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Aberrant DNA methylation is a hallmark of acute myeloid leukemia (AML). Various studies showed that t(8;21) AML presented a distinct DNA methylation profile and could be categorized into a separate cluster according to DNA methylation sequencing. Yet, there is still a lack of understanding regarding the causes and mechanisms of this phenomenon. Knowing how the DNA methylation is regulated in t(8;21) AML would enhance our understanding of leukemogenesis and may assist clinical decision-making regarding DNA methylation-targeted therapy. Herein, we summarized our current knowledge concerning DNA methylation regulation in t(8;21) AML and discussed their potential clinical significance in this article.

SummaryBoth orbitofrontal cortex (OFC) and hippocampus (HC) are implicated in the formation of cognitive maps and their generalization into schemas. However how these areas interact in supporting this function remains an open question, with some proposals supporting a serial model in which OFC draws upon task representations created by HC to extract key behavioral features and others proposing a parallel model in which both regions construct representations that highlight different types of information. Here we tested between these two models by asking how schema correlates in OFC would be affected by inactivation of HC output, after learning and during transfer across problems. We found the prevalence and content of schema correlates were unaffected by inactivation after learning, while inactivation during learning accelerated their formation. These results contradict a serial model and favor the proposal that OFC and HC operate in parallel to extract different features defining cognitive maps and schemas.

PCR Primers

Figure S1 - p53-Null K562 and KCL-22 cells were resistance to MLN4924; Figure S2 - MLN4924 induces apoptosis in IM-sensitive and -resistant CML cells harboring WT-p53 in a time-dependent fashion; Figure S3 - MLN4924 suppresses survival of BCR-ABL+ CML LSCs in vivo; Figure S4 - p27kip1 knockdown attenuates the effect of MLN4924 on CML LSCs in vivo.

Table S1 shows information of antibodies for Western blotting analysis.

Table S1 shows genetic status of the known altered genes in UM cell lines; Table S2 shows detailed information for 45 patients with UM; Table S3 shows the association between NAE1 expression and clinicopathologic features in UM patients; Table S4 shows limiting dilution analysis in NOD-SCID mice; Table S5 shows primers for qRT-PCR analysis.

AXL inhibition reduces long-term engraftment of human CML CD34+ cells in NSI mice.

Purpose: Liver metastasis is the major and direct cause of death in patients with uveal melanoma (UM). There is no effective therapy for patients with metastatic UM. Improved treatments of hepatic metastatic patients with UM were urgently needed. Inspired by readily detectable key components in the neddylation pathway in UM cells, we aimed at exploring whether neddylation pathway was a therapeutic target for liver metastatic UM.Experimental Design: Expression of key proteins in the neddylation pathway in UM was detected by Western blotting, real-time quantitative RT-PCR (qRT-PCR), and immunohistochemical staining. Cellular proliferation, apoptosis, cell cycle, migration, and cancer stem-like cells (CSCs) properties were examined upon treatment with MLN4924, a potent and selective NAE inhibitor. Antitumor activity and frequency of CSCs were determined by using a NOD-SCID mouse xenograft model. Liver metastasis was evaluated by use of a NOD-scid-IL2Rg−/− mouse model.Results: NAE1 expression was readily detectable in UM. Inhibition of the neddylation pathway by MLN4924 repressed the CSCs properties in UM (capacities of tumorsphere formation and serially replating, aldehyde dehydrogenase-positive cells, and frequency of CSC) through Slug protein degradation. MLN4924 treatment disturbed the paracrine secretion of NF-κB-mediated VEGF-C and its dependent angiogenesis. The inhibitory effect of neddylation blockade on proliferation, which was confirmed by xenografted UM tumor in NOD-SCID mice, was involved in activation of ATM-Chk1-Cdc25C DNA damage response, and G2–M phase arrest. Neddylation inhibition profoundly inhibited hepatic metastasis in UM.Conclusions: Our studies validate the neddylation pathway as a promising therapeutic target for the treatment of patients with hepatic metastasis of UM. Clin Cancer Res; 24(15); 3741–54. ©2017 AACR.See related commentary by Yang et al., p. 3477

