WorldWideScience

Sample records for multiple checkpoint proficiency

  1. Multiple functions of the S-phase checkpoint mediator.

    Tanaka, Katsunori

    2010-01-01

    There is mounting evidence that replication defects are the major source of spontaneous genomic instability in cells, and that S-phase checkpoints are the principal defense against such instability. The S-phase checkpoint mediator protein Mrc1/Claspin mediates the checkpoint response to replication stress by facilitating phosphorylation of effector kinase by a sensor kinase. In this review, the multiple functions and the regulation of the S-phase checkpoint mediator are discussed.

  2. Multiple Duties for Spindle Assembly Checkpoint Kinases in Meiosis

    Marston, Adele L.; Wassmann, Katja

    2017-01-01

    Cell division in mitosis and meiosis is governed by evolutionary highly conserved protein kinases and phosphatases, controlling the timely execution of key events such as nuclear envelope breakdown, spindle assembly, chromosome attachment to the spindle and chromosome segregation, and cell cycle exit. In mitosis, the spindle assembly checkpoint (SAC) controls the proper attachment to and alignment of chromosomes on the spindle. The SAC detects errors and induces a cell cycle arrest in metaphase, preventing chromatid separation. Once all chromosomes are properly attached, the SAC-dependent arrest is relieved and chromatids separate evenly into daughter cells. The signaling cascade leading to checkpoint arrest depends on several protein kinases that are conserved from yeast to man. In meiosis, haploid cells containing new genetic combinations are generated from a diploid cell through two specialized cell divisions. Though apparently less robust, SAC control also exists in meiosis. Recently, it has emerged that SAC kinases have additional roles in executing accurate chromosome segregation during the meiotic divisions. Here, we summarize the main differences between mitotic and meiotic cell divisions, and explain why meiotic divisions pose special challenges for correct chromosome segregation. The less-known meiotic roles of the SAC kinases are described, with a focus on two model systems: yeast and mouse oocytes. The meiotic roles of the canonical checkpoint kinases Bub1, Mps1, the pseudokinase BubR1 (Mad3), and Aurora B and C (Ipl1) will be discussed. Insights into the molecular signaling pathways that bring about the special chromosome segregation pattern during meiosis will help us understand why human oocytes are so frequently aneuploid. PMID:29322045

  3. Multiple Duties for Spindle Assembly Checkpoint Kinases in Meiosis

    Adele L. Marston

    2017-12-01

    Full Text Available Cell division in mitosis and meiosis is governed by evolutionary highly conserved protein kinases and phosphatases, controlling the timely execution of key events such as nuclear envelope breakdown, spindle assembly, chromosome attachment to the spindle and chromosome segregation, and cell cycle exit. In mitosis, the spindle assembly checkpoint (SAC controls the proper attachment to and alignment of chromosomes on the spindle. The SAC detects errors and induces a cell cycle arrest in metaphase, preventing chromatid separation. Once all chromosomes are properly attached, the SAC-dependent arrest is relieved and chromatids separate evenly into daughter cells. The signaling cascade leading to checkpoint arrest depends on several protein kinases that are conserved from yeast to man. In meiosis, haploid cells containing new genetic combinations are generated from a diploid cell through two specialized cell divisions. Though apparently less robust, SAC control also exists in meiosis. Recently, it has emerged that SAC kinases have additional roles in executing accurate chromosome segregation during the meiotic divisions. Here, we summarize the main differences between mitotic and meiotic cell divisions, and explain why meiotic divisions pose special challenges for correct chromosome segregation. The less-known meiotic roles of the SAC kinases are described, with a focus on two model systems: yeast and mouse oocytes. The meiotic roles of the canonical checkpoint kinases Bub1, Mps1, the pseudokinase BubR1 (Mad3, and Aurora B and C (Ipl1 will be discussed. Insights into the molecular signaling pathways that bring about the special chromosome segregation pattern during meiosis will help us understand why human oocytes are so frequently aneuploid.

  4. Arabidopsis ARGONAUTE7 selects miR390 through multiple checkpoints during RISC assembly.

    Endo, Yayoi; Iwakawa, Hiro-oki; Tomari, Yukihide

    2013-07-01

    Plant ARGONAUTE7 (AGO7) assembles RNA-induced silencing complex (RISC) specifically with miR390 and regulates the auxin-signalling pathway via production of TAS3 trans-acting siRNAs (tasiRNAs). However, how AGO7 discerns miR390 among other miRNAs remains unclear. Here, we show that the 5' adenosine of miR390 and the central region of miR390/miR390* duplex are critical for the specific interaction with AGO7. Furthermore, despite the existence of mismatches in the seed and central regions of the duplex, cleavage of the miR390* strand is required for maturation of AGO7-RISC. These findings suggest that AGO7 uses multiple checkpoints to select miR390, thereby circumventing promiscuous tasiRNA production.

  5. Acquisition of Skill Proficiency Over Multiple Sessions of a Novel Rover Simulation

    Dean, S. L.; DeDios,Y. E.; MacDougall, H. G.; Moore, S. T.; Wood, S. J.

    2011-01-01

    Following long-duration exploration transits, adaptive changes in sensorimotor function may impair the crew's ability to safely perform manual control tasks such as operating pressurized rovers. Postflight performance will also be influenced by the level of preflight skill proficiency they have attained. The purpose of this study was to characterize the acquisition of skills in a motion-based rover simulation over multiple sessions, and to investigate the effects of varying the simulation scenarios. METHODS: Twenty healthy subjects were tested in 5 sessions, with 1-3 days between sessions. Each session consisted of a serial presentation of 8 discrete tasks to be completed as quickly and accurately as possible. Each task consisted of 1) perspective-taking, using a map that defined a docking target, 2) navigation toward the target around a Martian outpost, and 3) docking a side hatch of the rover to a visually guided target. The simulator utilized a Stewart-type motion base (CKAS, Australia), single-seat cabin with triple scene projection covering 150 deg horizontal by 50 deg vertical, and joystick controller. Subjects were randomly assigned to a control group (tasks identical in the first 4 sessions) or a varied-practice group. The dependent variables for each task included accuracy toward the target and time to completion. RESULTS: The greatest improvements in time to completion occurred during the docking phase. The varied-practice group showed more improvement in perspective-taking accuracy. Perspective-taking accuracy was also affected by the relative orientation of the rover to the docking target. Skill acquisition was correlated with self-ratings of previous gaming experience. DISCUSSION: Varying task selection and difficulty will optimize the preflight acquisition of skills when performing novel operational tasks. Simulation of operational manual control will provide functionally relevant evidence regarding the impact of sensorimotor adaptation on early

  6. Speaking in Multiple Languages: Neural Correlates of Language Proficiency in Multilingual Word Production

    Videsott, Gerda; Herrnberger, Barbel; Hoenig, Klaus; Schilly, Edgar; Grothe, Jo; Wiater, Werner; Spitzer, Manfred; Kiefer, Markus

    2010-01-01

    The human brain has the fascinating ability to represent and to process several languages. Although the first and further languages activate partially different brain networks, the linguistic factors underlying these differences in language processing have to be further specified. We investigated the neural correlates of language proficiency in a…

  7. An Iterative Maximum a Posteriori Estimation of Proficiency Level to Detect Multiple Local Likelihood Maxima

    Magis, David; Raiche, Gilles

    2010-01-01

    In this article the authors focus on the issue of the nonuniqueness of the maximum likelihood (ML) estimator of proficiency level in item response theory (with special attention to logistic models). The usual maximum a posteriori (MAP) method offers a good alternative within that framework; however, this article highlights some drawbacks of its…

  8. Identifying College Students' Multiple Intelligences to Enhance Motivation and Language Proficiency

    Madkour, Magda; Mohamed, Rafik Ahmed Abdel Moati

    2016-01-01

    While most research studies on the theory of multiple intelligences focused on the application of the multiple intelligences domains as separate components, this quasi-experimental research targeted the effect of multiple intelligences as integrated abilities for teaching and learning English at higher education. The purpose of this study was to…

  9. Relationship between Multiple Intelligence, Reading Proficiency, and Implementing Motivational Strategies: A Study of Iranian Secondary Students

    Fayazi-Nasab, Ensieh; Ghafournia, Narjes

    2016-01-01

    There exist many factors, affecting reading ability. Multiple intelligence and motivational strategies are among the factors that seem to make significant contribution to the reading process. Thus, the present study probed the probable significant relation between Iranian language learners' multiple intelligences and reading ability. The study…

  10. Detailed Modeling and Evaluation of a Scalable Multilevel Checkpointing System

    Mohror, Kathryn [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Moody, Adam [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Bronevetsky, Greg [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); de Supinski, Bronis R. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2014-09-01

    High-performance computing (HPC) systems are growing more powerful by utilizing more components. As the system mean time before failure correspondingly drops, applications must checkpoint frequently to make progress. But, at scale, the cost of checkpointing becomes prohibitive. A solution to this problem is multilevel checkpointing, which employs multiple types of checkpoints in a single run. Moreover, lightweight checkpoints can handle the most common failure modes, while more expensive checkpoints can handle severe failures. We designed a multilevel checkpointing library, the Scalable Checkpoint/Restart (SCR) library, that writes lightweight checkpoints to node-local storage in addition to the parallel file system. We present probabilistic Markov models of SCR's performance. We show that on future large-scale systems, SCR can lead to a gain in machine efficiency of up to 35 percent, and reduce the load on the parallel file system by a factor of two. In addition, we predict that checkpoint scavenging, or only writing checkpoints to the parallel file system on application termination, can reduce the load on the parallel file system by 20 × on today's systems and still maintain high application efficiency.

  11. On the Relationship of Multiple Intelligences with Listening Proficiency and Attitudes among Iranian TEFL University Students

    Naeini, Ma'ssoumeh Bemani; Pandian, Ambigapathy

    2010-01-01

    Gardner's (1983) Multiple Intelligences Theory (MIT) has been found to have profound implications in teaching English as a foreign language (TEFL) in that it provides a way for teachers to recognize learners' individual cognitive and affective differences by providing favorable motivational conditions for learning. However, little investigation…

  12. Southeast Asian Languages Proficiency Examinations.

    Brown, James Dean; And Others

    The design, administration, revision, and validation of the Southeast Asian Summer Studies Institute proficiency examinations are reported. The examinations were created as parallel language proficiency tests in each of five languages: Indonesian, Khmer, Tagalog, Thai, and Vietnamese. Four tests were developed in each language: multiple-choice…

  13. Role of the Checkpoint Clamp in DNA Damage Response

    Mihoko Kai

    2013-01-01

    Full Text Available DNA damage occurs during DNA replication, spontaneous chemical reactions, and assaults by external or metabolism-derived agents. Therefore, all living cells must constantly contend with DNA damage. Cells protect themselves from these genotoxic stresses by activating the DNA damage checkpoint and DNA repair pathways. Coordination of these pathways requires tight regulation in order to prevent genomic instability. The checkpoint clamp complex consists of Rad9, Rad1 and Hus1 proteins, and is often called the 9-1-1 complex. This PCNA (proliferating cell nuclear antigen-like donut-shaped protein complex is a checkpoint sensor protein that is recruited to DNA damage sites during the early stage of the response, and is required for checkpoint activation. As PCNA is required for multiple pathways of DNA metabolism, the checkpoint clamp has also been implicated in direct roles in DNA repair, as well as in coordination of the pathways. Here we discuss roles of the checkpoint clamp in DNA damage response (DDR.

  14. Action-oriented use of ergonomic checkpoints for healthy work design in different settings.

    Kogi, Kazutaka

    2007-12-01

    Recent experiences in the action-oriented use of ergonomic checkpoints in different work settings are reviewed. The purpose is to know what features are useful for healthy work design adjusted to each local situation. Based on the review results, common features of ergonomic checkpoints used in participatory training programs for improving workplace conditions in small enterprises, construction sites, home work and agriculture in industrially developing countries in Asia are discussed. These checkpoints generally compile practical improvement options in a broad range of technical areas, such as materials handling, workstation design, physical environment and work organization. Usually, "action checklists" comprising the tiles of the checkpoints are used together. A clear focus is placed on readily applicable low-cost options. Three common features of these various checkpoints appear to be important. First, the checkpoints represent typical good practices in multiple areas. Second, each how-to section of these checkpoints presents simple improvements reflecting basic ergonomic principles. Examples of these principles include easy reach, fewer and faster transport, elbow-level work, coded displays, isolated or screened hazards and shared teamwork. Third, the illustrated checkpoints accompanied by corresponding checklists are used as group work tools in short-term training courses. Many practical improvements achieved are displayed in websites for inter-country work improvement networks. It is suggested to promote the use of locally adjusted checkpoints in various forms of participatory action-oriented training in small-scale workplaces and in agriculture particularly in industrially developing countries.

  15. Efficient Incremental Checkpointing of Java Programs

    Lawall, Julia Laetitia; Muller, Gilles

    2000-01-01

    This paper investigates the optimization of language-level checkpointing of Java programs. First, we describe how to systematically associate incremental checkpoints with Java classes. While being safe, the genericness of this solution induces substantial execution overhead. Second, to solve...

  16. Network support for system initiated checkpoints

    Chen, Dong; Heidelberger, Philip

    2013-01-29

    A system, method and computer program product for supporting system initiated checkpoints in parallel computing systems. The system and method generates selective control signals to perform checkpointing of system related data in presence of messaging activity associated with a user application running at the node. The checkpointing is initiated by the system such that checkpoint data of a plurality of network nodes may be obtained even in the presence of user applications running on highly parallel computers that include ongoing user messaging activity.

