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Traffic flow prediction is the key problem of intelligent transportation system. Accurate prediction results are indispensable for traffic management and road planning. However, due to the complex spatial-temporal correlation of traffic flow data, including the spatial correlation and temporal correlation of adjacency, periodicity, and trend that exist between different roads. The existing forecasting methods consider the spatial-temporal correlation but lack the dynamic modeling of spatial-temporal correlation. To deal with this dynamic feature, this paper proposes a multi-dimensional attention-based spatial-temporal network (MA-STN). It mainly contains three parts, the spatial-temporal attention unit, the spatial-temporal feature extraction unit based on Graph Convolutional Network (GCN) and the fusion prediction unit, and the residual connection is also added to the model to avoid the gradient disappearance problem. Meanwhile, this paper divides the dataset into three subsets to deal with the three features in the temporal dimension separately. To verify the effectiveness of the proposed model, two real-world road traffic flow data collected by PeMS system are used for validation. By comparing six different models, the proposed network in this paper has a 7% accuracy improvement compared to the baseline model. To verify the effectiveness of the attention mechanism, ablation experiments are used in this paper for validation, and the results show that the attention mechanism can achieve a 5% accuracy improvement.

In this paper, the soliton solutions which indicate long wave parallel to the magnetic fields of Kaup-Newell models are argued via described method. Modified extended Simple equation is suggested to explore the novel solitons and other wave structures of two different types of Kaup-Nawell equations, which have never been constructed before. As a consequence, bright-dark solitons, singular solitons, multi-wave solitons, breather type wave of strange structures and other waves solutions of two Kaup-Newell (K-N) Schrodinger equations are achieved in different form. The obtained novel solitons and other exact wave solutions have key applications in engineering and applied physics. Novel wave structures of solitons are explained graphically by providing suitable values to parameters that help for understanding the physical phenomena of these models. The constructed solutions are evaluated with available results in the literature. This technique can be productively utilized to more equations that occur in mathematical physics.

APG115 is a highly selective small-molecule inhibitor of MDM2-p53 interaction with oral activity, which restores p53 activation in patients with solid tumors in clinical trials. The Bruton tyrosine kinase inhibitor (BTKi) ibrutinib exhibits significant efficacy in chronic lymphocytic leukemia (CLL) patients including high-risk patients. However, the chemoresistance of ibrutinib still needs to be addressed urgently. Herein, we first demonstrated that the APG115 exerted apoptogenic and antiproliferative effects, and induced G0/G1 cell cycle arrest in CLL. As an agent used either alone or in combination with ibrutinib together, APG115 provided remarkable antitumor activity and overall survival extension in vivo. Mechanistically, the activation of p53 positively regulates the p53/p21 pathway, prompting MCL-1 degradation via inducing its ubiquitination. On basis of the upregulation of MCL-1 in CLL cells with ibrutinib resistance, these evidences explain how APG115 reduces the resistance of ibrutinib in CLL. This study offers promising prospects to constitute effective regimens of APG115 combined with ibrutinib for the CLL treatment.

Air route crossing waypoint optimization is one of the effective ways to improve airspace utilization, capacity and resilience in dealing with air traffic congestion and delay. However, research is lacking on the optimization of multiple Crossing Waypoints (CWPs) in the fragmented airspace separated by Prohibited, Restricted and Dangerous areas (PRDs). To tackle this issue, this paper proposes an Artificial Potential Field (APF) model considering attractive forces produced by the optimal routes and repulsive forces generated by obstacles. An optimization framework based on the APF model is proposed to optimize the different airspace topologies varying the number of CWPs, air route segments, and PRDs. Based on the framework, an adaptive method is developed to dynamically control the optimization process in minimizing the total air route cost. The proposed model is applied to busy controlled airspace. And the obtained results show that after optimization the safety-related indicators: conflict number and controller workload reduced by 7.75% and 6.51% respectively. As for the cost-effectiveness indicators: total route length, total air route cost and non-linear coefficient, declined by 1.74%, 3.13% and 1.70% respectively. While the predictability indicator, total flight delay, saw a notable reduction by 7.96%. The proposed framework and methodology can also provide an insight in the understanding of the optimization to other network systems. Civil Aviation Authority of Singapore (CAAS) Published version This research was supported by the Civil Aviation Authority of Singapore and the Nanyang Technological University, Singapore under their collaboration in the Air Traffic Management Research Institute. Any opinions, findings and conclusions or recommendations expressed in this material are those of the authors and do not reflect the views of the Civil Aviation Authority of Singapore.