Supplementary Materials，Methods and Figure Legends

Purpose: Quiescent leukemia stem cells (LSC) are important resources of resistance and relapse in chronic myelogenous leukemia (CML). Thus, strategies eradicating CML LSCs are required for cure. In this study, we discovered that AXL tyrosine kinase was selectively overexpressed in primary CML CD34+ cells. However, the role of AXL and its ligand Gas6 secreted by stromal cells in the regulation of self-renewal capacity of LSCs has not been well investigated.Experimental Design: The function of CML CD34+ cells was evaluated by flow cytometer, CFC/replating, long-term culture-initiating cells (LTC-IC), CML mouse model driven by human BCR-ABL gene and NOD-scid-IL2Rg−/− (NSI) mice.Results: AXL was selectively overexpressed in primary CML CD34+ cells. AXL knockdown reduced the survival and self-renewal capacity of human CML CD34+ cells. Pharmacologic inhibition of AXL reduced the survival and self-renewal capacity of human CML LSCs in vitro and in long-term grafts in NSI mice. Human CML CD34+ cells conscripted bone marrow–derived stromal cells (BMDSC) and primary mesenchymal stem cells (MSC) to secrete Gas6 to form a paracrine loop that promoted self-renewal of LSCs. Suppression of AXL by shRNA and inhibitor prolonged survival of CML mice and reduced the growth of LSCs in mice. Gas6/AXL ligation stabilizes β-catenin in an AKT-dependent fashion in human CML CD34+ cells.Conclusions: Our findings improve the understanding of LSC regulation and validate Gas6/AXL as a pair of therapeutic targets to eliminate CML LSCs. Clin Cancer Res; 23(11); 2842–55. ©2016 AACR.

Supplementary Information

Figure S1 - Biological and pharmacological inhibition of EZH2 potently dampens growth of IM-sensitive and -resistant CML cells; Figure S2 - GSK126 induces apoptosis in CML cells in a dose- and time-dependent manner; Figure S3 - GSK126 elicits cytochrome c release and mitochondrial damage; Figure S4 - Administration of GSK126 in CML mice reduces LSCs in spleen nucleated cells from CML mice; Figure S5 - Knockdown of EZH2 reduces in vivo LSCs in CML mice; Figure S6 - Pharmacological and biological inhibition of EZH2 in CML mice has minimal effect on LSCs and progenitor cells in BM and spleen nucleated cells from CML mice; Figure S7 - BCR-ABL is not involved in the EZH2 knockdown-enabled PTEN transcriptional elevation; Figure S8 - Knockdown of PTEN weakens the effect of LSCs reduction mediated by silencing EZH2.

Supplementary information

Supplementary Information

Imatinib revolutionized the treatment of chronic myeloid leukemia (CML), but drug resistance and disease recurrence remain a challenge. In this study, we suggest a novel strategy based on blocking protein neddylation to address BCR-ABL point mutations and leukemia stem cells (LSC) that lie at the root of imatinib-resistant recurrences. On the basis of the finding that the NEDD8-activating enzyme subunit NAE1 is overexpressed in CML cells, we hypothesized that the function of certain neddylation-dependent protein substrates might be targeted to therapeutic ends in imatinib-resistant CML cells and LSCs. In support of this hypothesis, we demonstrated that the NAE1 inhibitor MLN4924 induced G2–M-phase arrest and apoptosis in bulk CML cells with wild-type p53, regardless of their T315I mutation status in BCR-ABL. Moreover, MLN4924 inhibited the survival and self-renewal of primary human CML CD34+ cells and LSCs in CML-bearing mice via accumulation of p27kip1 in the nucleus. Notably, p27kip1 silencing attenuated the suppressive effect of MLN4924 on the maintenance of LSCs in CML-bearing mice. Taken together, our findings offer a preclinical proof of concept for targeting protein neddylation as a novel therapeutic strategy to override mutational and LSC-derived imatinib resistance in CML.Significance: These findings highlight a mediator of protein neddylation, a type of protein turnover mechanism, as a viable therapeutic target against imatinib-resistant forms of chronic myelogenous leukemia. Cancer Res; 78(6); 1522–36. ©2018 AACR.