  17. Checkpointing for a hybrid computing node

    Cher, Chen-Yong

    2016-03-08

    According to an aspect, a method for checkpointing in a hybrid computing node includes executing a task in a processing accelerator of the hybrid computing node. A checkpoint is created in a local memory of the processing accelerator. The checkpoint includes state data to restart execution of the task in the processing accelerator upon a restart operation. Execution of the task is resumed in the processing accelerator after creating the checkpoint. The state data of the checkpoint are transferred from the processing accelerator to a main processor of the hybrid computing node while the processing accelerator is executing the task.

  18. Immune-Checkpoint Blockade and Active Immunotherapy for Glioma

    Ahn, Brian J. [Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Pollack, Ian F. [Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Okada, Hideho, E-mail: okadah@upmc.edu [Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States)

    2013-11-01

    Cancer immunotherapy has made tremendous progress, including promising results in patients with malignant gliomas. Nonetheless, the immunological microenvironment of the brain and tumors arising therein is still believed to be suboptimal for sufficient antitumor immune responses for a variety of reasons, including the operation of “immune-checkpoint” mechanisms. While these mechanisms prevent autoimmunity in physiological conditions, malignant tumors, including brain tumors, actively employ these mechanisms to evade from immunological attacks. Development of agents designed to unblock these checkpoint steps is currently one of the most active areas of cancer research. In this review, we summarize recent progresses in the field of brain tumor immunology with particular foci in the area of immune-checkpoint mechanisms and development of active immunotherapy strategies. In the last decade, a number of specific monoclonal antibodies designed to block immune-checkpoint mechanisms have been developed and show efficacy in other cancers, such as melanoma. On the other hand, active immunotherapy approaches, such as vaccines, have shown encouraging outcomes. We believe that development of effective immunotherapy approaches should ultimately integrate those checkpoint-blockade agents to enhance the efficacy of therapeutic approaches. With these agents available, it is going to be quite an exciting time in the field. The eventual success of immunotherapies for brain tumors will be dependent upon not only an in-depth understanding of immunology behind the brain and brain tumors, but also collaboration and teamwork for the development of novel trials that address multiple layers of immunological challenges in gliomas.

  19. Immune-Checkpoint Blockade and Active Immunotherapy for Glioma

    Ahn, Brian J.; Pollack, Ian F.; Okada, Hideho

    2013-01-01

    Cancer immunotherapy has made tremendous progress, including promising results in patients with malignant gliomas. Nonetheless, the immunological microenvironment of the brain and tumors arising therein is still believed to be suboptimal for sufficient antitumor immune responses for a variety of reasons, including the operation of “immune-checkpoint” mechanisms. While these mechanisms prevent autoimmunity in physiological conditions, malignant tumors, including brain tumors, actively employ these mechanisms to evade from immunological attacks. Development of agents designed to unblock these checkpoint steps is currently one of the most active areas of cancer research. In this review, we summarize recent progresses in the field of brain tumor immunology with particular foci in the area of immune-checkpoint mechanisms and development of active immunotherapy strategies. In the last decade, a number of specific monoclonal antibodies designed to block immune-checkpoint mechanisms have been developed and show efficacy in other cancers, such as melanoma. On the other hand, active immunotherapy approaches, such as vaccines, have shown encouraging outcomes. We believe that development of effective immunotherapy approaches should ultimately integrate those checkpoint-blockade agents to enhance the efficacy of therapeutic approaches. With these agents available, it is going to be quite an exciting time in the field. The eventual success of immunotherapies for brain tumors will be dependent upon not only an in-depth understanding of immunology behind the brain and brain tumors, but also collaboration and teamwork for the development of novel trials that address multiple layers of immunological challenges in gliomas

  20. Proficiency tests, Evaluating

    Cofino, W.P.; Molenaar, J.; Torfs, P.J.J.F.

    2017-01-01

    Marine monitoring programs provide data that are essential for marine management. The reliability of such data is underpinned by proficiency tests. In the context of Quasimeme, a proficiency testing program for the marine environment, a statistical model has been developed in 2000 to evaluate data

  1. Cell size checkpoint control by the retinoblastoma tumor suppressor pathway.

    Fang, Su-Chiung; de los Reyes, Chris; Umen, James G

    2006-10-13

    Size control is essential for all proliferating cells, and is thought to be regulated by checkpoints that couple cell size to cell cycle progression. The aberrant cell-size phenotypes caused by mutations in the retinoblastoma (RB) tumor suppressor pathway are consistent with a role in size checkpoint control, but indirect effects on size caused by altered cell cycle kinetics are difficult to rule out. The multiple fission cell cycle of the unicellular alga Chlamydomonas reinhardtii uncouples growth from division, allowing direct assessment of the relationship between size phenotypes and checkpoint function. Mutations in the C. reinhardtii RB homolog encoded by MAT3 cause supernumerous cell divisions and small cells, suggesting a role for MAT3 in size control. We identified suppressors of an mat3 null allele that had recessive mutations in DP1 or dominant mutations in E2F1, loci encoding homologs of a heterodimeric transcription factor that is targeted by RB-related proteins. Significantly, we determined that the dp1 and e2f1 phenotypes were caused by defects in size checkpoint control and were not due to a lengthened cell cycle. Despite their cell division defects, mat3, dp1, and e2f1 mutants showed almost no changes in periodic transcription of genes induced during S phase and mitosis, many of which are conserved targets of the RB pathway. Conversely, we found that regulation of cell size was unaffected when S phase and mitotic transcription were inhibited. Our data provide direct evidence that the RB pathway mediates cell size checkpoint control and suggest that such control is not directly coupled to the magnitude of periodic cell cycle transcription.

  2. Checkpoint inhibitors in breast cancer

    Polk, Anne; Svane, Inge-Marie; Andersson, Michael

    2018-01-01

    INTRODUCTION: An increasing number of compounds directed against immune checkpoints are currently under clinical development. In this review we summarize current research in breast cancer. MATERIAL AND METHODS: A computer-based literature search was carried out using PubMed and EMBASE; data...... reported at international meetings and clinicaltrials.gov were included as well. RESULTS: The obtained overall response rate of PD-1/PD-L1 monotherapy varied from 5 to 30% in heavily pretreated triple negative breast cancer (TNBC). The median duration of progression free survival and overall survival were...... and induce long standing anti-tumor immunity in a subgroup of breast cancer patients. However, the identification of predictive biomarkers is crucial for further development of this treatment modality....

  3. Dpb11/TopBP1 plays distinct roles in DNA replication, checkpoint response and homologous recombination

    Germann, Susanne Manuela; Østergaard, Vibe Hallundbæk; Haas, Caroline

    2011-01-01

    DPB11/TopBP1 is an essential evolutionarily conserved gene involved in initiation of DNA replication and checkpoint signaling. Here, we show that Saccharomyces cerevisiae Dpb11 forms nuclear foci that localize to sites of DNA damage in G1, S and G2 phase, a recruitment that is conserved for its...... and Tel1, and of the checkpoint mediator Rad9. In a site-directed mutagenesis screen, we identify a separation-of-function mutant, dpb11-PF, that is sensitive to DSB-inducing agents yet remains proficient for DNA replication and the S-phase checkpoint at the permissive temperature. The dpb11-PF mutant...... homologue TopBP1 in Gallus gallus. Damage-induced Dpb11 foci are distinct from Sld3 replication initiation foci. Further, Dpb11 foci are dependent on the checkpoint proteins Mec3 (9-1-1 complex) and Rad24, and require the C-terminal domain of Dpb11. Dpb11 foci are independent of the checkpoint kinases Mec1...

  4. Checkpoint blockade in combination with cancer vaccines.

    Morse, Michael A; Lyerly, H Kim

    2015-12-16

    Checkpoint blockade, prevention of inhibitory signaling that limits activation or function of tumor antigen-specific T cells responses, is revolutionizing the treatment of many poor prognosis malignancies. Indeed monoclonal antibodies that modulate signaling through the inhibitory molecules CTLA-4 and PD-1 are now clinically available; however, many tumors, demonstrate minimal response suggesting the need for combinations with other therapeutic strategies. Because an inadequate frequency of activated tumor antigen-specific T cells in the tumor environment, the so-called non-inflamed phenotype, is observed in some malignancies, other rationale partners are modalities that lead to enhanced T cell activation (vaccines, cytokines, toll-like receptor agonists, and other anticancer therapies such as chemo-, radio- or targeted therapies that lead to release of antigen from tumors). This review will focus on preclinical and clinical data supporting the use of cancer vaccines with anti-CTLA-4 and anti-PD-1/PD-L1 antibodies. Preliminary preclinical data demonstrate enhanced antitumor activity although the results in human studies are less clear. Broader combinations of multiple immune modulators are now under study. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Maintenance proficiency evaluation test bank

    Maier, Loran

    2003-01-01

    The Maintenance Proficiency Evaluation Test Bank (MPETB) is an Electric Power Research Institute- (EPRJ-) operated, utility-sponsored means of developing, maintaining, and disseminating secure, high-quality written and performance maintenance proficiency tests. EPRTs charter is to ensure that all tests and test items that go into the Test Bank have been validated, screened for reliability, and evaluated to high standards of psychometric excellence. Proficiency tests of maintenance personnel.(mechanics, electricians, and instrumentation and control [I and C] technicians) are most often used to determine if an experienced employee is capable of performing maintenance tasks without further training. Such tests provide objective evidence for decisions to exempt an employee from what, for the employee, is unnecessary training. This leads to considerable savings in training costs and increased productivity because supervisors can assign personnel to tasks at which their competence is proven. The ultimate objective of proficiency evaluation is to ensure that qualified maintenance personnel are available to meet the maintenance requirements of the plant Numerous task-specific MPE tests (both written and performance) have been developed and validated using the EPRI MPE methodology by the utilities participating in the MPETB project A task-specific MPE consists of a multiple-choice written examination and a multi-step performance evaluation that can be used to assess an individual's present knowledge and skill level for a given maintenance task. The MPETB contains MPEs and test items for the mechanical, electrical, and I and C classifications that are readily available to participating utilities. Presently, utilities are placing emphasis on developing MPEs to evaluate outage-related maintenance tasks that demonstrate the competency and qualifications of plant and contractor personnel before the start of outage work. Utilities are also using the MPE methodology and process to

  6. Beyond CTLA-4 and PD-1, the generation Z of negative checkpoint regulators.

    Isabelle eLe Mercier

    2015-08-01

    Full Text Available In the last two years, clinical trials with blocking antibodies to the negative checkpoint regulators CTLA-4 and PD-1 have rekindled the hope for cancer immunotherapy. Multiple negative checkpoint regulators protect the host against autoimmune reactions but also restrict the ability of T cells to effectively attack tumors. Releasing these brakes has emerged as an exciting strategy for cancer treatment. Conversely, these pathways can be manipulated to achieve durable tolerance for treatment of autoimmune diseases and transplantation. In the future, treatment may involve combination therapy to target multiple cell types and stages of the adaptive immune responses. In this review, we describe the current knowledge on the recently discovered negative checkpoint regulators, future targets for immunotherapy.

  7. Beyond CTLA-4 and PD-1, the Generation Z of Negative Checkpoint Regulators.

    Le Mercier, Isabelle; Lines, J Louise; Noelle, Randolph J

    2015-01-01

    In the last two years, clinical trials with blocking antibodies to the negative checkpoint regulators CTLA-4 and PD-1 have rekindled the hope for cancer immunotherapy. Multiple negative checkpoint regulators protect the host against autoimmune reactions but also restrict the ability of T cells to effectively attack tumors. Releasing these brakes has emerged as an exciting strategy for cancer treatment. Conversely, these pathways can be manipulated to achieve durable tolerance for treatment of autoimmune diseases and transplantation. In the future, treatment may involve combination therapy to target multiple cell types and stages of the adaptive immune responses. In this review, we describe the current knowledge on the recently discovered negative checkpoint regulators, future targets for immunotherapy.

  8. Asynchronous Checkpoint Migration with MRNet in the Scalable Checkpoint / Restart Library

    Mohror, K; Moody, A; de Supinski, B R

    2012-03-20

    Applications running on today's supercomputers tolerate failures by periodically saving their state in checkpoint files on stable storage, such as a parallel file system. Although this approach is simple, the overhead of writing the checkpoints can be prohibitive, especially for large-scale jobs. In this paper, we present initial results of an enhancement to our Scalable Checkpoint/Restart Library (SCR). We employ MRNet, a tree-based overlay network library, to transfer checkpoints from the compute nodes to the parallel file system asynchronously. This enhancement increases application efficiency by removing the need for an application to block while checkpoints are transferred to the parallel file system. We show that the integration of SCR with MRNet can reduce the time spent in I/O operations by as much as 15x. However, our experiments exposed new scalability issues with our initial implementation. We discuss the sources of the scalability problems and our plans to address them.

  9. Molecular Mechanisms of DNA Replication Checkpoint Activation

    Bénédicte Recolin

    2014-03-01

    Full Text Available The major challenge of the cell cycle is to deliver an intact, and fully duplicated, genetic material to the daughter cells. To this end, progression of DNA synthesis is monitored by a feedback mechanism known as replication checkpoint that is untimely linked to DNA replication. This signaling pathway ensures coordination of DNA synthesis with cell cycle progression. Failure to activate this checkpoint in response to perturbation of DNA synthesis (replication stress results in forced cell division leading to chromosome fragmentation, aneuploidy, and genomic instability. In this review, we will describe current knowledge of the molecular determinants of the DNA replication checkpoint in eukaryotic cells and discuss a model of activation of this signaling pathway crucial for maintenance of genomic stability.

