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Dual specificity tyrosine phosphorylation regulated kinase 1A, DYRK1A, functions in multiple cellular pathways, including signaling, endocytosis, synaptic transmission, and transcription. Alterations in dosage of DYRK1A leads to defects in neurogenesis, cell growth, and differentiation, and may increase the risk of certain cancers. DYRK1A localizes to a number of subcellular structures including vesicles where it is known to phosphorylate a number of proteins and regulate vesicle biology. However, the mechanism by which it translocates to vesicles is poorly understood. Here we report the discovery of TRAF2, an E3 ligase, as an interaction partner of DYRK1A. Our data suggest that TRAF2 binds to PVQE motif residing in between the PEST and histidine repeat domain (HRD) of DYRK1A protein, and mediates K63-linked ubiquitination of DYRK1A. This results in translocation of DYRK1A to the vesicle membrane. DYRK1A increases phosphorylation of Sprouty 2 on vesicles, leading to the inhibition of EGFR degradation, and depletion of TRAF2 expression accelerates EGFR degradation. Further, silencing of DYRK1A inhibits the growth of glioma cells mediated by TRAF2. Collectively, these findings suggest that the axis of TRAF2–DYRK1A-Sprouty 2 can be a target for new therapeutic development for EGFR-mediated human pathologies.

Tumor hypoxia and circular RNAs (circRNAs) are considered to play key roles in tumor progression and malignancy, respectively. Nevertheless, the biological functions and underlying mechanisms of specific circRNAs exposed to hypoxic microenvironments in colorectal cancer (CRC) remain largely elusive. Herein, a novel circRNA, circTDRD3, which is upregulated under hypoxic conditions, was identified. The expression of circTDRD3 was highly expressed in CRC tissues and positively correlated with overall survival, tumor size, lymph node invasion and clinical stage. CircTDRD3 facilitated CRC cell proliferation, migration and metastasis in vitro and in vivo. Mechanistically, circTDRD3 promoted HIF1α expression by sponging miR-1231, which facilitated CRC progression. Meanwhile, HIF1α directly combined with TDRD3 promoter to increase the expression of TDRD3 pre-mRNA. Then HIF1a-induced PTBP1 accelerated the formation of circTDRD3. Our findings reveal that circTDRD3 facilitates the proliferation and metastasis of CRC through a positive feedback loop mediated by the HIF1α/PTBP1/circTDRD3/miR-1231/HIF1α axis. Therefore, circTDRD3 may serve as a prognostic biomarker and therapeutic target for patients with CRC.

Chronic myeloid leukemia (CML) originates from normal hematopoietic stem cells acquiring BCR-ABL fusion gene, specific BCR-ABL inhibitors (e.g., imatinib mesylate, IM) have greatly improved patient management. However, some patients are still suffering from relapse and drug resistance, which urges better understanding of the growth/survival mechanisms of CML stem/progenitor cells. In the present study, the role and its underlying mechanism of heterogeneous nuclear ribonucleoprotein D-like (HNRPDL) in CML cells were investigated. Firstly, overexpression of HNRPDL promoted the growth of murine BaF3 cells in vitro and induced leukemia in vivo, which was enhanced by co-expression of BCR-ABL. Conversely, HNRPDL silencing inhibited colony-forming cell (CFC) production of CML CD34+ cells and attenuated BCR-ABL induced leukemia. In addition, HNRPDL modulated imatinib response of K562 cells and HNRPDL silencing sensitized CML CD34+ cells to imatinib treatment. Mechanistically, we found the stability of pre-B-cell leukemia homeobox 1 (PBX1) mRNA was sustained by HNRPDL through its binding to a specific motif (ACUAGC) in 3′-untranslated region (3′-UTR) of PBX1. The expression of PBX1 was significantly higher in CML CD34+ cells than that in control cells and PBX silencing inhibited the growth of CML cells and sensitized them to imatinib treatment. In contrast, overexpression of PBX1 elevated the CFC production of normal hematopoietic CD34+ cells and “rescued” HNRPDL silencing induced growth inhibition and imatinib sensitization. Taken together, our data have demonstrated that HNRPDL transforms hematopoietic cells and a novel HNRPDL/PBX1 axis plays an important role in human CML CD34+ cells.