Different from the usual surveillance task in which the goal is to achieve complete coverage of the specified area, the cooperative path planning problem of drones for persistent surveillance task is studied in this paper considering multiple constraints of the covered area. The goal is to maximize the combinational coverage area of drones while giving preference to the area that hasn’t been visited beyond a certain time interval. The influence of shooting resolution and blocking of buildings are considered, and the state information of each grid is defined to record the visit information of the ground area. Considering the characteristic of the established model, the multi-constrained cooperative path planning (MCCPP) algorithm is developed. The grids which have not been visited for a long time are received special attentions, and the drone is led to reducing the flight height to cover the gird which has a special requirement on the shooting resolution. The cooperation mechanism among drones is also set to ensure that all the drones can determine the next path point synchronously. An emergency path planning algorithm with the continuous checking strategy is designed for a drone to fly to the specified area and finish a complete coverage of it.

Pakistan is one of those countries that are heavily dependent on hydrocarbon fuel for energy production. This results in severe CO2 emissions that lead to climate change. Although renewable energy resources such as wind are available in abundance, they have not been fully utilized and so energy crises in Pakistan increase every year. This study focuses on using wind energy as an alternative to thermal power sources as the main source of power generation in Pakistan. This research also helps in designing a project management tool to prioritize sources of power generation, including both renewables and nonrenewables, while also considering projects’ technical, environmental, social and economic criteria. An Analytical Hierarchy Process has been used to analyze the four main criteria and 12 subcriteria. The analysis revealed that wind energy is the best source among all options for power generation source, followed by solar. Oil, gas, and coal, the other three alternatives, were well below in a comparative analysis. Gas achieves overall better performance if only economic criteria are considered, but due to shortfalls in availability and diminishing reserves, this source is also not feasible. Relying on wind power as the only energy source will not be technically possible, but it can become a leading energy source inside Pakistan. This will reduce the burden on thermal energy sources and make the country more energy-secure, rather than relying heavily on imported oil and gas, as it currently does. Wind power generation capacity in Pakistan is increasing, so that the cumulative capacity is around 2118 MW installed and commissioned by the end of 2018.

Barley, as an important crop, is poorly understood in terms of non-transcriptome regulation of its growth and development It remains unclear whether barley lncRNAs are responsive to Piriformospora indica colonization. Considering the increasing demand for grain, it is necessary to study the molecular mechanism lying behind growth and development in barley. We found barley roots exhibited fast development and large roots branched after P. indica colonization. Genome-wide high throughput RNA-seq and bioinformatical analysis showed that 4356 and 5154 differentially expressed LncRNAs (DELs) were found in responsive to P. indica at 3 and 7 day after colonization (dai), respectively. And 2456 DELs were found at 7 dai compared to 3 dai. Among these, 2024 were up-regulated and 2332 were down-regulated after 3 days’ colonization, and 2486 were up-regulated and 2668 were down-regulated after 7 days’ colonization, 1433 were up-regulated and 1023 were down-regulated in 7 dai to 3 dai comparison group. Based on the co-expression correlation of lncRNA-mRNA, we found that 98.6% lncRNAs (10726 out of 10878) were positively correlated to 3430 mRNAs at 3 dai and 7 dai. GO and KEGG analysis indicated that a few lncRNAs might be involved in diverse biological processes upon P. indica colonization. Further GO analysis showed that 30 lncRNAs might play roles as transcription factor (TF); 23 lncRNAs might participate in cell cycle regulation. Moreover, the metabolites analysis indicated that Chlorophyll a, sucrose, protein, gibberellin and auxin were accordance with the results of the transcriptome and the respective lncRNAs were positively correlated to these target RNAs. Gene silencing experiment suggested that lncRNA TCONS_00262342 is probably a key regulator of the GA3 synthesis pathway which participate in P. indica and barley interaction. We concluded that, acting as molecular material basis and recource, lncRNAs response to P. indica colonization by regulating metabolites distribution in barley and coordinate the complex regulatory process of higher life by constructing highly positively correlations with its target mRNA. As our understanding of lncRNAs improves, interactions of lncRNAs with respective coding sequences and with various classes may define new functional networks that may be modulated for molecular breeding.