  10. Checkpoint inhibitors in advanced melanoma: effect on the field of immunotherapy.

    O'reilly, Aine; Larkin, James

    2017-07-01

    The success of the immune checkpoint inhibitors in melanoma has reinvigorated the field of immunotherapy. Immune checkpoint inhibitors are now the standard of care in multiple cancer types including lung cancer, head and neck cancer, urothelial cancer and renal cell cancer. The field of immunotherapy is currently expanding rapidly and will be a focus of research and development for decades to come. Areas covered: This review covers the early development of immune checkpoint inhibitors and the changes that occurred in the drug development paradigm to facilitate the development of immunotherapy. The review will summarise the areas into which immune checkpoint inhibitors have been adopted and will review the data that supported this. Furthermore, we will discuss future developments in immunotherapy and the current landscape regarding maximising the potential of immunotherapy in clinical practice. Expert commentary: In the author's opinion, the potential of immunotherapy is vast. To date immune checkpoint inhibition has already delivered durable responses in a proportion of patients with cancer types which were previously universally lethal. The future of immunotherapy will rely upon the intelligent application of translational research to clinical practice, such that immunotherapy can be effective for a wider population and maintain its current growth.

  11. Transparent checkpointing and process migration in a distributed system

    2004-01-01

    A distributed system for creating a checkpoint for a plurality of processes running on the distributed system. The distributed system includes a plurality of compute nodes with an operating system executing on each compute node. A checkpoint library resides at the user level on each of the compute nodes, and the checkpoint library is transparent to the operating system residing on the same compute node and to the other compute nodes. Each checkpoint library uses a windowed messaging logging p...

  12. Checkpointing and Recovery in Distributed and Database Systems

    Wu, Jiang

    2011-01-01

    A transaction-consistent global checkpoint of a database records a state of the database which reflects the effect of only completed transactions and not the results of any partially executed transactions. This thesis establishes the necessary and sufficient conditions for a checkpoint of a data item (or the checkpoints of a set of data items) to…

  13. Targeting the Checkpoint to Kill Cancer Cells

    Benada, Jan; Macůrek, Libor

    2015-01-01

    Roč. 6, č. 3 (2015), s. 1912-1937 ISSN 2218-273X R&D Projects: GA ČR(CZ) GA14-34264S Institutional support: RVO:68378050 Keywords : checkpoint * DNA damage response * cancer Subject RIV: EB - Genetics ; Molecular Biology

  14. Immune mediated neuropathy following checkpoint immunotherapy.

    Gu, Yufan; Menzies, Alexander M; Long, Georgina V; Fernando, S L; Herkes, G

    2017-11-01

    Checkpoint immunotherapy has revolutionised cancer therapy and is now standard treatment for many malignancies including metastatic melanoma. Acute inflammatory neuropathies, often labelled as Guillain-Barre syndrome, are an uncommon but potentially severe complication of checkpoint immunotherapy with individual cases described but never characterised as a group. We describe a case of acute sensorimotor and autonomic neuropathy following a single dose of combination ipilimumab and nivolumab for metastatic melanoma. A literature search was performed, identifying 14 other cases of acute neuropathy following checkpoint immunotherapy, with the clinical, electrophysiological and laboratory features summarised. Most cases described an acute sensorimotor neuropathy (92%) with hyporeflexia (92%) that could occur from induction up till many weeks after the final dose of therapy. In contrast to Guillain-Barre syndrome, the cerebrospinal fluid (CSF) analysis often shows a lymphocytic picture (50%) and the electrophysiology showed an axonal pattern (55%). Treatment was variable and often in combination. 11 cases received steroid therapy with only 1 death within this group, whereas of the 4 patients who did not receive steroid therapy there were 3 deaths. In conclusion checkpoint immunotherapy - induced acute neuropathies are distinct from and progress differently to Guillain-Barre syndrome. As with other immunotherapy related adverse events corticosteroid therapy should be initiated in addition to usual therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Clinical Wisdom among Proficient Nurses

    Uhrenfeldt, Lisbeth; Hall, Elisabeth

    2007-01-01

    This paperexamines clinical wisdom which has emerged from a broader study anout nurse managers´influence on proficient registered nurse turnover and retention. The purpose of the study was to increase understanding of proficient nurses´experience and clinical practice by giving voice to the nurses...

  16. Rituximab does not reset defective early B cell tolerance checkpoints

    Chamberlain, Nicolas; Massad, Christopher; Oe, Tyler; Cantaert, Tineke; Herold, Kevan C.; Meffre, Eric

    2015-01-01

    Type 1 diabetes (T1D) patients show abnormalities in early B cell tolerance checkpoints, resulting in the accumulation of large numbers of autoreactive B cells in their blood. Treatment with rituximab, an anti-CD20 mAb that depletes B cells, has been shown to preserve β cell function in T1D patients and improve other autoimmune diseases, including rheumatoid arthritis and multiple sclerosis. However, it remains largely unknown how anti–B cell therapy thwarts autoimmunity in these pathologies. Here, we analyzed the reactivity of Abs expressed by single, mature naive B cells from 4 patients with T1D before and 52 weeks after treatment to determine whether rituximab resets early B cell tolerance checkpoints. We found that anti–B cell therapy did not alter the frequencies of autoreactive and polyreactive B cells, which remained elevated in the blood of all patients after rituximab treatment. Moreover, the limited proliferative history of autoreactive B cells after treatment revealed that these clones were newly generated B cells and not self-reactive B cells that had escaped depletion and repopulated the periphery through homeostatic expansion. We conclude that anti–B cell therapy may provide a temporary dampening of autoimmune processes through B cell depletion. However, repletion with autoreactive B cells may explain the relapse that occurs in many autoimmune patients after anti–B cell therapy. PMID:26642366

  17. Extending the Binomial Checkpointing Technique for Resilience

    Walther, Andrea; Narayanan, Sri Hari Krishna

    2016-10-10

    In terms of computing time, adjoint methods offer a very attractive alternative to compute gradient information, re- quired, e.g., for optimization purposes. However, together with this very favorable temporal complexity result comes a memory requirement that is in essence proportional with the operation count of the underlying function, e.g., if algo- rithmic differentiation is used to provide the adjoints. For this reason, checkpointing approaches in many variants have become popular. This paper analyzes an extension of the so-called binomial approach to cover also possible failures of the computing systems. Such a measure of precaution is of special interest for massive parallel simulations and adjoint calculations where the mean time between failure of the large scale computing system is smaller than the time needed to complete the calculation of the adjoint information. We de- scribe the extensions of standard checkpointing approaches required for such resilience, provide a corresponding imple- mentation and discuss numerical results.

  18. National radon measurement-proficiency program: Individual proficiency report

    1992-05-01

    In February 1986, the U.S. Environmental Protection Agency (EPA) established the Radon Measurement Proficiency (RMP) Program to assist the public in identifying organizations capable of providing reliable radon measurement services. In December 1991, EPA announced the new individual proficiency listing category in the RMP Program. Individuals applying for this new listing status must demonstrate knowledge of radon measurement fundamentals by passing a written proficiency examination, maintain affiliation with an RMP listed organization, and meet other program requirements. This report lists those individuals who have met the requirements of the RMP Program as of April 30, 1992. These requirements are designed to provide minimum proficiency criteria for individuals who provide radon measurement services on-site in a residential environment

  19. National Radon Contractor Proficiency Program. Proficiency report: Supplement

    1991-02-01

    The report, a supplement to the RCP Proficiency Report, will further assist governmental officials in providing advice to the public on the selection of proficient radon mitigation contractors. These reports list 1,123 contractors who have met the requirements of the RCP Program as of December 15, 1990. The Proficiency Report provides information on each contractor's name, RCP identification number, company name, address, phone number, and geographic service area. The report provides two additional tables, indexed by company name and by RCP identification number. The report is intended to help users quickly identify a proficient contractor if only the company name is known, or to verify which contractor is associated with a particular ID number

  20. National Radon Contractor Proficiency (RCP) Program. Proficiency report, June 1991

    1991-06-01

    The primary objective of the U.S. Environmental Protection Agency's (EPA) efforts to address the indoor radon problem is to reduce radon levels in buildings throughout the country. Achieving the objective requires a nationwide supply of capable radon mitigation contractors. In the Indoor Radon Abatement Act of 1988, Congress authorized EPA to establish a program to evaluate radon mitigation contractors and to provide the information to the public in cooperation with the States. The Radon Contractor Proficiency (RCP) Program was developed to assist States, EPA Regions, local government officials, and the public in selecting contractors who have demonstrated their proficiency in reducing indoor radon levels. The program is managed by the EPA Office of Radiation Programs' Radon Division. Under the voluntary program, radon contractors demonstrate their proficiency by meeting specific Program requirements. Individual contractors who meet these requirements are then listed in periodic RCP Proficiency Reports

  1. Immune checkpoint inhibitors for metastatic bladder cancer.

    Massari, Francesco; Di Nunno, Vincenzo; Cubelli, Marta; Santoni, Matteo; Fiorentino, Michelangelo; Montironi, Rodolfo; Cheng, Liang; Lopez-Beltran, Anto; Battelli, Nicola; Ardizzoni, Andrea

    2018-03-01

    Chemotherapy has represented the standard therapy for unresectable or metastatic urothelial carcinoma for more than 20 years. The growing knowledge of the interaction between tumour and immune system has led to the advent of new classes of drugs, the immune-checkpoints inhibitors, which are intended to change the current scenario. To date, immunotherapy is able to improve the overall responses and survival. Moreover, thanks to its safety profile immune-checkpoint inhibitors could be proposed also to patients unfit for standard chemotherapy. No doubts that these agents have started a revolution expected for years, but despite this encouraging results it appears clear that not all subjects respond to these agents and requiring the development of reliable predictive response factors able to isolate patients who can more benefit from these treatments as well as new strategies aimed to improve immunotherapy clinical outcome. In this review we describe the active or ongoing clinical trials involving Programmed Death Ligand 1 (PD-L1), Programmed Death receptor 1 (PD-1) and Cytotoxic-T Lymphocyte Antigen 4 (CTLA 4) inhibitors in urothelial carcinoma focusing our attention on the developing new immune-agents and combination strategies with immune-checkpoint inhibitors. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Advances of Immune Checkpoint Inhibitors in Tumor Immunotherapy

    Guo, Qiao

    2018-01-01

    Immune checkpoints are cell surface molecules that can fine-tune the immune responses, they are crucial for modulating the duration and amplitude of immune reactions while maintaining self-tolerance in order to minimize autoimmune responses. Numerous studies have demonstrated that tumors cells can directly express immune-checkpoint molecules, or induce many inhibitory molecules expression in the tumor microenvironment to inhibit the anti-tumor immunity. Releasing these brakes has emerged as an exciting strategy to cure cancer. In the past few years, clinical trials with therapeutic antibodies targeting to the checkpoint molecules CTLA-4 and PD-1 have rekindled the hope for cancer immunotherapy. In contrast to the conventional treatment, checkpoint inhibitors induce broad and durable antitumor responses. In the future, treatment may involve combination therapy to target different checkpoint molecules and stages of the adaptive immune responses. In this review, we summarized the recent advances of the study and development of other checkpoint molecules in tumor immunotherapy.

  3. Template based parallel checkpointing in a massively parallel computer system

    Archer, Charles Jens [Rochester, MN; Inglett, Todd Alan [Rochester, MN

    2009-01-13

    A method and apparatus for a template based parallel checkpoint save for a massively parallel super computer system using a parallel variation of the rsync protocol, and network broadcast. In preferred embodiments, the checkpoint data for each node is compared to a template checkpoint file that resides in the storage and that was previously produced. Embodiments herein greatly decrease the amount of data that must be transmitted and stored for faster checkpointing and increased efficiency of the computer system. Embodiments are directed to a parallel computer system with nodes arranged in a cluster with a high speed interconnect that can perform broadcast communication. The checkpoint contains a set of actual small data blocks with their corresponding checksums from all nodes in the system. The data blocks may be compressed using conventional non-lossy data compression algorithms to further reduce the overall checkpoint size.

  4. Testing Proficiency in Interpersonal Communication

    Byers, Burton H.

    1973-01-01

    Discusses several hypotheses about the measurement of speech-communication proficiency which are being tested at the University of Hawaii and a testing instrument entitled Dy Comm'' (dyadic communication) which emerged from this research. (DD)

  5. Does a peer model's task proficiency influence children's solution choice and innovation?

    Wood, Lara A; Kendal, Rachel L; Flynn, Emma G

    2015-11-01

    The current study investigated whether 4- to 6-year-old children's task solution choice was influenced by the past proficiency of familiar peer models and the children's personal prior task experience. Peer past proficiency was established through behavioral assessments of interactions with novel tasks alongside peer and teacher predictions of each child's proficiency. Based on these assessments, one peer model with high past proficiency and one age-, sex-, dominance-, and popularity-matched peer model with lower past proficiency were trained to remove a capsule using alternative solutions from a three-solution artificial fruit task. Video demonstrations of the models were shown to children after they had either a personal successful interaction or no interaction with the task. In general, there was not a strong bias toward the high past-proficiency model, perhaps due to a motivation to acquire multiple methods and the salience of other transmission biases. However, there was some evidence of a model-based past-proficiency bias; when the high past-proficiency peer matched the participants' original solution, there was increased use of that solution, whereas if the high past-proficiency peer demonstrated an alternative solution, there was increased use of the alternative social solution and novel solutions. Thus, model proficiency influenced innovation. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Proficiency testing for radionuclides

    Faanhof, A.; Kotze, O.; Louw, I.

    2010-01-01

    Proficiency testing in general is only useful when it suites a certain purpose. With regards to radionuclides basically three fields of interest can be identified: (I)Foodstuffs-Introduced in the early 1960's to monitor the fall-out of nuclear tests and eventually the pathway to foodstuffs fit for human consumption. The demand for analysis increased substantially after the Chernobyl accident. (II) Natural radioactivity-Associated with mining and mineral processing of uranium and thorium baring mineral resources throughout the world where the radionuclides from the natural uranium and thorium decay series are found to pose concern for professional and public exposure. (III) Artificial radioactivity-This category covers mostly the long-lived nuclides generated by nuclear fission of the fuel used in nuclear power plants, research reactors and nuclear bomb tests. All three categories require a specific approach for laboratories to test their ability to analyze specific radio nuclides of interest in a variety of matrices. In this lecture I will give a compiled overview of the required radioanalytical skills, analysis sensitivity needed and radionuclides of interest, with more specific emphasis on QAQC of water sources and the recommended monitoring approach. And provide information on available reference materials and organizations/institutes that provide regular exercises for participating laboratories. I will also briefly communicate on the advantages and disadvantages of ISO/IEC 17025 accreditation for test laboratories, which is these days a prerequisite in national and international trade especially where foodstuffs and mineral products are concerned.