The role of conventional serum tumor marker, carbohydrate antigen 72-4 (CA72-4), in assisting diagnosis, monitoring dynamic progression, and evaluating the prognosis of gastric cancer (GC) should not be ignored, especially in the Chinese population. Even though CA72-4 has been used in clinical practice for decades, its modest positivity rate, sensitivity, and specificity did not meet the high demand of the clinical application. However, over the years, some progress in the functions of CA72-4 has been achieved, suggesting that CA72-4 can still be considered a promising marker in oncology. As a biomarker, CA72-4 can achieve improved sensitivity (SEN) and specificity (SPE) when combined with other biomarkers, selecting suitable reference values, improving detection techniques, and identifying the risk threshold. As a predictor, elevated serum CA72-4 levels were found to be significantly associated with prognostic risk factors, further assessing therapeutic validity and resectability. Recently, an effective method to reduce the toxicity of CA72-4 targeted therapy has been developed. Moreover, CA72-4 could induce novel aptamers to react with tumor cells and enhance the efficacy of trastuzumab in HER2-positive GC. Therefore, in this review, we discuss the most recent application of CA72-4 in the diagnosis, prognosis, and treatment of GC.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) represent a large family of RNA-binding proteins. Heterogeneous nuclear ribonucleoprotein D-like (HNRPDL) is a member of this family. Though aberrant expression of HNRPDL has been reported in a few cancers, whether HNRPDL is deregulated in colon cancer patients and what role this protein plays in these cells are not known yet. In this study, we found that HNRPDL was significantly up-regulated in colon cancer specimens than control. We also demonstrated that HNRPDL silencing inhibited the growth of SW620 cells both in vitro and in vivo. Conversely, we constructed a retroviral vector to deliver HNRPDL into non-malignant NIH-3T3 cells and injected these cells into nude mice. HNRPDL-overexpressing NIH-3T3 cells generated tumors in nude mice but not the control cells. Mechanistically, HNRPDL promoted cell-cycle progression associated with enhanced expressions of cyclin D3 and Ki-67 but decreased expressions of p53 and p21. Taken together, our data demonstrate that HNRPDL is aberrantly expressed in colon cancer cells, which promotes the growth of these cells by activating cell-cycle progression.

Chronic myeloid leukemia (CML) originates from normal hematopoietic stem cells acquiring BCR-ABL fusion gene, specific BCR-ABL inhibitors (e.g., imatinib mesylate, IM) have greatly improved patient management. However, some patients are still suffering from relapse and drug resistance, which urges better understanding of the growth/survival mechanisms of CML stem/progenitor cells. In the present study, the role and its underlying mechanism of heterogeneous nuclear ribonucleoprotein D-like (HNRPDL) in CML cells were investigated. Firstly, overexpression of HNRPDL promoted the growth of murine BaF3 cells in vitro and induced leukemia in vivo, which was enhanced by co-expression of BCR-ABL. Conversely, HNRPDL silencing inhibited colony-forming cell (CFC) production of CML CD34

Effectively detecting pH changes plays a critical role in exploring cellular functions and determining physiological and pathological processes. A novel ratiometric pH probe based on a glycopolymer, armored with properties of serum-stability, tumor-targeting, and pH monitoring, is designed. Random copolymers of 2-(methacrylamido) glucopyranose and fluorescein O-methacrylate are first synthesized by reversible addition fragmentation chain transfer polymerization. Acryloxyethyl thiocarbamoyl rhodamine B is then attached to the polymer chain to prepare ratiometric fluorescent pH probes via a thiol-ene reaction. The synthesized polymeric probes are characterized by NMR, gel permeation chromatography, UV-vis spectroscopy, and transmission electron microscopy, and the fluorescence responses are examined in phosphate buffer at different pHs. The cytotoxicity and confocal imaging experiments of the probes are detected using HeLa cells, demonstrating a low toxicity and superior biocompatibility for detecting pH changes in bioapplications.