We propose a causal framework to explain the catastrophic forgetting in Class-Incremental Learning (CIL) and then derive a novel distillation method that is orthogonal to the existing anti-forgetting techniques, such as data replay and feature/label distillation. We first 1) place CIL into the framework, 2) answer why the forgetting happens: the causal effect of the old data is lost in new training, and then 3) explain how the existing techniques mitigate it: they bring the causal effect back. Based on the framework, we find that although the feature/label distillation is storage-efficient, its causal effect is not coherent with the end-to-end feature learning merit, which is however preserved by data replay. To this end, we propose to distill the Colliding Effect between the old and the new data, which is fundamentally equivalent to the causal effect of data replay, but without any cost of replay storage. Thanks to the causal effect analysis, we can further capture the Incremental Momentum Effect of the data stream, removing which can help to retain the old effect overwhelmed by the new data effect, and thus alleviate the forgetting of the old class in testing. Extensive experiments on three CIL benchmarks: CIFAR-100, ImageNet-Sub&Full, show that the proposed causal effect distillation can improve various state-of-the-art CIL methods by a large margin (0.72%--9.06%).

Traffic flow forecasting is a typical problem of spatial-temporal data forecasting. Because traffic data show complex patterns and traffic graph is difficult to process, it is very challenging. And most existing traffic flow prediction methods lack the ability to model the dynamic spatial-temporal features. These methods cannot yield satisfactory prediction results. In the paper, we propose Attention Based Multi-Unit Spatial-Temporal Network (AMU-STN) solve the traffic flow forecasting problem. The model mainly consisting three units, specifically, spatial-temporal attention unit to effectively capture the dynamic spatial-temporal correlations, spatial-temporal feature extraction unit to extract long-range feature, and prediction unit to predict the feature status. For dealing with long-term predictions, we stack multiple layers of attention units and feature extraction units. We use a residual connection to avoid gradient vanish due to deepening of network layers. Experimental results on two real-world datasets from Caltrans Performance Measurement System (PeMS) prove ours model outperforms the state-of-the-art baselines. We also analyze the weight of the attention matrix; the result shows the effectiveness of the attention mechanism and reflects the interpretability of ours model.

Objective: This study aimed to determine prognostic significance of C-reactive protein (CRP), CRP kinetics and CRP to albumin ratio (CAR) in indolent B-cell non-Hodgkin lymphoma (B-iNHL) patients. Methods: The association among these blood makers and overall survival (OS), disease-free survival (DFS), progression-free survival (PFS) were analyzed in 243 B-iNHL patients. OS, DFS and PFS were determined by Kaplan–Meier curves. Cox proportional analysis was performed to examine the prognostic significance of clinicopathological variables. Results: Multivariate analyses identified that elevated pretreatment CRP (HR: 5.110, 95% CI: 1.904-13.717, p=0.001), post-treatment CRP (HR: 5.826, 95% CI: 1.659-20.458, p=0.006), continuously elevated CRP (HR: 6.461, 95% CI: 2.620-15.930, pp=0.008) had association with worse OS. Likewise, elevated pretreatment CRP (HR: 3.767, 95% CI: 1.777-7.984, p=0.001), post-treatment CRP (HR: 2.384, 95% CI: 1.027-5.534, p=0.043), ever-elevated CRP (HR: 2.425, 95% CI: 1.105-5.322, p=0.027), continuously elevated CRP (HR: 4.748, 95% CI: 2.114-10.660, pp=0.007) were in independent significance with worse DFS. Elevated pretreatment CRP (HR: 2.606, 95% CI: 1.338-5.076, p=0.005), ever-elevated CRP (HR: 2.086, 95% CI: 1.040-4.188, p=0.039), continuously elevated CRP (HR: 3.296, 95% CI: 1.594-6.818, p=0.001) and elevated CAR (HR: 1.991, 95% CI: 1.021-3.882, p=0.043) were determined in independent significance with poor PFS. The effect was statistically significant in both follicular lymphoma (FL) and chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/ SLL) patients.Conclusions: In conclusion, we demonstrate that CRP level, CRP kinetics and CAR could be potential prognostic indicators with independent significance in patients with B-iNHL, also in FL and CLL/ SLL subgroups. CRP and CAR make an implementation for prognostic evaluation more easily and effectively in B-iNHL patients.

