–mRNA co-expression network, which was composed of 43 lncRNA nodes, 253 mRNA nodes, 11 miRNA nodes, and 475 edges. Six lncRNAs in the ceRNA network were closely related to overall survival, and a three-lncRNA signature predicted survival of PAAD patients. Protein–protein interaction network data revealed that five genes were associated with overall survival. These results provide novel insight into the function of a lncRNA-associated ceRNA network in the pathogenesis of PAAD, and indicate that the identified three-lncRNA signature may serve as an independent prognostic marker in PAAD.

In this paper, a footprint determination algorithm for entry vehicles based on three-dimensional acceleration profile is proposed, which solves the problem of fast determination of the entry coverage with complex multi-constraints. The aerodynamic adjustment capability is greatly improved since both the angle of attack and bank are regarded as primary variables, and in this way larger entry footprint is achieved. Furthermore, due to the introduction of quasi-equilibrium glide condition (QEGC), the altitude of the entry trajectory changes smoothly without jumping. Firstly, based on the QEGC, a new type of longitudinal acceleration corridor and lateral lift to drag corridor are designed, and the profiles are chose as the interpolation results of the upper and lower boundaries. Secondly, based on PID theory, a three-dimensional profile tracker is designed to realize the corresponding entry trajectories. Finally, the traversal of the interpolation parameters in the corridors is carried out, and the entry footprint satisfying various complex constraints is obtained. The approach is tested using Common Aero Vehicle-H model, and the results demonstrate that the proposed algorithm can determinate the footprint of entry vehicles rapidly while satisfying all the path and terminal constraints.

A rapid boost trajectory generation algorithm is presented in this paper, considering the new requirements of hypersonic boost-glide missiles, such as the low terminal altitude, high velocity, and wide range coverage. The algorithm divides the boost trajectory into the longitudinal and lateral sub-planes. In the longitudinal sub-plane, the angle of pitch is designed as the time segment function. The maximum angle of attack and the pitch rate are selected as the key parameters to be determined. Newton iteration scheme is used to calculate the key parameters, according to the strict terminal altitude and velocity constraints. In the lateral sub-plane, an analytical calculation of the azimuth angle is proposed based on the theory of spherical triangle, which guarantees an initial aiming at the preselected target. Furthermore, new boost modes, such as intermittent boost mode and low altitude direct boost mode, are proposed. The trajectory characteristics and the application prospect are deeply analyzed. Finally, a three-stage solid rocket is used in the simulation. The results demonstrate that the algorithm can rapidly generate the boost trajectory for hypersonic boost-glide missile and achieve complex flight missions.

In this paper, a planning approach of maneuver trajectory based on dynamic inversion is proposed, which can greatly improve the penetrability of hypersonic glide vehicles in dive phase. Maeuvering and guiding overloads are combined using a weight coefficient, which is designed as the function of altitude. Enough adjust ability is guranteed at the end of dive phase, and more complex maneuver trajectories are achieved. Firstly, four different modes of maneuver trajectories are realized by coordinating the maneuver in longitudinal and lateral sub-planes, respectively. Dynamic inversion is employed to establish the relationship between the designed trajectory and the needed overload. Secondly, the minimum energy loss is selected as the optimization index, and the optimal overload is obtained based on the maximum principle. the final path angle constraint is also considered in this algorithm. Finally, the maneuvering and guiding overloads are combined using a weight coefficient, and the corresponding angle of attack and bank are obtained. The approach is tested using common aero vehicle-H (CAV-H) model, and the results demonstrate that the method proposed in this paper can realize the maneuver trajectory in dive phase with high terminal accuracy and strong penetration ability.