  7. Enhancing Immune Checkpoint Inhibitor Therapy in Kidney Cancer

    2017-10-01

    AWARD NUMBER: W81XWH-15-1-0141 TITLE: Enhancing Immune Checkpoint Inhibitor therapy in Kidney Cancer PRINCIPAL INVESTIGATOR: Hans-Joerg Hammers...SUBTITLE Enhancing Immune Checkpoint Inhibitor therapy in Kidney Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH- 15-1-0141 5c. PROGRAM ELEMENT NUMBER...immune checkpoint inhibition in kidney cancer . The work is designed to test different strategies to induce or enhance the abscopal in a kidney cancer

  8. Hypoxia‐induced alterations of G2 checkpoint regulators

    Hasvold, Grete; Lund-Andersen, Christin; Lando, Malin; Patzke, Sebastian; Hauge, Sissel; Suo, ZhenHe; Lyng, Heidi; Syljuåsen, Randi G.

    2016-01-01

    Hypoxia promotes an aggressive tumor phenotype with increased genomic instability, partially due to downregulation of DNA repair pathways. However, genome stability is also surveilled by cell cycle checkpoints. An important issue is therefore whether hypoxia also can influence the DNA damage‐induced cell cycle checkpoints. Here, we show that hypoxia (24 h 0.2% O2) alters the expression of several G2 checkpoint regulators, as examined by microarray gene expression analysis and immunoblotting o...

  9. Checkpoint independence of most DNA replication origins in fission yeast

    Mickle, Katie L; Ramanathan, Sunita; Rosebrock, Adam; Oliva, Anna; Chaudari, Amna; Yompakdee, Chulee; Scott, Donna; Leatherwood, Janet; Huberman, Joel A

    2007-01-01

    Abstract Background In budding yeast, the replication checkpoint slows progress through S phase by inhibiting replication origin firing. In mammals, the replication checkpoint inhibits both origin firing and replication fork movement. To find out which strategy is employed in the fission yeast, Schizosaccharomyces pombe, we used microarrays to investigate the use of origins by wild-type and checkpoint-mutant strains in the presence of hydroxyurea (HU), which limits the pool of deoxyribonucleo...

  10. Computer proficiency questionnaire: assessing low and high computer proficient seniors.

    Boot, Walter R; Charness, Neil; Czaja, Sara J; Sharit, Joseph; Rogers, Wendy A; Fisk, Arthur D; Mitzner, Tracy; Lee, Chin Chin; Nair, Sankaran

    2015-06-01

    Computers and the Internet have the potential to enrich the lives of seniors and aid in the performance of important tasks required for independent living. A prerequisite for reaping these benefits is having the skills needed to use these systems, which is highly dependent on proper training. One prerequisite for efficient and effective training is being able to gauge current levels of proficiency. We developed a new measure (the Computer Proficiency Questionnaire, or CPQ) to measure computer proficiency in the domains of computer basics, printing, communication, Internet, calendaring software, and multimedia use. Our aim was to develop a measure appropriate for individuals with a wide range of proficiencies from noncomputer users to extremely skilled users. To assess the reliability and validity of the CPQ, a diverse sample of older adults, including 276 older adults with no or minimal computer experience, was recruited and asked to complete the CPQ. The CPQ demonstrated excellent reliability (Cronbach's α = .98), with subscale reliabilities ranging from .86 to .97. Age, computer use, and general technology use all predicted CPQ scores. Factor analysis revealed three main factors of proficiency related to Internet and e-mail use; communication and calendaring; and computer basics. Based on our findings, we also developed a short-form CPQ (CPQ-12) with similar properties but 21 fewer questions. The CPQ and CPQ-12 are useful tools to gauge computer proficiency for training and research purposes, even among low computer proficient older adults. © The Author 2013. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  11. Parallelization and checkpointing of GPU applications through program transformation

    Solano-Quinde, Lizandro Damian [Iowa State Univ., Ames, IA (United States)

    2012-01-01

    GPUs have emerged as a powerful tool for accelerating general-purpose applications. The availability of programming languages that makes writing general-purpose applications for running on GPUs tractable have consolidated GPUs as an alternative for accelerating general purpose applications. Among the areas that have benefited from GPU acceleration are: signal and image processing, computational fluid dynamics, quantum chemistry, and, in general, the High Performance Computing (HPC) Industry. In order to continue to exploit higher levels of parallelism with GPUs, multi-GPU systems are gaining popularity. In this context, single-GPU applications are parallelized for running in multi-GPU systems. Furthermore, multi-GPU systems help to solve the GPU memory limitation for applications with large application memory footprint. Parallelizing single-GPU applications has been approached by libraries that distribute the workload at runtime, however, they impose execution overhead and are not portable. On the other hand, on traditional CPU systems, parallelization has been approached through application transformation at pre-compile time, which enhances the application to distribute the workload at application level and does not have the issues of library-based approaches. Hence, a parallelization scheme for GPU systems based on application transformation is needed. Like any computing engine of today, reliability is also a concern in GPUs. GPUs are vulnerable to transient and permanent failures. Current checkpoint/restart techniques are not suitable for systems with GPUs. Checkpointing for GPU systems present new and interesting challenges, primarily due to the natural differences imposed by the hardware design, the memory subsystem architecture, the massive number of threads, and the limited amount of synchronization among threads. Therefore, a checkpoint/restart technique suitable for GPU systems is needed. The goal of this work is to exploit higher levels of parallelism and

  12. National Radon Contractor Proficiency (RCP) program. Proficiency report, September 1991

    1991-09-01

    The primary objective of the U.S. Environmental Protection Agency's (EPA) efforts to address the indoor radon problem is to reduce radon levels in buildings throughout the country. Achieving this objective requires a nationwide supply of capable radon mitigation contractors. In the Indoor Radon Abatement Act of 1988, Congress authorized EPA to establish a program to evaluate radon mitigation contractors and to provide this information to the public in cooperation with the States. The Radon Contractor Proficiency (RCP) Program was developed to assist States, EPA Regions, local government officials, and the public in selecting contractors who have demonstrated their proficiency in reducing indoor radon levels. The program is managed by the EPA Office of Radiation Programs' Radon Division. Under this voluntary program, radon contractors demonstrate their proficiency by meeting specific Program requirements. Individual contractors who meet these requirements are then listed in the Report

  13. National Radon Contractor Proficiency (RCP) Program. Proficiency report, January 1992

    1992-01-01

    The primary objective of the U.S. Environmental Protection Agency's (EPA) efforts to address the indoor radon problem is to reduce radon levels in buildings throughout the country. Achieving the objective requires a nationwide supply of capable radon mitigation contractors. In the Indoor Radon Abatement Act of 1988, Congress authorized EPA to establish a program to evaluate radon mitigation contractors and to provide the information to the public in cooperation with the States. The Radon Contractor Proficiency (RCP) Program was developed to assist States, EPA Regions, local government officials, and the public in selecting contractors who have demonstrated their proficiency in reducing indoor radon levels. The program is managed by the EPA Office of Radiation Programs' Radon Division. Under the voluntary program, radon contractors demonstrate their proficiency by meeting specific Program requirements. Individual contractors who meet these requirements are then listed in the Report

  14. Anaphase onset before complete DNA replication with intact checkpoint responses

    Torres-Rosell, Jordi; De Piccoli, Giacomo; Cordon-Preciado, Violeta

    2007-01-01

    Cellular checkpoints prevent mitosis in the presence of stalled replication forks. Whether checkpoints also ensure the completion of DNA replication before mitosis is unknown. Here, we show that in yeast smc5-smc6 mutants, which are related to cohesin and condensin, replication is delayed, most...

  15. Verb-Noun Collocation Proficiency and Academic Years

    Fatemeh Ebrahimi-Bazzaz

    2014-01-01

    Full Text Available Generally vocabulary and collocations in particular have significant roles in language proficiency. A collocation includes two words that are frequently joined concurrently in the memory of native speakers. There have been many linguistic studies trying to define, to describe, and to categorise English collocations. It contains grammatical collocations and lexical collocations which include nouns, adjectives, verbs, and adverb. In the context of a foreign language environment such as Iran, collocational proficiency can be useful because it helps the students improve their language proficiency. This paper investigates the possible relationship between verb-noun collocation proficiency among students from one academic year to the next. To reach this goal, a test of verb-noun collocations was administered to Iranian learners. The participants in the study were 212 Iranian students in an Iranian university. They were selected from the second term of freshman, sophomore, junior, and senior years. The students’ age ranged from 18 to 35.The results of ANOVA showed there was variability in the verb-noun collocations proficiency within each academic year and between the four academic years. The results of a post hoc multiple comparison tests demonstrated that the means are significantly different between the first year and the third and fourth years, and between the third and the fourth academic year; however, students require at least two years to show significant development in verb-noun collocation proficiency. These findings provided a vital implication that lexical collocations are learnt and developed through four academic years of university, but requires at least two years showing significant development in the language proficiency.

  16. PD-1 Checkpoint Inhibitor Associated Autoimmune Encephalitis

    Stephanie Schneider

    2017-05-01

    Full Text Available Objective: To report first-hand narrative experience of autoimmune encephalitis and to briefly review currently available evidence of autoimmune encephalitis in cancer patients treated with immune checkpoint inhibitors. Setting: A case study is presented on the management of a patient who developed autoimmune encephalitis during nivolumab monotherapy occurring after 28 weeks on anti-PD-1 monotherapy (nivolumab 3 mg/kg every 2 weeks for non-small cell lung cancer. Results: No substantial improvement was observed by antiepileptic treatment. After administration of 80 mg methylprednisolone, neurologic symptoms disappeared within 24 h and the patient fully recovered. Conclusions: Immune checkpoint inhibitor treatment can lead to autoimmune encephalitis. Clinical trial data indicate a frequency of autoimmune encephalitis of ≥0.1 to <1% with a higher probability during combined or sequential anti-CTLA-4/anti-PD-1 therapy than during anti-PD-1 or anti-PD-L1 monotherapy. Further collection of evidence and translational research is warranted.

  17. PD-1 checkpoint inhibition: Toxicities and management.

    Hahn, Andrew W; Gill, David M; Agarwal, Neeraj; Maughan, Benjamin L

    2017-12-01

    With the recent approval of 5 PD-1/PD-L1 inhibitors for a number of malignancies, PD-1 axis inhibition is drastically changing the treatment landscape of immunotherapy in cancer. As PD-1/PD-L1 are involved in peripheral immune tolerance, inhibition of this immune checkpoint has led to novel immune-related adverse events including colitis, hepatitis, pneumonitis, rash, and endocrinopathies among many others. In this seminar, we will analyze the incidence of immune-related adverse events for nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab. Then, we will discuss the specific management of the most common immune-mediated adverse events including colitis, hepatitis, pneumonitis, rash, endocrinopathies, nephritis, and neurologic toxicities. Immune-related adverse events are frequently treated with immunosuppressive medication such as steroids and mycofenolate mofetil. There are specific immune-related adverse events which are frequently seen by the treating oncologist from checkpoint inhibitors. It is essential to understand the recommended treatment options to minimize toxicity and mortality from this important class of anti-neoplastic therapies. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Newly Emerging Immune Checkpoints: Promises for Future Cancer Therapy

    Robert J. Torphy

    2017-12-01

    Full Text Available Cancer immunotherapy has been a great breakthrough, with immune checkpoint inhibitors leading the way. Despite the clinical effectiveness of certain immune checkpoint inhibitors, the overall response rate remains low, and the effectiveness of immunotherapies for many tumors has been disappointing. There is substantial interest in looking for additional immune checkpoint molecules that may act as therapeutic targets for cancer. Recent advances during the last decade have identified several novel immune checkpoint targets, including lymphocyte activation gene-3 (LAG-3, B and T lymphocyte attenuator (BTLA, programmed death-1 homolog (PD-1H, T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIM-3/carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1, and the poliovirus receptor (PVR-like receptors. The investigations into these molecules have generated promising results in preclinical studies. Herein, we will summarize our current progress and understanding of these newly-characterized immune checkpoints and their potential application in cancer immunotherapy.

  19. "Isogaba Maware": quality control of genome DNA by checkpoints.

    Kitazono, A; Matsumoto, T

    1998-05-01

    Checkpoints maintain the interdependency of cell cycle events by permitting the onset of an event only after the completion of the preceding event. The DNA replication checkpoint induces a cell cycle arrest until the completion of the DNA replication. Similarly, the DNA damage checkpoint arrests cell cycle progression if DNA repair is incomplete. A number of genes that play a role in the two checkpoints have been identified through genetic studies in yeasts, and their homologues have been found in fly, mouse, and human. They form signaling cascades activated by a DNA replication block or DNA damage and subsequently generate the negative constraints on cell cycle regulators. The failure of these signaling cascades results in producing offspring that carry mutations or that lack a portion of the genome. In humans, defects in the checkpoints are often associated with cancer-prone diseases. Focusing mainly on the studies in budding and fission yeasts, we summarize the recent progress.