Increasing use of Unmanned Aerial Vehicle (UAV) in urban environments poses to an increased risk of fallen UAVs impacting people and vehicles on the ground, as well as colliding with manned aircraft in the vicinity of airports. Risk management of UAV flights for safe operations is essential. We proposed a comprehensive risk assessment model for UAV operation in urban environments. Three risk categories (people, vehicles, and manned aircraft) were considered and each risk cost was quantified using collision probability. We adjusted the risk costs in various magnitudes to a same scale and conducted a sensitivity analysis to determine the optimal coefficients of the three risk cost models. We then computed the total risk and generated a risk cost map for path planning. Modified path planning algorithms were used to produce a cost-effective path, and we compared their performances in terms of total risk cost and computational time. Lastly, we performed simulations to validate the feasibility and effectiveness of our proposed risk assessment model. The results show that the risk-cost-based path planning method can generate safer path for UAV operations than the traditional shortest-distance-based method. Our proposed model can be extended to complex urban environments by including more relevant parameters and data. Nanyang Technological University Published version This work was supported in part by the National Key R&D Program of China under Grant 2016YFB0502400, and in part by the UAS Programme in the Air Traffic Management Research Institute (ATMRI), Nanyang Technological University (NTU), Singapore.

Purpose Conflicts among top management team (TMT) members have a significant impact on sustainable development of family enterprises in China. The complex attributes of different kinds of conflicts in a TMT have dual effects on firm performance and its stability. Thus, avoiding conflicts in a TMT through a systematic conflict management strategy is very important. This paper aims to therefore investigate how to maximize the performance and income level of the TMT in family enterprises through managing conflict systematically, while adopting the best conflict coping strategies. Design/methodology/approach In this study, the authors apply conflict coping strategies as a useful tool of conflict management and propose five kinds of dynamic conflict coping strategies among TMT members. Repeated game and multi-agent simulation by computer experiment are used to dynamically simulate the rules and evolution of individual conflict coping strategy choices. Findings It is found that with the passage of time, different conflict coping strategies have different effects on earnings of individuals and teams at different conflict levels. It is also revealed that conflict coping strategies affect not only the earnings of individuals and teams but also their distribution; it also reflects the conflict level in TMT of a family enterprise but in reverse. Originality/value This study contributes to the existing literature on conflict management in relevance to the choice and revolution of conflict coping strategies in a Chinese business culture context. It focuses on strengthening the unity and cooperation of TMT members. Controlling the conflict level of TMT members at a reasonable level, investigating the primary cause of conflict and identifying its nature lead to better performance of the TMT and the sustainable development of Chinese family enterprises. Based on these outcomes, different conflict coping strategies can be appropriately used to solve TMT conflicts.