Table S1 shows the Characteristics of patients with CML; Table S2 shows the sequence of shRNA; Table S3 shows the limiting dilution assay of mouse LT-HSC after shEZH2 treatment

Purpose: Leukemia stem cells (LSCs) are an important source of tyrosine kinase inhibitor resistance and disease relapse in patients with chronic myelogenous leukemia (CML). Targeting LSCs may be an attractive strategy to override this thorny problem. Given that EZH2 was overexpressed in primary CML CD34+ cells, our purpose in this study was to evaluate the effects of targeting EZH2 on CML LSCs and clarify its underlying mechanism.Experimental Design: Human primary CML CD34+ cells and retrovirally BCR–ABL-driven CML mouse models were employed to evaluate the effects of suppression of EZH2 by GSK126- or EZH2-specific shRNA in vitro and in vivo. Recruitment of EZH2 and H3K27me3 on the promoter of tumor-suppressor gene PTEN in CML cells was measured by chromatin immunoprecipitation assay.Results: Our results showed that pharmacologic inhibition of EZH2 by GSK126 not only elicited apoptosis and restricted cell growth in CML bulk leukemia cells, but also decreased LSCs in CML CD34+ cells while sparing those from normal bone marrow CD34+ cells. Suppression of EZH2 by GSK126 or specific shRNA prolonged survival of CML mice and reduced the number of LSCs in mice. EZH2 knockdown resulted in elevation of PTEN and led to impaired recruitment of EZH2 and H3K27me3 on the promoter of PTEN gene. The effect of EZH2 knockdown in the CML mice was at least partially reversed by PTEN knockdown.Conclusions: These findings improve the understanding of the epigenetic regulation of stemness in CML LSCs and warrant clinical trial of GSK126 in refractory patients with CML. Clin Cancer Res; 24(1); 145–57. ©2017 AACR.

Figure S1-The specificity of NAE1 antibody for immunohistochemical analysis was verified; Figure S2-MLN4924 induces apoptosis in human UM cells; Figure S3-MLN4924 is synergistic with vinblastine to induce apoptosis in UM cells; Figure S4-MLN4924 induces DNA damage response and G2/M-phase arrest in UM cells; Figure S5-Inhibiting checkpoint of DNA damage potentiates the cytotoxicity of MLN4924; Figure S6-MLN4924 suppresses ALDH+ cells in UM cells; Figure S7-Slug is required for maintenance of CSCs properties in UM cells; Figure S8-MLN4924 inhibits migration and invasion of human UM cells; Figure S9-MLN4924 inhibits hepatic metastasis of UM cells by attenuating VEGF-C secretion.

One dominant hypothesis about the function of the orbitofrontal cortex (OFC) is that the OFC signals the subjective values of possible outcomes to other brain areas for learning and decision making. This popular view generally neglects the fact that OFC is not necessary for simple value-based behavior (i.e., when values have been directly experienced). An alternative, emerging view suggests that OFC plays a more general role in representing structural information about the task or environment, derived from prior experience, and relevant to predicting behavioral outcomes, such as value. From this perspective, value signaling is simply one derivative of the core underlying function of OFC. New data in favor of both views have been accumulating rapidly. Here we review these new data in discussing the relative merits of these two ideas.

This paper investigates the problem of sliding mode control (SMC) for a class of discrete-time stochastic systems subject to hybrid cyber attacks. Both stochastic nonlinearities and norm-bounded parameter uncertainties are introduced into the system, which occur according to mutually independent Bernoulli-distributed white noise sequences. Moreover, hybrid cyber attacks consisting of denial-of-service attack and deception attack are considered in the transmission channel. By employing the Lyapunov stability theory, sufficient conditions are established for guaranteeing the stability of the state trajectory in the specified sliding surface. Meanwhile, an SMC law is given to ensure the reachability of the specified sliding surface. Finally, a simulation example is put forward to verify the effectiveness of the proposed theoretical results.