  20. Language proficiency and nursing registration.

    Müller, Amanda

    2016-02-01

    This discussion paper focuses on English proficiency standards for nursing registration in Australia, how Australia has dealt with the issue of language proficiency, and the factors which have led to the establishment of the current language standards. Also, this paper will provide a comparison of the two language tests that are currently accepted in Australia (OET and IELTS), including the appropriateness of these tests and the minimum standards used. The paper will also examine the use of educational background as an indicator of language proficiency. Finally, communication-based complaints in the post-registration environment will be explored, and some discussion will be provided about why pre-registration measures might have failed to prevent such problematic situations from occurring. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. National Radon Contractor Proficiency Program. Proficiency report, October 1990

    1990-10-01

    The report lists those individual contractors in the United States who have met the requirements of the Radon Contractor Proficiency (RCP) Program as of August 18, 1990. These requirements are designed to provide minimum proficiency criteria for individuals who design and supervise the installation of radon mitigation systems in buildings. (Some States have more stringent requirements as part of their radon certification programs. The States should be consulted directly for details on their programs; see Section 5 for a list of State radon contacts). The RCP Program measures the proficiency of an individual contractor, not their company. Therefore, users of the report who select a mitigation firm should ensure that the services are provided by the listed contractor. The National RCP Program does not accredit mitigation contractors, nor does it certify, recommend, or endorse participating companies. Only the listed contractor, not their company of affilation, are deemed proficient. The inclusion of a contractor in the report should not be interpreted as a certification or accreditation of the individual or affiliated company

  2. Learning Strategies in Proficient and Less Proficient Readers in Medicine

    Nemati, Majid; Nodoushan, Mohammad Ali Salmani; Ashrafzadeh, Anis

    2010-01-01

    The current study aimed to diagnose the probable significant differences in the use of language learning strategies among medical-text readers of opposite sex from different levels of proficiency. 120 (N = 120) participants were randomly selected from Azad Medical University of Mashhad: 60 medical students (age range 23-25; 30 = male and 30 =…

  3. Discrepancies between perceptions of English proficiency and ...

    multilingual awareness pedagogy” embedded in Dörnyei's (2009) L2 Motivational Self System theory. Key words: self-reported perceptions, language proficiency, English proficiency, multilingualism, pedagogy, resilience, L2 Motivational Self System ...

  4. Checkpoint independence of most DNA replication origins in fission yeast.

    Mickle, Katie L; Ramanathan, Sunita; Rosebrock, Adam; Oliva, Anna; Chaudari, Amna; Yompakdee, Chulee; Scott, Donna; Leatherwood, Janet; Huberman, Joel A

    2007-12-19

    In budding yeast, the replication checkpoint slows progress through S phase by inhibiting replication origin firing. In mammals, the replication checkpoint inhibits both origin firing and replication fork movement. To find out which strategy is employed in the fission yeast, Schizosaccharomyces pombe, we used microarrays to investigate the use of origins by wild-type and checkpoint-mutant strains in the presence of hydroxyurea (HU), which limits the pool of deoxyribonucleoside triphosphates (dNTPs) and activates the replication checkpoint. The checkpoint-mutant cells carried deletions either of rad3 (which encodes the fission yeast homologue of ATR) or cds1 (which encodes the fission yeast homologue of Chk2). Our microarray results proved to be largely consistent with those independently obtained and recently published by three other laboratories. However, we were able to reconcile differences between the previous studies regarding the extent to which fission yeast replication origins are affected by the replication checkpoint. We found (consistent with the three previous studies after appropriate interpretation) that, in surprising contrast to budding yeast, most fission yeast origins, including both early- and late-firing origins, are not significantly affected by checkpoint mutations during replication in the presence of HU. A few origins (approximately 3%) behaved like those in budding yeast: they replicated earlier in the checkpoint mutants than in wild type. These were located primarily in the heterochromatic subtelomeric regions of chromosomes 1 and 2. Indeed, the subtelomeric regions defined by the strongest checkpoint restraint correspond precisely to previously mapped subtelomeric heterochromatin. This observation implies that subtelomeric heterochromatin in fission yeast differs from heterochromatin at centromeres, in the mating type region, and in ribosomal DNA, since these regions replicated at least as efficiently in wild-type cells as in checkpoint

  5. Checkpoint independence of most DNA replication origins in fission yeast

    Mickle, Katie L; Ramanathan, Sunita; Rosebrock, Adam; Oliva, Anna; Chaudari, Amna; Yompakdee, Chulee; Scott, Donna; Leatherwood, Janet; Huberman, Joel A

    2007-01-01

    Background In budding yeast, the replication checkpoint slows progress through S phase by inhibiting replication origin firing. In mammals, the replication checkpoint inhibits both origin firing and replication fork movement. To find out which strategy is employed in the fission yeast, Schizosaccharomyces pombe, we used microarrays to investigate the use of origins by wild-type and checkpoint-mutant strains in the presence of hydroxyurea (HU), which limits the pool of deoxyribonucleoside triphosphates (dNTPs) and activates the replication checkpoint. The checkpoint-mutant cells carried deletions either of rad3 (which encodes the fission yeast homologue of ATR) or cds1 (which encodes the fission yeast homologue of Chk2). Results Our microarray results proved to be largely consistent with those independently obtained and recently published by three other laboratories. However, we were able to reconcile differences between the previous studies regarding the extent to which fission yeast replication origins are affected by the replication checkpoint. We found (consistent with the three previous studies after appropriate interpretation) that, in surprising contrast to budding yeast, most fission yeast origins, including both early- and late-firing origins, are not significantly affected by checkpoint mutations during replication in the presence of HU. A few origins (~3%) behaved like those in budding yeast: they replicated earlier in the checkpoint mutants than in wild type. These were located primarily in the heterochromatic subtelomeric regions of chromosomes 1 and 2. Indeed, the subtelomeric regions defined by the strongest checkpoint restraint correspond precisely to previously mapped subtelomeric heterochromatin. This observation implies that subtelomeric heterochromatin in fission yeast differs from heterochromatin at centromeres, in the mating type region, and in ribosomal DNA, since these regions replicated at least as efficiently in wild-type cells as in

  6. Checkpoint independence of most DNA replication origins in fission yeast

    Scott Donna

    2007-12-01

    Full Text Available Abstract Background In budding yeast, the replication checkpoint slows progress through S phase by inhibiting replication origin firing. In mammals, the replication checkpoint inhibits both origin firing and replication fork movement. To find out which strategy is employed in the fission yeast, Schizosaccharomyces pombe, we used microarrays to investigate the use of origins by wild-type and checkpoint-mutant strains in the presence of hydroxyurea (HU, which limits the pool of deoxyribonucleoside triphosphates (dNTPs and activates the replication checkpoint. The checkpoint-mutant cells carried deletions either of rad3 (which encodes the fission yeast homologue of ATR or cds1 (which encodes the fission yeast homologue of Chk2. Results Our microarray results proved to be largely consistent with those independently obtained and recently published by three other laboratories. However, we were able to reconcile differences between the previous studies regarding the extent to which fission yeast replication origins are affected by the replication checkpoint. We found (consistent with the three previous studies after appropriate interpretation that, in surprising contrast to budding yeast, most fission yeast origins, including both early- and late-firing origins, are not significantly affected by checkpoint mutations during replication in the presence of HU. A few origins (~3% behaved like those in budding yeast: they replicated earlier in the checkpoint mutants than in wild type. These were located primarily in the heterochromatic subtelomeric regions of chromosomes 1 and 2. Indeed, the subtelomeric regions defined by the strongest checkpoint restraint correspond precisely to previously mapped subtelomeric heterochromatin. This observation implies that subtelomeric heterochromatin in fission yeast differs from heterochromatin at centromeres, in the mating type region, and in ribosomal DNA, since these regions replicated at least as efficiently in wild

  7. 2-Aminopurine overrides multiple cell cycle checkpoints in BHK cells.

    Andreassen, P R; Margolis, R L

    1992-01-01

    BHK cells blocked at any of several points in the cell cycle override their drug-induced arrest and proceed in the cycle when exposed concurrently to the protein kinase inhibitor 2-aminopurine (2-AP). For cells arrested at various points in interphase, 2-AP-induced cell cycle progression is made evident by arrival of the drug-treated cell population in mitosis. Cells that have escaped from mimosine G1 arrest, from hydroxyurea or aphidicolin S-phase arrest, or from VM-26-induced G2 arrest subs...

  8. An Accounting Writing Proficiency Survey

    Firch, Tim; Campbell, Annhenrie; Filling, Steven; Lindsay, David H.

    2011-01-01

    Although there has been much discussion about improving college student writing with college-level courses, little is known about how accounting programs, in particular, are addressing the writing proficiency challenge. This study surveys the 852 accounting programs in the United States to identify the frequency and types of accounting writing…

  9. Neuromuscular complications of immune checkpoint inhibitor therapy.

    Kolb, Noah A; Trevino, Christopher R; Waheed, Waqar; Sobhani, Fatemeh; Landry, Kara K; Thomas, Alissa A; Hehir, Mike

    2018-01-17

    Immune checkpoint inhibitor (ICPI) therapy unleashes the body's natural immune system to fight cancer. ICPIs improve overall cancer survival, however, the unbridling of the immune system may induce a variety of immune-related adverse events. Neuromuscular immune complications are rare but they can be severe. Myasthenia gravis and inflammatory neuropathy are the most common neuromuscular adverse events but a variety of others including inflammatory myopathy are reported. The pathophysiologic mechanism of these autoimmune disorders may differ from that of non-ICPI-related immune diseases. Accordingly, while the optimal treatment for ICPI-related neuromuscular disorders generally follows a traditional paradigm, there are important novel considerations in selecting appropriate immunosuppressive therapy. This review presents 2 new cases, a summary of neuromuscular ICPI complications, and an approach to the diagnosis and treatment of these disorders. Muscle Nerve, 2018. © 2018 Wiley Periodicals, Inc.

  10. Keeping checkpoint/restart viable for exascale systems.

    Riesen, Rolf E.; Bridges, Patrick G. (IBM Research, Ireland, Mulhuddart, Dublin); Stearley, Jon R.; Laros, James H., III; Oldfield, Ron A.; Arnold, Dorian (University of New Mexico, Albuquerque, NM); Pedretti, Kevin Thomas Tauke; Ferreira, Kurt Brian; Brightwell, Ronald Brian

    2011-09-01

    Next-generation exascale systems, those capable of performing a quintillion (10{sup 18}) operations per second, are expected to be delivered in the next 8-10 years. These systems, which will be 1,000 times faster than current systems, will be of unprecedented scale. As these systems continue to grow in size, faults will become increasingly common, even over the course of small calculations. Therefore, issues such as fault tolerance and reliability will limit application scalability. Current techniques to ensure progress across faults like checkpoint/restart, the dominant fault tolerance mechanism for the last 25 years, are increasingly problematic at the scales of future systems due to their excessive overheads. In this work, we evaluate a number of techniques to decrease the overhead of checkpoint/restart and keep this method viable for future exascale systems. More specifically, this work evaluates state-machine replication to dramatically increase the checkpoint interval (the time between successive checkpoint) and hash-based, probabilistic incremental checkpointing using graphics processing units to decrease the checkpoint commit time (the time to save one checkpoint). Using a combination of empirical analysis, modeling, and simulation, we study the costs and benefits of these approaches on a wide range of parameters. These results, which cover of number of high-performance computing capability workloads, different failure distributions, hardware mean time to failures, and I/O bandwidths, show the potential benefits of these techniques for meeting the reliability demands of future exascale platforms.

  11. Prevention of DNA Rereplication Through a Meiotic Recombination Checkpoint Response

    Nicole A. Najor

    2016-12-01

    Full Text Available In the budding yeast Saccharomyces cerevisiae, unnatural stabilization of the cyclin-dependent kinase inhibitor Sic1 during meiosis can trigger extra rounds of DNA replication. When programmed DNA double-strand breaks (DSBs are generated but not repaired due to absence of DMC1, a pathway involving the checkpoint gene RAD17 prevents this DNA rereplication. Further genetic analysis has now revealed that prevention of DNA rereplication also requires MEC1, which encodes a protein kinase that serves as a central checkpoint regulator in several pathways including the meiotic recombination checkpoint response. Downstream of MEC1, MEK1 is required through its function to inhibit repair between sister chromatids. By contrast, meiotic recombination checkpoint effectors that regulate gene expression and cyclin-dependent kinase activity are not necessary. Phosphorylation of histone H2A, which is catalyzed by Mec1 and the related Tel1 protein kinase in response to DSBs, and can help coordinate activation of the Rad53 checkpoint protein kinase in the mitotic cell cycle, is required for the full checkpoint response. Phosphorylation sites that are targeted by Rad53 in a mitotic S phase checkpoint response are also involved, based on the behavior of cells containing mutations in the DBF4 and SLD3 DNA replication genes. However, RAD53 does not appear to be required, nor does RAD9, which encodes a mediator of Rad53, consistent with their lack of function in the recombination checkpoint pathway that prevents meiotic progression. While this response is similar to a checkpoint mechanism that inhibits initiation of DNA replication in the mitotic cell cycle, the evidence points to a new variation on DNA replication control.

  12. Combination approaches with immune checkpoint blockade in cancer therapy

    Maarten Swart

    2016-11-01

    Full Text Available In healthy individuals, immune checkpoint molecules prevent autoimmune responses and limit immune cell-mediated tissue damage. Tumors frequently exploit these molecules to evade eradication by the immune system. Over the past years, immune checkpoint blockade of cytotoxic T lymphocyte antigen-4 (CTLA-4 and programmed death-1 (PD-1 emerged as promising strategies to activate anti-tumor cytotoxic T cell responses. Although complete regression and long-term survival is achieved in some patients, not all patients respond. This review describes promising, novel combination approaches involving immune checkpoint blockade, aimed at increasing response-rates to the single treatments.