Introduction Chronic lymphocytic leukemia (CLL) is a highly heterogeneous disease characterized by malignant clonal expansion of mature B lymphocytes. Competitive endogenous RNAs(ceRNAs) such as long noncoding RNAs (lncRNAs) and circular RNAs (circ RNAs) have miRNA response elements (MREs) and can bind to miRNAs to influence mRNA expression. An increasing number of studies have shown that the ceRNA network played an important role in the initiation and progression of tumors. However, the roles and functions of the ceRNA network in chronic lymphocytic leukemia (CLL) are still unclear. This study aims to explore the molecular mechanism of CLL and provide potential prognostic markers and therapeutic targets through the integrated analysis of the ceRNA network in CLL. Methods The expression profile of RNAs of CLL patients, CLL cell lines (MEC1 and EHEB) and healthy group were obtained by the illumina sequencing. R software was used for functional enrichment analysis. The data in the genome microarray map GSE22762 was used for survival analysis. The circRNA-miRNA-mRNA ceRNA networks were visualized by Cytoscape 3.7.2. The expression of the circRNA hsa_circ_0007675/hsa-miR-185-3p/TCF7L1 axis were verified by Quantitative real-time PCR and the correlation between hsa_circ_0007675 and TCF7L1 was analyzed. Results In total, we identified 57 differentially expressed mRNAs (DEmRNAs), 1391 DElncRNAs, 335 DEmiRNAs and 2413 DEcircRNAs by comparing CLL patients with healthy donors. Meanwhile, 482 mRNAs, 6085 lncRNAs, 302 miRNAs and 1847 circRNAs were explored differently expressed between CLL cell lines and healthy donors. GO analysis results showed that the functions of differentially expressed genes (DEGs) between CLL patients and control are mainly enriched in sequence−specific DNA binding, chromatin and gene expression (Figure 1A) while between CLL cell lines and control they were mainly enriched in oxidoreductase activity, ribosomal subunit and lipid metabolism (Figure 1C). KEGG pathway analysis revealed that the DEGs between CLL patients and control were mainly enriched in Notch signaling pathway, JAK-STAT signaling pathway and cGMP-PKG signaling pathway (Figure 1B). Meanwhile between CLL cell lines and control, DEGs were mainly enriched in mTOR signaling pathway, cell cycle and p53 signaling pathway (Figure 1D). The survival analyses showed that 15 DEGs (INIP, IL3RA, CHD1, NLRP12, IL20RB, HNRNPC, B3GALT4, SIT1, ACOT8, PCLAF, C19orf18, SELENOS, OR7A17, PCDH7, PHGDH) were significantly differentially expressed in the survival analyses. The overall survival of the high expression group of INIP, IL3RA, CHD1, NLRP12, IL20RB and HNRNPC were higher than that of the low expression group (Figure 2A-F) while the overall survival of the low expression group of B3GALT4, SIT1, ACOT8, PCLAF, C19orf18, SELENOS, OR7A17, PCDH7 and PHGDH were higher than that of the high expression group (Figure 2G-O). The ceRNA network were built by Cytoscape3.7.2. In total, 11 mRNA nodes, 19 miRNA nodes, 251 circRNA nodes were identified as differentially expressed profiles between CLL patients and control (Figure 3A). We verified the circRNA hsa_circ_0007675/hsa-miR-185-3p/TCF7L1 axis. Compared with normal people, the expression of TCF7L1 and hsa_circ_0007675 in patient specimens were significantly increased (p Conclusions In this study, we identified the expression profile of RNAs in CLL patients and CLL cell lines. Functional enrichment analysis and survival analysis revealed the potential functions of DEGs. The ceRNA network we established can help to further understand the pathogenesis of CLL and provide potential prognostic biomarkers and novel therapeutic targets. Keywords: Chronic lymphocytic leukemia; Competing endogenous RNA; Non-coding RNAs; Prognostic biomarkers; Therapeutic targets Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Introduction: Waldenström macroglobulinaemia/ Lymphoplasmacytoid lymphoma (WM/LPL) is a rare lymphoproliferative neoplasm characterized by small B lymphocytes proliferation. Abnormalities of thyroid hormones are common in clinical courses. Yet, the role of thyroid complications has not been explored in WM/LPL. Hence, the aim of this study was to investigate the clinical significance of thyroid complications in WM/LPL. Methods: 105 clinically diagnostic WM/LPL patients from Shandong Provincial Hospital were enrolled with informed consents. Baseline and clinical data concerning sex, age, International Staging System Waldenstrom Macroglobulinemia (ISSWM) score et al were collected. Chi-square test was used for comparison of clinical characteristics. The Kaplan-Meier method was used for analysis of survival outcomes. Cox regression analyses were utilized to identify prognostic-related key factors associated with overall survival (OS) and progression-free survival (PFS) in WM/LPL patients. Microarray datasets GSE6691 were obtained from Gene Expression Omnibus. Results: Over the 105 WM/LPL patients, the median overall survival (OS) was not reached and median progression-free survival (PFS) was 96 months (Figure 1A, 1B). Patients classified as complete response (CR)/ partial response (PR)/ stable disease (SD), showed better OS and PFS than patients with progression disease (PD) (Figure 1C, D). There were 13.3% of enrolled patients with mixed thyroid complications. The results of Chi-square test showed that thyroid complications were significantly associated with reduced IgM level (p=0.036) and elevated β2-macroglobulin (p=0.032). Moreover, patients without thyroid comorbidities were more likely to get overall response (CR+PR) to the first-line treatment (p=0.004). Kaplan-Meier curves showed patients with thyroid complications had significantly shorter OS (p=0.02) and PFS (p In the univariate Cox regression model, age (p=0.022), ISSWM score (p=0.014) and thyroid complications (p Microarray dataset analysis was conducted to further investigate the role of thyroid-related genes in WM/LPL patients. A network of interactions among thyroid-related genes and critical factors in WM/LPL, including MYD88 and CXCR4, was shown in Figure 1G. Correlations were statistically significant between SLC5A5 (p Conclusion: Taken together, the present study was the first investigation on the role of thyroid complications in WM/LPL. Patients with thyroid complications showed worse clinical characteristics and conferred independent prognostic significance. The primary strength of this study is that it provides robust real-world evidence on the prognostic role of thyroid complications, highlighting the need to monitor and appropriately manage WM/LPL patients with thyroid complications in medical admissions. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