How do we learn about what to learn about? Specifically, how do the neural elements in our brain generalize what has been learned in one situation to recognize the common structure of – and speed learning in – other, similar situations? We know this happens; we and our mammalian kith become better at solving new problems – learning and deploying schemas 1–5 – as we go through life. However, we have little insight into this process. Here we show that using prior knowledge to facilitate learning is accompanied by the evolution of a neural schema in the orbitofrontal cortex (OFC). Single units were recorded from rats deploying a schema to learn a succession of odor sequence problems. With learning, OFC ensembles converged on a low-dimensional neural manifold across both problems and subjects; this manifold represented the common structure of the problems and its evolution accelerated across their learning. These results demonstrate the formation and use of a schema in a prefrontal brain region to support a complex cognitive operation. Our results not only reveal an important new role for the OFC in learning but also have significant implications for using ensemble analyses to tap into complex cognitive functions.

Relapse of patients with chronic myelogenous leukemia (CML) may occur at least partially because leukemia stem cells (LSCs) lack sensitivity to tyrosine kinase inhibitors (TKIs) such as imatinib. The precise regulation of LSC stemness is incompletely understood. Given that traits of LSCs are subject to epigenetic regulation, we hypothesized that LSCs might be dependent on continuous active transcription of genes associated with super-enhancers (SEs), which might, in turn, suggest an opportunity for intervention. In this study, we tested this hypothesis and delineated the SE landscape in LSCs from patients with CML. Disruption of the SE-associated gene transcription by THZ1, a covalent cyclin-dependent kinase 7 (CDK7) inhibitor, efficiently eradicated LSCs in retroviral BCR-ABL–driven CML mice while sparing normal hematopoietic stem cells. Furthermore, we found that X-box binding protein 1 (

Deep Reinforcement Learning (Deep RL) agents have in recent years emerged as successful models of animal behavior in a variety of complex learning tasks, as exemplified by Song et al. [2017]. As agents are typically trained to mimic an animal subject, the emphasis in past studies on behavior as a means of evaluating the fitness of models to experimental data is only natural. But the true power of Deep RL agents lies in their ability to learn neural computations and codes that generate a particular behavior—factors that are also of great relevance and interest to computational neuroscience. On that basis, we believe that model evaluation should include an examination of neural representations and validation against neural recordings from animal subjects. In this paper, we introduce a procedure to test hypotheses about the relationship between internal representations of Deep RL agents and those in animal neural recordings. Taking a sequential learning task as a running example, we apply our method and show that the geometry of representations learnt by artificial agents is similar to that of the biological subjects’, and that such similarities are driven by shared information in some latent space. Our method is applicable to any Deep RL agent that learns a Markov Decision Process, and as such enables researchers to assess the suitability of more advanced Deep Learning modules, or map hierarchies of representations to different parts of a circuit in the brain, and help shed light on their function. To demonstrate that point, we conduct an ablation study to deduce that, in the sequential task under consideration, temporal information plays a key role in molding a correct representation of the task.

Online monitoring and closed-loop control are essential to accurately remove the rust layer and effectively avoid damage to the substrate. A collaborative utilization of machine vision and laser-induced breakdown spectroscopy (LIBS) to monitor and control the laser derusting process on Q235B steel is reported. The optimum overlap ratio of 50% is obtained by using machine vision. Monitoring derusting with different thicknesses relies on the Pearson correlation coefficient of the LIBS spectrum between the rust layer and substrate. By developing a collaborative monitoring and control system on LabVIEW, the functions of date acquisition, coordinate transformation, and data calculation are realized to automatically control the laser derusting process on rusty steel in a large area. The cooperation of two methods can achieve high-quality laser derusting with a derusting degree of 99.1%, roughness of 1.45 µm, and extremely low oxygen content on the surface, which verifies the accuracy and practicability of the developed monitoring system. Moreover, the potentiodynamic polarization curves demonstrate that the performance of the corrosion resistance of the Q235B steel is effectively improved after laser derusting.