  13. Relationships Between English Language Proficiency, Health Literacy, and Health Outcomes in Somali Refugees.

    Murphy, Jessica E; Smock, Laura; Hunter-Adams, Jo; Xuan, Ziming; Cochran, Jennifer; Paasche-Orlow, Michael K; Geltman, Paul L

    2018-06-15

    Little is known about the impacts of health literacy and English proficiency on the health status of Somali refugees. Data came from interviews in 2009-2011 of 411 adult Somali refugees recently resettled in Massachusetts. English proficiency, health literacy, and physical and mental health were measured using the Basic English Skills Test Plus, the Short Test of Health Literacy in Adults, and the Physical and Mental Component Summaries of the Short Form-12. Associations were analyzed using multiple linear regression. In adjusted analyses, higher English proficiency was associated with worse mental health in males. English proficiency was not associated with physical health. Health literacy was associated with neither physical nor mental health. Language proficiency may adversely affect the mental health of male Somali refugees, contrary to findings in other immigrant groups. Research on underlying mechanisms and opportunities to understand this relationship are needed.

  14. Radiotherapy and immune checkpoint blockades: a snapshot in 2016

    Koo, Tae Yool [Dept. of Radiation Oncology, Hallym University Chuncheon Sacred Heart Hospital, Chuncheon (Korea, Republic of); Kim, In Ah [Dept. of Radiation Oncology, Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2016-12-15

    Immune checkpoint blockades including monoclonal antibodies (mAbs) of cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and programmed death-ligand 1 (PD-L1) have been emerged as a promising anticancer therapy. Several immune checkpoint blockades have been approved by US Food and Drug Administration (FDA), and have shown notable success in clinical trials for patients with advanced melanoma and non-small cell lung cancer. Radiotherapy is a promising combination partner of immune checkpoint blockades due to its potent pro-immune effect. This review will cover the current issue and the future perspectives for combined with radiotherapy and immune checkpoint blockades based upon the available preclinical and clinical data.

  15. A New Adaptive Checkpointing Strategy for Mobile Computing

    MENChaoguang; ZUODecheng; YANGXiaozong

    2005-01-01

    Adaptive checkpointing strategy is an efficient recovery scheme, which is suitable for mobile computing system. However, all existing adaptive checkpointing schemes are not correct to recover system when failure occurs in some special period. In this paper, the issues that will lead to system inconsistency are first discussed and then a new adaptive strategy that can recover system to correct consistent state is proposed. Our algorithm improves system recovery performance because only failure process needs rollback through logging.

  16. Assessment of Proficiency During Simulated Rover Operations Following Long-Duration Spaceflight

    Wood, S. J.; Dean, S. L.; De Dios, Y. E.; MacDougall, H. G.; Moore, S. T.

    2011-01-01

    Following long-duration space travel, pressurized rovers will enhance crew mobility to explore Mars and other planetary surfaces. Adaptive changes in sensorimotor function may limit the crew s proficiency when performing some rover operations shortly after transition to the new gravitoinertial environment. The primary goal of this investigation is to quantify postflight decrements in operational proficiency in a motion-based rover simulation after International Space Station (ISS) expeditions. Given that postflight performance will also be influenced by the level of preflight proficiency attained, a ground-based normative study was conducted to characterize the acquisition of skills over multiple sessions.

  17. Phosphorylation of Minichromosome Maintenance 3 (MCM3) by Checkpoint Kinase 1 (Chk1) Negatively Regulates DNA Replication and Checkpoint Activation.

    Han, Xiangzi; Mayca Pozo, Franklin; Wisotsky, Jacob N; Wang, Benlian; Jacobberger, James W; Zhang, Youwei

    2015-05-08

    Mechanisms controlling DNA replication and replication checkpoint are critical for the maintenance of genome stability and the prevention or treatment of human cancers. Checkpoint kinase 1 (Chk1) is a key effector protein kinase that regulates the DNA damage response and replication checkpoint. The heterohexameric minichromosome maintenance (MCM) complex is the core component of mammalian DNA helicase and has been implicated in replication checkpoint activation. Here we report that Chk1 phosphorylates the MCM3 subunit of the MCM complex at Ser-205 under normal growth conditions. Mutating the Ser-205 of MCM3 to Ala increased the length of DNA replication track and shortened the S phase duration, indicating that Ser-205 phosphorylation negatively controls normal DNA replication. Upon replicative stress treatment, the inhibitory phosphorylation of MCM3 at Ser-205 was reduced, and this reduction was accompanied with the generation of single strand DNA, the key platform for ataxia telangiectasia mutated and Rad3-related (ATR) activation. As a result, the replication checkpoint is activated. Together, these data provide significant insights into the regulation of both normal DNA replication and replication checkpoint activation through the novel phosphorylation of MCM3 by Chk1. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  18. Checkpoint responses to replication stalling: inducing tolerance and preventing mutagenesis

    Kai, Mihoko; Wang, Teresa S.-F

    2003-11-27

    Replication mutants often exhibit a mutator phenotype characterized by point mutations, single base frameshifts, and the deletion or duplication of sequences flanked by homologous repeats. Mutation in genes encoding checkpoint proteins can significantly affect the mutator phenotype. Here, we use fission yeast (Schizosaccharomyces pombe) as a model system to discuss the checkpoint responses to replication perturbations induced by replication mutants. Checkpoint activation induced by a DNA polymerase mutant, aside from delay of mitotic entry, up-regulates the translesion polymerase DinB (Pol{kappa}). Checkpoint Rad9-Rad1-Hus1 (9-1-1) complex, which is loaded onto chromatin by the Rad17-Rfc2-5 checkpoint complex in response to replication perturbation, recruits DinB onto chromatin to generate the point mutations and single nucleotide frameshifts in the replication mutator. This chain of events reveals a novel checkpoint-induced tolerance mechanism that allows cells to cope with replication perturbation, presumably to make possible restarting stalled replication forks. Fission yeast Cds1 kinase plays an essential role in maintaining DNA replication fork stability in the face of DNA damage and replication fork stalling. Cds1 kinase is known to regulate three proteins that are implicated in maintaining replication fork stability: Mus81-Eme1, a hetero-dimeric structure-specific endonuclease complex; Rqh1, a RecQ-family helicase involved in suppressing inappropriate recombination during replication; and Rad60, a protein required for recombinational repair during replication. These Cds1-regulated proteins are thought to cooperatively prevent mutagenesis and maintain replication fork stability in cells under replication stress. These checkpoint-regulated processes allow cells to survive replication perturbation by preventing stalled replication forks from degenerating into deleterious DNA structures resulting in genomic instability and cancer development.

  19. Checkpoint responses to replication stalling: inducing tolerance and preventing mutagenesis

    Kai, Mihoko; Wang, Teresa S.-F.

    2003-01-01

    Replication mutants often exhibit a mutator phenotype characterized by point mutations, single base frameshifts, and the deletion or duplication of sequences flanked by homologous repeats. Mutation in genes encoding checkpoint proteins can significantly affect the mutator phenotype. Here, we use fission yeast (Schizosaccharomyces pombe) as a model system to discuss the checkpoint responses to replication perturbations induced by replication mutants. Checkpoint activation induced by a DNA polymerase mutant, aside from delay of mitotic entry, up-regulates the translesion polymerase DinB (Polκ). Checkpoint Rad9-Rad1-Hus1 (9-1-1) complex, which is loaded onto chromatin by the Rad17-Rfc2-5 checkpoint complex in response to replication perturbation, recruits DinB onto chromatin to generate the point mutations and single nucleotide frameshifts in the replication mutator. This chain of events reveals a novel checkpoint-induced tolerance mechanism that allows cells to cope with replication perturbation, presumably to make possible restarting stalled replication forks. Fission yeast Cds1 kinase plays an essential role in maintaining DNA replication fork stability in the face of DNA damage and replication fork stalling. Cds1 kinase is known to regulate three proteins that are implicated in maintaining replication fork stability: Mus81-Eme1, a hetero-dimeric structure-specific endonuclease complex; Rqh1, a RecQ-family helicase involved in suppressing inappropriate recombination during replication; and Rad60, a protein required for recombinational repair during replication. These Cds1-regulated proteins are thought to cooperatively prevent mutagenesis and maintain replication fork stability in cells under replication stress. These checkpoint-regulated processes allow cells to survive replication perturbation by preventing stalled replication forks from degenerating into deleterious DNA structures resulting in genomic instability and cancer development

  20. Knowledge Management and Organizational Proficiency with NPP

    Marler, M.

    2016-01-01

    Full text: The pace of new NPP construction, startup, and operation is straining the supply of proficient operators, technicians, and engineers. This technical brief explains an approach implemented by a US nuclear utility to capture and transfer knowledge possessed by proficient workers to new workers using the VISION learning content management system. This approach could also be used to accelerate worker proficiency in new NPP organizations. (author

  1. Berkeley lab checkpoint/restart (BLCR) for Linux clusters

    Hargrove, Paul H; Duell, Jason C

    2006-01-01

    This article describes the motivation, design and implementation of Berkeley Lab Checkpoint/Restart (BLCR), a system-level checkpoint/restart implementation for Linux clusters that targets the space of typical High Performance Computing applications, including MPI. Application-level solutions, including both checkpointing and fault-tolerant algorithms, are recognized as more time and space efficient than system-level checkpoints, which cannot make use of any application-specific knowledge. However, system-level checkpointing allows for preemption, making it suitable for responding to ''fault precursors'' (for instance, elevated error rates from ECC memory or network CRCs, or elevated temperature from sensors). Preemption can also increase the efficiency of batch scheduling; for instance reducing idle cycles (by allowing for shutdown without any queue draining period or reallocation of resources to eliminate idle nodes when better fitting jobs are queued), and reducing the average queued time (by limiting large jobs to running during off-peak hours, without the need to limit the length of such jobs). Each of these potential uses makes BLCR a valuable tool for efficient resource management in Linux clusters

  2. [Laboratory accreditation and proficiency testing].

    Kuwa, Katsuhiko

    2003-05-01

    ISO/TC 212 covering clinical laboratory testing and in vitro diagnostic test systems will issue the international standard for medical laboratory quality and competence requirements, ISO 15189. This standard is based on the ISO/IEC 17025, general requirements for competence of testing and calibration laboratories and ISO 9001, quality management systems-requirements. Clinical laboratory services are essential to patient care and therefore should be available to meet the needs of all patients and clinical personnel responsible for human health care. If a laboratory seeks accreditation, it should select an accreditation body that operates according to this international standard and in a manner which takes into account the particular requirements of clinical laboratories. Proficiency testing should be available to evaluate the calibration laboratories and reference measurement laboratories in clinical medicine. Reference measurement procedures should be of precise and the analytical principle of measurement applied should ensure reliability. We should be prepared to establish a quality management system and proficiency testing in clinical laboratories.

  3. Motor Proficiency in Young Children

    Fotini Venetsanou

    2016-01-01

    Full Text Available This study aimed to examine motor proficiency in young children, focusing on potential gender differences. For that purpose, the Bruininks-Oseretsky Test of Motor Proficiency–Long Form (BOTMP-LF was administered to 540 children (272 boys, 4½ to 6 years old. First, the 2 (sex × 4 (age groups ANOVA computed on children’s total BOTMP-LF scores showed that age had a statistically significant effect, whereas gender did not. Second, the one-way MANCOVA applied on subtest scores, with age as covariate, revealed statistical significant gender differences; however, η2 values were found to be small or moderate. Finally, the MANCOVA applied on items where significant gender differences have been reported showed a significant effect of gender. Nonetheless, η2 values exceeded the limit of practical significance only on two items (“standing on preferred leg on floor”, “throwing a ball at a target with preferred hand” that are associated with gender-stereotyped activities. It can be concluded that (a besides statistical significance, effect sizes should be examined for the results of a study to be adequately interpreted; (b young boys’ and girls’ motor proficiency is similar rather than different. Gender differences in specific skills should be used for movement programs to be individualized.

  4. Proficiency test for aflatoxin in pig feed

    Elbers, I.J.W.; Nijs, de W.C.M.

    2015-01-01

    Proficiency testing is conducted to provide laboratories with a powerful tool to evaluate and demonstrate the reliability of the data that are produced. Next to validation and accreditation, proficiency testing is an important requirement of the EU Additional Measures Directive 93/99/EEC [1] and is

  5. Proficiency study for quinolones in egg

    Berendsen, B.J.A.; Stolker, A.A.M.

    2008-01-01

    The aim of this proficiency study was to give laboratories the possibility to evaluate or demonstrate their competence for the analysis of quinolones in egg. Furthermore the specificity of the applied methods is evaluated by including possibly interfering compounds in the proficiency study. This

  6. Measuring receptive collocational competence across proficiency ...

    The present study investigates (i) English as Foreign Language (EFL) learners' receptive collocational knowledge growth in relation to their linguistic proficiency level; (ii) how much receptive collocational knowledge is acquired as linguistic proficiency develops; and (iii) the extent to which receptive knowledge of ...

  7. Proficiency test for allergens in food 2014

    Bremer, M.G.E.G.; Alamenou, P.; Elbers, I.J.W.

    2015-01-01

    In the autumn of 2014 a proficiency test for allergens in baby cereal was organized by RIKILT, Wageningen UR. This PT-test enabled laboratories to evaluate their competence for the analysis of allergens in baby cereal. Both quantitative and qualitative methods were accepted. The proficiency test was

  8. Language proficiency: Current strategies, future remedies ...

    Language proficiency among young South Africans is low. This is true not only of mother tongue speakers of English and Afrikaans, but also, and especially, of non-mother tongue speakers of English, among whom language proficiency levels raise serious concern. Some examples are given to illustrate the importance of ...