The demand on the public transportation in many cities has been increasing with the diversity of commuters’ activities that require the regular travelling across the urban and suburb areas. However, the public transport systems still suffer from the traffic congestion and detour, which will then reduce the efficiency. Accordingly, extensive efforts have been made for decades to optimize the operations of metro ground traffic with trains, subways, and buses (2D public transportation). On the other hand, unmanned aerial vehicles (UAVs) have been widely applied in the event-triggered tasks, such as delivery, rescue and surveillance in urban environments, and they have a great potential to relieve the pressure in 2D ground public transportation. Inspired from metro systems, AirMetro is a new concept proposed for future 3D public air transportation service, which carries the passengers commuting from a point to the destination, routinely and periodically. In this paper, the flight scheduling problem for AirMetro is studied based on the flight route of UAVs. The low-altitude airspace in urban environments is divided into several layers by altitude, and AirMetro is conducted in the allocated airspace as the public lanes. First, a pipeline-based route planning algorithm is proposed for the gridded urban environments to further reduce the length of a flight route generated by A* algorithm. The UAV is not required to pass through the centre of a cube in the pipeline-based algorithm when compared with the A* algorithm. This can then potentially result in a shorter flight route. As for resolving the conflict among UAVs, a minimum influence-based approach is developed to delay the flight and reduce the influence of adjustment on the follow-up flights of the UAV. By further introducing a modified simulated annealing (MSA) algorithm, the delay of flight can be further reduced by optimizing the UAV sequence conducting the conflict resolution. Results of the case studies demonstrate that the trajectory-based flight scheduling method can improve the flight efficiency by ensuring the flight safety of UAVs and reducing the average delay of UAVs as well in AirMetro. Ministry of Education (MOE) Nanyang Technological University This research work is supported by the Chongqing Research Program of Basic Research and Frontier Technology (grant number of cstc2020jcyj-msxmX0602) and the Fundamental Research Funds for the Central Universities (grant number of 2020 CDJ-LHZZ-066). Thanks are also due to China Scholarship Council (project reference number 201906055030) for the financial support of the research attachment of the first author to the ATMRI in the NTU, Singapore. This collaborative research, findings presented, and interactions among teams are also relevant to the Ministry of Education (MOE, Singapore) Tier-1 project research grant (Project ID: 2018-T1-002-124) and the UAS Program on “Urban Aerial Transport Traffic Management and Systems” in the ATMRI, NTU, Singapore. The current work also provides the basis and idea for the recently approved National Natural Science Foundation of China (grant number of 52102453).

Introduction: C-reactive protein (CRP), the most commonly used clinical indicator of inflammation, plays an important role in disease diagnosis and efficacy evaluation. Recent studies identified elevated CRP level and CRP kinetics, dynamic change of CRP level throughout treatment, were associated with decreased clinical outcome in some malignancies. Because of increased catabolism and the reduce of hepatic synthesis, albumin is oppositely associated with inflammatory. CRP/ albumin ratio (CAR) is a novel and superior prognostic factor involving inflammatory and nutritional factors in various cancers. However, the prognostic role of CRP, CRP kinetics and CRA in B-cell chronic lymphoproliferative diseases (B-CLPD) were not well characterized yet. Our study focused on the prognostic role of CRP, CRP kinetics and CRA in newly diagnosed B-CLPD. Methods: In total, 243 newly diagnosed B-CLPD patients from January 2012 to December 2019 at the Shandong provincial hospital in China were analyzed for overall survival (OS) and disease-free survival (DFS), depending on CRP, CRP kinetics and CRA. OS and DFS were determined by Kaplan-Meier curves and log-rank test. Cox proportional analysis was performed to examine the prognostic significance of clinicopathological variables in multivariate analyses. Results: The five-year OS of patients with elevated pretreatment CRP level (94.3% vs. 56.7%, p Multivariate analyses identified that elevated pretreatment CRP level (HR: 5.110, p=0.001) (Table 1), elevated post-treatment CRP level (HR: 5.826, p=0.006) (Table 2), continuously elevated CRP level (HR: 6.461, p Conclusions : We demonstrate that CRP level, CRP kinetics and CAR could be potential prognostic indicators with independent significance in patients with B-CLPD. CRP and CAR make an implementation for prognostic evaluation more easily and effectively in B-CLPD patients. Disclosures No relevant conflicts of interest to declare.