The orbitofrontal cortex (OFC) has been proposed to encode expected outcomes, which is thought to be important for outcome-directed behavior. However, such neural encoding can also often be explained by the recall of information about the recent past. To dissociate the retrospective and prospective aspects of encoding in the OFC, we designed a non-spatial, continuous, alternating odor-sequence task that mimicked a continuous T-maze. The task consisted of two alternating sequences of four odor-guided trials (2 sequences × 4 positions). In each trial, rats were asked to make a “go” or “no-go” action based on a fixed odor-reward contingency. Odors at both the first and last positions were distinct across the two sequences, such that they resembled unique paths in the past and future, respectively; odors at positions in between were the same and thus resembled a common path. We trained classifiers using neural activity to distinguish between either sequences or positions and asked whether the neural activity patterns in the common path were more like the ones in the past or the future. We found a proximal prospective code for sequence information as well as a distal prospective code for positional information, the latter of which was closely associated with rats’ ability to predict future outcomes. This study demonstrates a prospective behaviorally-relevant predictive code in rat OFC.

In the combined mining of ultra-close multiple seams with thin upper seam and thick lower seam, the mining of thin upper seam may lead to damages of the interburden and collapse of overburden. As a result, the roof of the thick lower seam in the fully mechanized caving process is turned into layers consisting of parts with different medium characteristics, in terms of damage severity and rock size, and the caving and recovery of top coal is significantly affected. Therefore, we propose a study of top coal caving and roof rock movement law under different fracture conditions based on two dimensional discrete element numerical simulation software program. The results revealed that roof rock channeling into the top coal was observed in the coal caving process in the presence of a huge difference between the lump sizes of roof rock and top coal of the lower seam, resulting in low recovery ratio. And the one cut/one caving upward caving pattern was the optimized top coal caving parameter. This study serves as a reference for future studies of top coal recovery in the combined mining of contiguous coal seams with thin upper seam and thick lower coal seam.

In order to solve the problems of heavy labor burden, cumbersome work, patients can not get comfortable care and low medical efficiency, an intelligent drip infusion control system based on Huawei Internet of things platform is designed. The system first describes the system implementation technical principle, hardware design idea, Huawei cloud platform upper management application solution idea, using NB-IoT to communicate with Huawei cloud platform, Huawei cloud server design, web back-end, web front-end and mobile app design process. The test results show that the system has the functions of web page and mobile app remote centralized monitoring, remote speed regulation and remote run out alarm, which reduces the burden of nurses, reduces the contact time between nurses and patients, and improves the medical efficiency.

Imatinib revolutionized the treatment of chronic myeloid leukemia (CML), but drug resistance and disease recurrence remain a challenge. In this study, we suggest a novel strategy based on blocking protein neddylation to address BCR-ABL point mutations and leukemia stem cells (LSC) that lie at the root of imatinib-resistant recurrences. On the basis of the finding that the NEDD8-activating enzyme subunit NAE1 is overexpressed in CML cells, we hypothesized that the function of certain neddylation-dependent protein substrates might be targeted to therapeutic ends in imatinib-resistant CML cells and LSCs. In support of this hypothesis, we demonstrated that the NAE1 inhibitor MLN4924 induced G2–M-phase arrest and apoptosis in bulk CML cells with wild-type p53, regardless of their T315I mutation status in BCR-ABL. Moreover, MLN4924 inhibited the survival and self-renewal of primary human CML CD34+ cells and LSCs in CML-bearing mice via accumulation of p27kip1 in the nucleus. Notably, p27kip1 silencing attenuated the suppressive effect of MLN4924 on the maintenance of LSCs in CML-bearing mice. Taken together, our findings offer a preclinical proof of concept for targeting protein neddylation as a novel therapeutic strategy to override mutational and LSC-derived imatinib resistance in CML. Significance: These findings highlight a mediator of protein neddylation, a type of protein turnover mechanism, as a viable therapeutic target against imatinib-resistant forms of chronic myelogenous leukemia. Cancer Res; 78(6); 1522–36. ©2018 AACR.