  9. A Contextualized Approach to Describing Oral Proficiency.

    Chalhoub-Deville, Micheline

    1995-01-01

    Studies learners' second-language (L2) oral proficiency, incorporating an interview, a narration, and a read-aloud. Results show that the nature of the L2 oral construct is not constant. The article concludes that proficiency researchers should use dimensions empirically derived according to the specific elicitation task and audience. (53…

  10. Language Learning Strategy Use across Proficiency Levels

    Zarei, Abbas, Ali; Baharestani, Nooshin

    2014-01-01

    To investigate the use of language learning strategies (LLS) by Iranian EFL learners across proficiency levels, a total of 180 Iranian adult female EFL learners were selected and divided into three different proficiency level groups. To collect data, Oxford's (1990) Strategy Inventory for Language Learning (SILL) was used. One-way ANOVA procedures…

  11. Fundamental movement skills proficiency in children with developmental coordination disorder: does physical self-concept matter?

    Yu, Jie; Sit, Cindy H P; Capio, Catherine M; Burnett, Angus; Ha, Amy S C; Huang, Wendy Y J

    2016-01-01

    The purpose of this study was to (1) examine differences in fundamental movement skills (FMS) proficiency, physical self-concept, and physical activity in children with and without developmental coordination disorder (DCD), and (2) determine the association of FMS proficiency with physical self-concept while considering key confounding factors. Participants included 43 children with DCD and 87 age-matched typically developing (TD) children. FMS proficiency was assessed using the Test of Gross Motor Development - second edition. Physical self-concept and physical activity were assessed using self-report questionnaires. A two-way (group by gender) ANCOVA was used to determine whether between-group differences existed in FMS proficiency, physical self-concept, and physical activity after controlling for age and BMI. Partial correlations and hierarchical multiple regression models were used to examine the relationship between FMS proficiency and physical self-concept. Compared with their TD peers, children with DCD displayed less proficiency in various components of FMS and viewed themselves as being less competent in physical coordination, sporting ability, and physical health. Physical coordination was a significant predictor of ability in object control skills. DCD status and gender were significant predictors of FMS proficiency. Future FMS interventions should target children with DCD and girls, and should emphasize improving object control skills proficiency and physical coordination. Children with DCD tend to have not only lower FMS proficiency than age-matched typically developing children but also lower physical self-concept. Self-perceptions of physical coordination by children with DCD are likely to be valuable contributors to development of object control skills. This may then help to develop their confidence in performing motor skills. Children with DCD need supportive programs that facilitate the development of object control skills. Efficacy of training

  12. Developmental checkpoints and feedback circuits time insect maturation

    Rewitz, Kim Furbo; Yamanaka, Naoki; O'Connor, Michael B.

    2013-01-01

    as external cues, to time production and release of ecdysone. Based on results discussed here, we suggest that developmental progression to adulthood is controlled by checkpoints that regulate the genetic timing program enabling it to adapt to different environmental conditions. These checkpoints utilize...... a number of signaling pathways to modulate ecdysone production in the prothoracic gland. Release of ecdysone activates an autonomous cascade of both feedforward and feedback signals that determine the duration of the ecdysone pulse at each developmental transitions. Conservation of the genetic mechanisms...... that coordinate the juvenile-adult transition suggests that insights from the fruit fly Drosophila will provide a framework for future investigation of developmental timing in metazoans....

  13. The Dynamical Mechanisms of the Cell Cycle Size Checkpoint

    Feng Shi-Fu; Yang Ling; Yan Jie; Liu Zeng-Rong

    2012-01-01

    Cell division must be tightly coupled to cell growth in order to maintain cell size, whereas the mechanisms of how initialization of mitosis is regulated by cell size remain to be elucidated. We develop a mathematical model of the cell cycle, which incorporates cell growth to investigate the dynamical properties of the size checkpoint in embryos of Xenopus laevis. We show that the size checkpoint is naturally raised from a saddle-node bifurcation, and in a mutant case, the cell loses its size control ability due to the loss of this saddle-node point

  14. ATM and checkpoint responses to DNA double strand breaks

    Khanna, K.K.

    2003-01-01

    DNA damage checkpoints can be classified into G1/S, intra-S and G2/M checkpoints, so named according to the cell cycle transitions that they regulate. DNA damage incurred during the G1 or G2 phase of the cell cycle leads to growth arrest at the G1/S and G2/M phase boundaries, respectively, whereas genotoxic stress during S phase results in the transient suppression of DNA synthesis. In mammals, ATM (ataxia-telangiectasia mutated) is a protein kinase that controls all checkpoint responses to DNA damage. ATM is a versatile kinase which uses various means to regulate a given checkpoint pathway. It has been shown to act upon several proteins within the same pathway, many times controlling several different modifications of the same protein or using several different targets to arrive at the same end point. Some of the ATM targets act as adaptors by recruiting additional substrates for ATM. ATM controls two types of responses in G1. The p53-dependent responses inhibit Cyclin/Cdk activity by transcriptional induction of p21, whereas p53-independent responses inhibit CDKs through degradation of Cdc25A to maintain CdK2 inhibitory phosphorylation. In regulating p53, ATM directly phosphorylates p53 on Ser15, which likely causes p53 transcriptional activation, concurrently activating other kinases that phosphorylate p53 at other sites such as Ser20, which reduces the ability of MDM2 to bind p53, thus promoting its stability. ATM further ensures p53 stability by phosphorylating MDM2. At least six ATM targets, namely CHK2, CHK1, NBS1, BRCA1, SMC1 and FANCD2, have been implicated in the control of S-phase checkpoint. Cdc25A is the downstream effector of CHK1 and CHK2, though the underlying mechanism for control of intra S-phase checkpoint by other targets remain obscure. G2 checkpoint prevents mitotic entry solely through inhibitory phosphorylation of Cdc2/Cdk1. Several ATM targets including CHK1, CHK2, BRCA1, MDC1 and p53BP1 have been implicated in the control of G2/M

  15. The DNA Replication Checkpoint Directly Regulates MBF-Dependent G1/S Transcription▿

    Dutta, Chaitali; Patel, Prasanta K.; Rosebrock, Adam; Oliva, Anna; Leatherwood, Janet; Rhind, Nicholas

    2008-01-01

    The DNA replication checkpoint transcriptionally upregulates genes that allow cells to adapt to and survive replication stress. Our results show that, in the fission yeast Schizosaccharomyces pombe, the replication checkpoint regulates the entire G1/S transcriptional program by directly regulating MBF, the G1/S transcription factor. Instead of initiating a checkpoint-specific transcriptional program, the replication checkpoint targets MBF to maintain the normal G1/S transcriptional program du...

  16. Measuring receptive collocational competence across proficiency levels

    Déogratias Nizonkiza

    2015-12-01

    Full Text Available The present study investigates, (i English as Foreign Language (EFL learners’ receptive collocational knowledge growth in relation to their linguistic proficiency level; (ii how much receptive collocational knowledge is acquired as proficiency develops; and (iii the extent to which receptive knowledge of collocations of EFL learners varies across word frequency bands. A proficiency measure and a collocation test were administered to English majors at the University of Burundi. Results of the study suggest that receptive collocational competence develops alongside EFL learners’ linguistic proficiency; which lends empirical support to Gyllstad (2007, 2009 and Author (2011 among others, who reported similar findings. Furthermore, EFL learners’ collocations growth seems to be quantifiable wherein both linguistic proficiency level and word frequency occupy a crucial role. While more gains in terms of collocations that EFL learners could potentially add as a result of change in proficiency are found at lower levels of proficiency; collocations of words from more frequent word bands seem to be mastered first, and more gains are found at more frequent word bands. These results confirm earlier findings on the non-linearity nature of vocabulary growth (cf. Meara 1996 and the fundamental role played by frequency in word knowledge for vocabulary in general (Nation 1983, 1990, Nation and Beglar 2007, which are extended here to collocations knowledge.

  17. Cell cycle checkpoints: reversible when possible, irreversible when needed

    Krenning, L.

    2015-01-01

    Cell cycle checkpoints are reversible in nature, and can prevent progression into the next cell cycle phase if needed. In the case of DNA damage, cells can prevent progression from G1 into S phase, and from G2 into mitosis in the presence of DNA double strand breaks. Following DNA repair, these

  18. Development of cell-cycle checkpoint therapy for solid tumors.

    Tamura, Kenji

    2015-12-01

    Cellular proliferation is tightly controlled by several cell-cycle checkpoint proteins. In cancer, the genes encoding these proteins are often disrupted and cause unrestrained cancer growth. The proteins are over-expressed in many malignancies; thus, they are potential targets for anti-cancer therapies. These proteins include cyclin-dependent kinase, checkpoint kinase, WEE1 kinase, aurora kinase and polo-like kinase. Cyclin-dependent kinase inhibitors are the most advanced cell-cycle checkpoint therapeutics available. For instance, palbociclib (PD0332991) is a first-in-class, oral, highly selective inhibitor of CDK4/6 and, in combination with letrozole (Phase II; PALOMA-1) or with fulvestrant (Phase III; PALOMA-3), it has significantly prolonged progression-free survival, in patients with metastatic estrogen receptor-positive, HER2-negative breast cancer, in comparison with that observed in patients using letrozole, or fulvestrant alone, respectively. In this review, we provide an overview of the current compounds available for cell-cycle checkpoint protein-directed therapy for solid tumors. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  19. Immune checkpoint inhibitors for nonsmall cell lung cancer treatment

    Yuh-Min Chen

    2017-01-01

    Full Text Available Immune checkpoint inhibition with blocking antibodies that target cytotoxic T-lymphocyte antigen-4 (CTLA-4 and the programmed cell death protein 1 (PD-1 pathway [PD-1/programmed death-ligand 1 (PD-L1] have demonstrated promise in a variety of malignancies. While ipilimumab has been approved as a CTLA-4 blocking antibody by the US Food and Drug Administration for the treatment of advanced melanoma, it is still not approved for lung cancer treatment. In contrast, nivolumab and pembrolizumab, both PD-1 blocking antibodies, have been approved for second-line treatment of nonsmall cell lung cancer in 2015 because of their high potency and long-lasting effects in some patient subgroups. Other PD-1 and PD-L1 monoclonal antibodies are also in active development phase. Treatment with such immune checkpoint inhibitors is associated with a unique pattern of immune-related adverse events or side effects. Combination approaches involving CTLA-4 and PD-1/PD-L1 blockade or checkpoint inhibitors with chemotherapy or radiotherapy are being investigated to determine whether they may enhance the efficacy of treatment. Despite many challenges ahead, immunotherapy with checkpoint inhibitors has already become a new and important treatment modality for lung cancer in the last decade following the discovery of targeted therapy.

  20. A checkpoint compression study for high-performance computing systems

    Ibtesham, Dewan [Univ. of New Mexico, Albuquerque, NM (United States). Dept. of Computer Science; Ferreira, Kurt B. [Sandia National Laboratories (SNL-NM), Albuquerque, NM (United States). Scalable System Software Dept.; Arnold, Dorian [Univ. of New Mexico, Albuquerque, NM (United States). Dept. of Computer Science

    2015-02-17

    As high-performance computing systems continue to increase in size and complexity, higher failure rates and increased overheads for checkpoint/restart (CR) protocols have raised concerns about the practical viability of CR protocols for future systems. Previously, compression has proven to be a viable approach for reducing checkpoint data volumes and, thereby, reducing CR protocol overhead leading to improved application performance. In this article, we further explore compression-based CR optimization by exploring its baseline performance and scaling properties, evaluating whether improved compression algorithms might lead to even better application performance and comparing checkpoint compression against and alongside other software- and hardware-based optimizations. Our results highlights are: (1) compression is a very viable CR optimization; (2) generic, text-based compression algorithms appear to perform near optimally for checkpoint data compression and faster compression algorithms will not lead to better application performance; (3) compression-based optimizations fare well against and alongside other software-based optimizations; and (4) while hardware-based optimizations outperform software-based ones, they are not as cost effective.

  1. CHECKPOINT INHIBITOR IMMUNE THERAPY: Systemic Indications and Ophthalmic Side Effects.

    Dalvin, Lauren A; Shields, Carol L; Orloff, Marlana; Sato, Takami; Shields, Jerry A

    2018-06-01

    To review immune checkpoint inhibitor indications and ophthalmic side effects. A literature review was performed using a PubMed search for publications between 1990 and 2017. Immune checkpoint inhibitors are designed to treat system malignancies by targeting one of three ligands, leading to T-cell activation for attack against malignant cells. These ligands (and targeted drug) include cytotoxic T-lymphocyte antigen-4 (CTLA-4, ipilimumab), programmed death protein 1 (PD-1, pembrolizumab, nivolumab), and programmed death ligand-1 (PD-L1, atezolizumab, avelumab, durvalumab). These medications upregulate the immune system and cause autoimmune-like side effects. Ophthalmic side effects most frequently manifest as uveitis (1%) and dry eye (1-24%). Other side effects include myasthenia gravis (n = 19 reports), inflammatory orbitopathy (n = 11), keratitis (n = 3), cranial nerve palsy (n = 3), optic neuropathy (n = 2), serous retinal detachment (n = 2), extraocular muscle myopathy (n = 1), atypical chorioretinal lesions (n = 1), immune retinopathy (n = 1), and neuroretinitis (n = 1). Most inflammatory side effects are managed with topical or periocular corticosteroids, but advanced cases require systemic corticosteroids and cessation of checkpoint inhibitor therapy. Checkpoint inhibitors enhance the immune system by releasing inhibition on T cells, with risk of autoimmune-like side effects. Ophthalmologists should include immune-related adverse events in their differential when examining cancer patients with new ocular symptoms.