Introduction : microRNAs (miRNAs) could be released into the extracellular microenvironment and mediate cellular communication through exosomes. Circulation exosomal miRNAs have recently emerged as complimentary biomarkers and novel approaches for the non-invasive tests of early diagnosis or follow-up of neoplasms. Accumulating evidences have indicated that miR-107 plays vital functions in suppressing tumorigenesis. However, the significance of exosomal miR-107 in DLBCL remains unclear. Thus, this study aimed to explore candidate biomarkers and investigate the role of miR-107 in DLBCL as well as the molecular mechanisms involved. Methods : Differentially expressed miRNAs (DEMs) in DLBCL were identified based on Gene Expression Omnibus (GEO) datasets and verified in a cohort of DLBCL patients. The functions and biological pathways of DEMs were enriched by DAVID. Serum-derived exosomes of 42 DLBCL patients and 31 healthy volunteers were isolated with informed consents by Exo Easy Maxi Kit, and further detected by western blot and transmission electron microscopy (TEM). Receiver operating characteristic curves (ROC) were performed to evaluate the diagnostic value of DEMs. The biological function of miR-107 in DLBCL were evaluated by miR-107 Agomir. Survival analyses were performed by the Kaplan-Meier method. Potential targets genes of miR-107 were predicted by miRDB, PicTar, Targetscan and miRTarBase. Western blotting and confocal staining assay were used to detect the expression of YWHAH. Interaction of miR-107 and YWHAH was confirmed by dual-luciferase reporter assay. Results : 14 DEMs were identified in DLBCL through evaluating the miRNA microarray profile of GSE117063 (Fig. 1A-A) and GSE29493 (Fig. 1A-B). The biological processes of these DEMs mainly enriched in regulatory of transcription, protein phosphorylation and cell proliferation (Fig.1B). In order to explore candidate exosomal biomarkers for DLBCL, we then isolated serum-derived exosomes from DLBCL patients. As depicted in Fig.1C, exosomes not only expressed exosomal biomarkers Tsg101 and CD9 but also shown cup-shape morphology. We further assessed the expression of DEMs on exosomes by qRT-PCR. Compared with normal samples, only two down-regulated miRNAs (miR-107, miR-375) and one up-regulated miRNAs (miR-485) were statistically dysregulated in DLBCL patients (Fig.2A). ROC curve analysis demonstrated that exosomal miR-107, miR-375, and miR-485 might be potential biomarkers for DLBCL patients, with the AUC of 0.854, 0.769, and 0.703, respectively (Fig.2B). In addition, survival analysis revealed that low-expression of miR-107 in DLBCL patients significantly associated with undesirable clinical outcomes (Fig.2C, p Down-regulation of miR-107 was confirmed in DLBCL cell lines by qRT-PCR (Fig.3A). To validate our hypothesis, we up-regulated miR-107 expression by miRNA Agomir, which could significantly reduce cell proliferation and migration, and promote cell apoptosis (Fig.3B-D). The regulatory mechanisms of miR-107 in DLBCL was further explored. 28 target genes of miR-107 were identified and shown in Fig.4A. KEGG pathway analysis revealed that the targeted genes mainly enriched in the PI3K-Akt, Hippo, and AMPK signaling pathways (Fig.4B). We found out that the target gene YWHAH (14-3-3η) was significantly upregulated in the DLBCL cells (Fig.4C-D). Moreover, dual-luciferase assay revealed that miRNA-107 perform anti-tumor effect through targeting the 3'UTR region of YWHAH (Fig.4E-F). As previously reported, YWHAH associated with tumor metastasis, chemoresistance, apoptosis resistance and poor prognosis in DLBCL. Thus, we suggested that miR-107 antagonized DLBCL progression through downregulating YWHAH. Conclusion : In this study, we demonstrated for the first time that serum exosomal miR-107, miR-375, and miR-485 could be applied as potential non-invasive biomarkers in early diagnosis of DLBCL patients. Furthermore, miR-107 inhibited DLBCL progression by targeting YWHAH, which will provide a promising therapeutic approach for DLBCL. Disclosures No relevant conflicts of interest to declare.