Many distributed computing applications need transfer large files between distributed locations as fast as possible. A dynamic routing algorithm for optical network is designed to modify existing transfers and spare network resources for new request to satisfy both old and new transfers' requirements. In data intensive application on circuit-switch optical network, light-path resources are scarce and there should be concurrent file transfers competing for the same fibers. In static routing optical network, if new coming file transfer cannot acquire light-path with enough bandwidth, it could only wait for the releasing of current used resources. Due to the waiting, the delay time will be large. So we use our dynamic routing algorithm to schedule and modify existing light-paths, to spare a light-path with enough bandwidth for new coming file. Our optimized target is to make every file finish transferring in less time, so we propose two objectives defined in the paper: one is to make maximal delay time of all tasks less and the other is to make average delay time less. The algorithm proposed has two mainly steps: 1) Routing process; 2) Dynamic routing process. In routing step, when task of file arrives we firstly get k random paths, then use Least Congestion Algorithm (LCA) (or Shortest Path Algorithm (SPA)) to get the primary path P1 of maximal residual bandwidth (RB) from k paths and the alternate path P2 of the second maximal RB. If the bandwidth of P1 is enough for this task, transfer the file in P1 path. If not, we go to the dynamic routing process. In the second process, get all the links of P1 then we change the existing light paths of tasks in the P1 path one by one to their alternative paths until we can get enough bandwidth of P1. In the dynamic routing process, we design two different queuing strategies. The first strategy is First Arrive First Modified (FAFM) strategy, namely we schedule the first arrival task firstly. The other is Larger Bandwidth First Modified (LBFM) and the file with larger bandwidth is scheduled firstly. By comparison of simulation results, we can prove that our two kinds of dynamic routing algorithms can get better results for both decreasing maximal delay time and average delay time than LCA and SPA routing algorithms. In the two queuing strategies, LBFM can get better results than FAFM strategy. The receivers in the destinations can get better results by using our dynamic routing algorithm.

Optical Grid that provides a way to integrate the geographical distributed resources for large- scale grid applications. This paper mainly focuses on the task scheduling issue in Optical Grid and proposes two task scheduling algorithms to mini-mize the total time or scheduling length required for a given task. A simulated optical grid has been addressed to demon-strate the effectiveness of the schedulin g approach. The performance tests and anal ysis of the two algorithms are investi-gated to show the effect of the routing policy on the schedulin g length. A more flexible policy is able to further improve scheduling length. Keywords: Optical Grid, Task Scheduling Algorithm, Communication Contention I INTRODUCTION Distributed computing, also known as computational Grid, is a technology that makes it possible to utilize the geographi-cal distributed computational resources to solve the intensive computation of large-scale data. Most Grid systems were built over the IP packet switched networks in the past. In the situation when some data-intensive Grid applications re-quire moving Gigabytes or even larger of data, the low speed of the network becomes the bottleneck of Grid system, which could not allow the remote resources to be used efficiently. Nowadays the optical network with Synchronous Digital Hierarchy (SDH), Wavelength-D ivision Multiplexing (WDM), and Automa tic Switched Optical Network (ASON) infrastructure can provide a much larger amount of bandwidth than the electronic network, such as IP packet switched network. Therefore, it is significant to use the optical network as the network infrastructure of the computational Grid. We refer to this infrastructure as Optical Grid, which employs optical network to interconnect grid computational re-sources (e.g. supercomputers, computer clusters, storage and display devices) with dynamically provisioned lightpaths [1]. It has been realized that task scheduling is a fundamental issue in achieving high performance in grid environments [6]. Task scheduling aims to optimize the overall performance of a system, e.g., minimizing the average job response time and maximizing the number of jobs exec uted in certain period of time. Optical grid task scheduling is quite different from classic grid task scheduling model. In Optical Grid system, we can treat the optical network as a kind of resource, the scheduling algorithm in Optical Grid system should schedule the tasks to appropriate resources as we ll as scheduling the communications between tasks to appropriate optical links. The objec-tive of task scheduling is to minimize the completion time (we called it as scheduling length or make span ) of an appli-cation. Usually, this problem is modeled and solved under several assumptions. Unless the assumptions are simplified enough, the problem has been proven to be NP-complete [8]. Therefore, many heuristic algorithms have been proposed. But these heuristics either are based on the assumption that the processors are fully connected, or just don’t take into ac-count the optical network’s characters, es pecially the characters of WDM optical network. While actually, in the Optical Grid system, the computational resources are more likely not fully connected, and the communication contention is an important factor that affects the completion time of a Grid application. Thus, a new heuris tic algorithm that can schedule tasks and also the communications are needed. In this paper, we mainly focus on the static scheduling problem, which means the character of the Grid applica tion, including the task execution times, task dependencies, task communications and synchronization are known a priori.