Neural correlates implicate the orbitofrontal cortex (OFC) in value-based or economic decision making [1-3]. Yet inactivation of OFC in rats performing a rodent version of the standard economic choice task is without effect [4, 5], a finding more in accord with ideas that the OFC is primarily necessary for behavior when new information must be taken into account [6-9]. Neural activity in the OFC spontaneously updates to reflect new information, particularly about outcomes [10-16], and the OFC is necessary for adjustments to learned behavior only under these conditions [4, 16-26]. Here, we merge these two independent lines of research by inactivating lateral OFC during an economic choice that requires new information about the value of the predicted outcomes to be incorporated into an already established choice. Outcome value was changed by pre-feeding the rats one of two food options before testing. In control rats, this pre-feeding resulted in divergent changes in choice behavior that depended on the rats' prior preference for the pre-fed food. Optogenetic inactivation of the OFC disrupted this bi-directional effect of pre-feeding without affecting other measures that describe the underlying choice behavior. This finding unifies the role of the OFC in economic choice with its role in a host of other behaviors, causally demonstrating that the OFC is not necessary for economic choice per se-unless that choice incorporates new information about the outcomes.

Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm primarily due to the presence of the BCR-ABL fusion gene that produces the constitutively active protein, BCR-ABL. Imatinib, a BCR-ABL-targeted drug, is a first-line drug for the treatment of CML. Resistance to imatinib occurs as a result of mutations in the BCR-ABL kinase domains. In this study, we evaluated S116836, a novel BCR-ABL inhibitor, for its anti-cancer efficacy in the wild-type (WT) and T315I mutant BCR-ABL. S116836 was efficacious in BaF3 cells with WT or T315I mutated BCR-ABL genotypes. S116836 inhibits the phosphorylation of BCR-ABL and its downstream signaling in BaF3/WT and BaF3/T315I cells. Mechanistically, S116836 arrests the cells in the G0/G1 phase of cell cycle, induces apoptosis, increases ROS production, and decreases GSH production in BaF3/WT and BaF3/T315I cells. Moreover, in mouse tumor xenografts, S116836 significantly inhibits the growth and volume of tumors expressing the WT or T315I mutant BCR-ABL without causing significant cardiotoxicity. Overall, our results indicate that S116836 significantly inhibits the imatinib-resistant T315I BCR-ABL mutation and could be a novel drug candidate for treating imatinib-resistant CML patients.

Background Uveal melanoma (UM) is the most common primary intraocular tumor. Hepatic metastasis is the major and direct death-related reason in UM patients. Given that cancer stem-like cells (CSCs) are roots of metastasis, targeting CSCs may be a promising strategy to overcome hepatic metastasis in UM. Salinomycin, which has been identified as a selective inhibitor of CSCs in multiple types of cancer, may be an attractive agent against CSCs thereby restrain hepatic metastasis in UM. The objective of the study is to explore the antitumor activity of salinomycin against UM and clarify its underlying mechanism. Methods UM cells were treated with salinomycin, and its effects on cell proliferation, apoptosis, migration, invasion, CSCs population, and the related signal transduction pathways were determined. The in vivo antitumor activity of salinomycin was evaluated in the NOD/SCID UM xenograft model and intrasplenic transplantation liver metastasis mouse model. Results We found that salinomycin remarkably obviated growth and survival in UM cell lines and in a UM xenograft mouse model. Meanwhile, salinomycin significantly eliminated CSCs and efficiently hampered hepatic metastasis in UM liver metastasis mouse model. Mechanistically, Twist1 was fundamental for the salinomycin-enabled CSCs elimination and migration/invasion blockage in UM cells. Conclusions Our findings suggest that targeting UM CSCs by salinomycin is a promising therapeutic strategy to hamper hepatic metastasis in UM. These results provide the first pre-clinical evidence for further testing of salinomycin for its antitumor efficacy in UM patients with hepatic metastasis.