Introduction: Nucleolar spindle-associated protein 1 (NUSAP1), a microtubule binding protein with molecular weight of 55KD, plays an important role to ensure the normal regulation of cell cycle in chromosome separation, spindle assembly and DNA repair. NUSAP1 has been shown to be highly expressed in a variety of tumors, involved in tumor occurrence, invasion, migration, and drug resistance. Moreover, it is associated with poor prognosis. Whereas, no research has been reported regarding the role of NUSAP1 in diffuse large B-cell lymphoma (DLBCL). Methods: Peripheral blood samples from de novo DLBCL patients and healthy volunteers were collected with informed consents at the Department of Hematology in Shandong Provincial Hospital Affiliated to Shandong University (SPHASU). Microarray datasets GSE83632 and GSE32918 were obtained from Gene Expression Omnibus. Kaplan-Meier survival curves with log-rank test of overall survival (OS) were analyzed. Immunohistochemistry staining (IHC) was performed to assess NUSAP1 expression in specimens. Expression levels of NUSAP1 mRNA and protein were detected by quantitative RT-PCR and western blotting. The DLBCL cells were transfected by lentiviral shRNA and vectors to stably silence and up-regulate NUSAP1. Effects of doxorubicin on cell viabilities were assessed by cell counting kit-8. Besides, apoptosis and cell cycle were respectively detected by annexin V-PE/7AAD and PI/RNase staining via flow cytometry. Invasion ability was analyzed by transwell assay. ShNUSAP1 cells and Scramble cells were subcutaneously injected to SCID-Beige mice to establish xenograft models. Animal experiments were performed in accordance with the principles of the Institutional Animal Care. Results: According to clinical specimens and bioinformatics analysis, the expression level of NUSAP1 gene in samples of DLBCL patients was significantly increased than that of healthy donors (P Conclusions: This study first identified that the high expression of NUSAP1 in DLBCL patients is associated with poor prognosis through database analysis and in vitro experiments. Interference of NUSAP1 expression led to a slower DLBCL cell proliferation and a higher apoptosis rate, meanwhile induced the G1 phase arrest and promoted EMT-like process. Collectively, our study demonstrated that NUSAP1 plays a role in promoting tumor growth both in vivo and vitro through DNA damage response pathway, which providing a new direction for prognosis assessment and targeted therapy of DLBCL. Figure Disclosures No relevant conflicts of interest to declare.

Introduction N6-methyladenosine (m6A) is the most prevalent post-transcriptional modification of eukaryotic mRNA. Accumulating evidence suggests that RNA m6A methylation exerts crucial roles in oncogenesis. However, the mRNA m6A methylation pattern in chronic lymphocytic leukemia (CLL) has not been investigated. Hence, the aim of this study is to perform a comprehensive profiling to identify distinct m6A methylation signatures in CLL patients. Methods Peripheral blood samples from de novo CLL patients were collected with informed consents at the Department of Hematology in Shandong Provincial Hospital Affiliated to Shandong First Medical University. CD19+ B cells were isolated with informed consents from healthy donors. Methylated RNA immunoprecipitation sequencing (MeRIP-Seq) was conduct to profile mRNA m6A methylation of CLL-B cells and normal CD19+ B cells at Novogene (Beijing, China). The library preparations were sequenced on an Illumina Novaseq platform with a paired-end read length of 150 bp according to the standard protocols. The sequencing was carried out with 3 independent biological replicates. After mapping reads to the reference genome, exomePeak R package was used for the m6A peak identification in each anti-m6A immunoprecipitation group with the corresponding input samples serving as a control, and q-value threshold of enrichment of 0.05 was used for all data sets. The m6A-enriched motifs of each group were identified by HOMER. Differential peak calling was performed using exomePeak R package with parameters of p-value < 0.05 and fold_change > 1. Functional enrichment analyses of gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) of differentiated peaks associated genes were performed. All investigators comply with the guiding principles for experimental procedures found in the Declaration of Helsinki of the World Medical Association. Results By MeRIP sequencing, significant distribution of methylation peaks were detected in 5'UTR, 3'UTR and CDS regions of CLL primary cells (Figure 1A) and normal B cells (Figure 1B). Figure 1C-D illustrated the percentage of methylation peaks in the five regions, suggesting distinct m6A patterns in CLL cells. Moreover, Figure 1E-F revealed the positions of m6A methylation peaks in chromosomes of CLL and normal B cells. Furthermore, the compared distributions of m6A methylation peaks in CLL and normal B cells were presented in Figure 2A. Besides, the bean plot visibly displayed the obvious differentiation of methylation peaks in CLL group and normal B cells in read density (Figure 2B). Importantly, a total of 1836 significantly changed peaks, of which 1519 were significantly up-regulated and 317 peaks were significantly down-regulated (p1; Figure 2C). These m6A peaks were located across 1850 genes. Functional enrichment analyses identified that differentiated peaks associated genes were potentially regulate RNA metabolic process via oncogenic pathways in CLL pathogenesis (Figure 3A-B). In addition, HOMER analysis identified 38 significant de novo m6A peak motifs, top 10 most significant peak motifs of which were presented (Figure 3C), illuminating potential detailed mechanism of m6A RNA methylation in the tumorigenesis and progression of CLL. Conclusion Taken together, our investigations explored for the first time the m6A methylation pattern of mRNA in CLL. m6A modifications play crucial roles in the progression and survival of CLL patients,highlighting m6A modifications-targeted intervention formulating a novel treatment paradigm in progressed CLL that warrants clinical investigation. Disclosures No relevant conflicts of interest to declare.