  2. Checkpointing for graceful degradation in distributed embedded systems

    Sababha, Belal Hussein

    Graceful degradation is an approach to developing dependable safety-critical embedded applications, where redundant active or standby resources are used to cope with faults through a system reconfiguration at run-time. Compared to traditional hardware and software redundancy, it is a promising technique that may achieve dependability with a significant reduction in cost, size, weight, and power requirements. Reconfiguration at run-time necessitates using proper checkpointing protocols to support state reservation to ensure correct task restarts after a system reconfiguration. One of the most common checkpointing protocols are communication induced checkpointing (CIC) protocols, which are well developed and understood for large parallel and information systems, but not much has been done for resource limited embedded systems. This work implements and evaluates some of the most common CIC protocols in a periodic resource constrained distributed embedded system for graceful degradation purposes. A test-bed has been developed and used for the evaluation of the various protocols. The implemented protocols are thoroughly studied and performances are contrasted. Specifically the periodicity property and how it benefits checkpointing in embedded systems is investigated. This work introduces a unique effort of CIC protocol implementation and evaluation in the field of distributed embedded systems. Other than providing a test-bed for graceful degradation support, this work shows that some checkpointing protocols that are not efficient in large information systems and supercomputers perform well in embedded systems. We show that a simple index-based CIC protocol, such as the BCS protocol, is more appropriate in embedded system applications compared to other protocols that piggyback a significant amount of information to reduce the number of forced checkpoints. Finally, this work proposes a whole graceful degradation approach to achieve fault tolerance in resource constrained

  3. PROFICIENT CLASSROOM MANAGEMENT THROUGH FOCUSED MATHEMATIC TEACHING

    Marcus Samuelsson

    2017-12-01

    Full Text Available A not entirely unusual position among teachers is that they believe that they must first establish a peaceful classroom before they can begin to teach the subject. This research, shows how a proficient mathematics teacher teaches his subject and thereby creates a quiet and focused classroom and exerts effective leadership, just by teaching mathematics. The researchers observed a male mathematics teacher for almost half a year, i.e. one semester. The results of research present several patterns that the researchers saw during the observations of his teaching. The teacher showed an interest in each student’s mathematical thinking and expressed explicitly how students were expected to learn mathematics. He also directed students’ attention to mathematics and established a culture where all solutions were important in the teaching process. In the teaching process, he used multiple representations to motivate students and a lot of supportive expressions that made them feel that they were able to learn mathematics. He worked patiently to establish structures, and there was almost no disruptive behaviour. Students simply did not have time to interfere because they were so engaged in learning mathematics.

  4. Checkpoint inhibitors in endometrial cancer: preclinical rationale and clinical activity.

    Mittica, Gloria; Ghisoni, Eleonora; Giannone, Gaia; Aglietta, Massimo; Genta, Sofia; Valabrega, Giorgio

    2017-10-27

    Treatment of advanced and recurrent endometrial cancer (EC) is still an unmet need for oncologists and gynecologic oncologists. The Cancer Genome Atlas Research Network (TCGA) recently provided a new genomic classification, dividing EC in four subgroups. Two types of EC, the polymerase epsilon (POLE)-ultra-mutated and the microsatellite instability-hyper-mutated (MSI-H), are characterized by a high mutation rate providing the rationale for a potential activity of checkpoint inhibitors. We analyzed all available evidence supporting the role of tumor microenvironment (TME) in EC development and the therapeutic implications offered by immune checkpoint inhibitors in this setting. We performed a review on Pubmed with Mesh keywords 'endometrial cancer' and the name of each checkpoint inhibitor discussed in the article. The same search was operated on clinicaltrial.gov to identify ongoing clinical trials exploring PD-1/PD-L1 and CTLA-4 axis in EC, particularly focusing on POLE-ultra-muted and MSI-H cancer types. POLE-ultra-mutated and MSI-H ECs showed an active TME expressing high number of neo-antigens and an elevated amount of tumor infiltrating lymphocytes (TILs). Preliminary results from a phase-1 clinical trial (KEYNOTE-028) demonstrated antitumor activity of Pembrolizumab in EC. Moreover, both Pembrolizumab and Nivolumab reported durable clinical responses in POLE-ultra-mutated patients. Immune checkpoint inhibitors are an attractive option in POLE-ultra-mutated and MSI-H ECs. Future investigations in these subgroups include combinations of checkpoints inhibitors with chemotherapy and small tyrosine kinase inhibitors (TKIs) to enhance a more robust intra-tumoral immune response.

  5. A New Tool for Assessing Mobile Device Proficiency in Older Adults: The Mobile Device Proficiency Questionnaire.

    Roque, Nelson A; Boot, Walter R

    2018-02-01

    Mobile device proficiency is increasingly required to participate in society. Unfortunately, there still exists a digital divide between younger and older adults, especially with respect to mobile devices (i.e., tablet computers and smartphones). Training is an important goal to ensure that older adults can reap the benefits of these devices. However, efficient/effective training depends on the ability to gauge current proficiency levels. We developed a new scale to accurately assess the mobile device proficiency of older adults: the Mobile Device Proficiency Questionnaire (MDPQ). We present and validate the MDPQ and a short 16-question version of the MDPQ (MDPQ-16). The MDPQ, its subscales, and the MDPQ-16 were found to be highly reliable and valid measures of mobile device proficiency in a large sample. We conclude that the MDPQ and MDPQ-16 may serve as useful tools for facilitating mobile device training of older adults and measuring mobile device proficiency for research purposes.

  6. Nucleotide Selectivity at a Preinsertion Checkpoint of T7 RNA Polymerase Transcription Elongation.

    E, Chao; Duan, Baogen; Yu, Jin

    2017-04-20

    Nucleotide selection is crucial for transcription fidelity control, in particular, for viral T7 RNA polymerase (RNAP) lack of proofreading activity. It has been recognized that multiple kinetic checkpoints exist prior to full nucleotide incorporation. In this work, we implemented intensive atomistic molecular dynamics (MD) simulations to quantify how strong the nucleotide selection is at the initial checkpoint of an elongation cycle of T7 RNAP. The incoming nucleotides bind into a preinsertion site where a critical tyrosine residue locates nearby to assist the nucleotide selection. We calculated the relative binding free energy between a noncognate nucleotide and a cognate one at a preinsertion configuration via alchemical simulations, showing that a small selection free energy or the binding free energy difference (∼3 k B T) exists between the two nucleotides. Indeed, another preinsertion configuration favored by the noncognate nucleotides was identified, which appears to be off path for further nucleotide insertion and additionally assists the nucleotide selection. By chemical master equation (CME) approach, we show that the small selection free energy at the preinsertion site along with the off-path noncognate nucleotide filtering can help substantially to reduce the error rate and to maintain the elongation rate high in the T7 RNAP transcription.

  7. The impact of aviation checkpoint queues on optimizing security screening effectiveness

    Lee, Adrian J., E-mail: ajlee@citeri.or [Central Illinois Technology and Education Research Institute, 2312 Connie Drive, Springfield, IL 62704-8722 (United States); Jacobson, Sheldon H., E-mail: shj@illinois.ed [Department of Computer Science, University of Illinois at Urbana-Champaign, 201 N. Goodwin Ave. M/C 258, Urbana, IL 61801-2302 (United States)

    2011-08-15

    Passenger screening at aviation security checkpoints is a critical component in protecting airports and aircraft from terrorist threats. Recent developments in screening device technology have increased the ability to detect these threats; however, the average amount of time it takes to screen a passenger still remains a concern. This paper models the queueing process for a multi-level airport checkpoint security system, where multiple security classes are formed through subsets of specialized screening devices. An optimal static assignment policy is obtained which minimizes the steady-state expected amount of time a passenger spends in the security system. Then, an optimal dynamic assignment policy is obtained through a transient analysis that balances the expected number of true alarms with the expected amount of time a passenger spends in the security system. Performance of a two-class system is compared to that of a selective security system containing primary and secondary levels of screening. The key contribution is that the resulting optimal assignment policies increase security and passenger throughput by efficiently and effectively utilizing available screening resources.

  8. The impact of aviation checkpoint queues on optimizing security screening effectiveness

    Lee, Adrian J.; Jacobson, Sheldon H.

    2011-01-01

    Passenger screening at aviation security checkpoints is a critical component in protecting airports and aircraft from terrorist threats. Recent developments in screening device technology have increased the ability to detect these threats; however, the average amount of time it takes to screen a passenger still remains a concern. This paper models the queueing process for a multi-level airport checkpoint security system, where multiple security classes are formed through subsets of specialized screening devices. An optimal static assignment policy is obtained which minimizes the steady-state expected amount of time a passenger spends in the security system. Then, an optimal dynamic assignment policy is obtained through a transient analysis that balances the expected number of true alarms with the expected amount of time a passenger spends in the security system. Performance of a two-class system is compared to that of a selective security system containing primary and secondary levels of screening. The key contribution is that the resulting optimal assignment policies increase security and passenger throughput by efficiently and effectively utilizing available screening resources.

  9. Developing Adaptive Proficiency in Special Forces Officers

    White, Susan S; Mueller-Hanson, Rose A; Dorsey, David W; Pulakos, Elaine D; Wisecarver, Michelle M; Deagle, Edwin A., III; Mendini, Kip G

    2005-01-01

    Adaptive proficiency is critical for operating in the dynamic Special Forces (SF) mission environment and a recent focus on this requirement has resulted in a greater emphasis on adaptability in current training for SF...

  10. Silencing of poly(ADP-ribose) glycohydrolase sensitizes lung cancer cells to radiation through the abrogation of DNA damage checkpoint

    Nakadate, Yusuke [Shien-Lab, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 (Japan); Department of Bioengineering, Graduate School of Engineering, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585 (Japan); Kodera, Yasuo; Kitamura, Yuka [Shien-Lab, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 (Japan); Tachibana, Taro [Department of Bioengineering, Graduate School of Engineering, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585 (Japan); Tamura, Tomohide [Division of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 (Japan); Koizumi, Fumiaki, E-mail: fkoizumi@ncc.go.jp [Division of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 (Japan)

    2013-11-29

    Highlights: •Radiosensitization by PARG silencing was observed in multiple lung cancer cells. •PAR accumulation was enhanced by PARG silencing after DNA damage. •Radiation-induced G2/M arrest and checkpoint activation were impaired by PARG siRNA. -- Abstract: Poly(ADP-ribose) glycohydrolase (PARG) is a major enzyme that plays a role in the degradation of poly(ADP-ribose) (PAR). PARG deficiency reportedly sensitizes cells to the effects of radiation. In lung cancer, however, it has not been fully elucidated. Here, we investigated whether PARG siRNA contributes to an increased radiosensitivity using 8 lung cancer cell lines. Among them, the silencing of PARG induced a radiosensitizing effect in 5 cell lines. Radiation-induced G2/M arrest was largely suppressed by PARG siRNA in PC-14 and A427 cells, which exhibited significantly enhanced radiosensitivity in response to PARG knockdown. On the other hand, a similar effect was not observed in H520 cells, which did not exhibit a radiosensitizing effect. Consistent with a cell cycle analysis, radiation-induced checkpoint signals were not well activated in the PC-14 and A427 cells when treated with PARG siRNA. These results suggest that the increased sensitivity to radiation induced by PARG knockdown occurs through the abrogation of radiation-induced G2/M arrest and checkpoint activation in lung cancer cells. Our findings indicate that PARG could be a potential target for lung cancer treatments when used in combination with radiotherapy.

  11. Clinical characteristics of patient selection and imaging predictors of outcome in solid tumors treated with checkpoint-inhibitors

    Rossi, Sabrina; Toschi, Luca; Castello, Angelo; Grizzi, Fabio; Mansi, Luigi; Lopci, Egesta

    2017-01-01

    The rapidly evolving knowledge on tumor immunology and the continuous implementation of immunotherapy in cancer have recently led to the FDA and EMA approval of several checkpoint inhibitors as immunotherapic agents in clinical practice. Anti-CTLA-4, anti-PD-1, and anti-PDL-1 antibodies are becoming standard of care in advanced melanoma, as well as in relapsed or metastatic lung and kidney cancer, demonstrating higher and longer response compared to standard chemotherapy. These encouraging results have fostered the evaluation of these antibodies either alone or in combination with other therapies in several dozen clinical trials for the treatment of multiple tumor types. However, not all patients respond to immune checkpoint inhibitors, hence, specific biomarkers are necessary to guide and monitor therapy. The utility of PD-L1 expression as a biomarker has varied in different clinical trials, but, to date, no consensus has been reached on whether PD-L1 expression is an ideal marker for response and patient selection; approximately 20-25% of patients will respond to immunotherapy with checkpoint inhibitors despite a negative PD-L1 staining. On the other hand, major issues concern the evaluation of objective response in patients treated with immunotherapy. Pure morphological criteria as commonly used in solid tumors (i.e. RECIST) are not sufficient because change in size is not an early and reliable marker of tumor response to biological therapies. Thus, the scientific community has required a continuous adaptation of immune-related response criteria (irRC) to overcome the problem. In this context, metabolic information and antibody-based imaging with positron emission tomography (PET) have been investigated, providing a powerful approach for an optimal stratification of patients at staging and during the evaluation of the response to therapy. In the present review we provide an overview on the clinical characteristics of patient selection when using imaging

  12. Clinical characteristics of patient selection and imaging predictors of outcome in solid tumors treated with checkpoint-inhibitors

    Rossi, Sabrina; Toschi, Luca [Humanitas Clinical and Research Hospital, Medical Oncology, Rozzano (Italy); Castello, Angelo [Humanitas Clinical and Research Hospital, Nuclear Medicine, Rozzano (Italy); Grizzi, Fabio [Humanitas Clinical and Research Hospital, Immunology and Inflammation, Rozzano (Italy); Mansi, Luigi [Seconda Universita di Napoli, Nuclear Medicine, Naples (Italy); Lopci, Egesta [Humanitas Clinical and Research Hospital, Nuclear Medicine, Rozzano (Italy); Humanitas Cancer Center, Humanitas Clinical and Research Hospital, Nuclear Medicine, Rozzano, MI (Italy)

    2017-12-15

    The rapidly evolving knowledge on tumor immunology and the continuous implementation of immunotherapy in cancer have recently led to the FDA and EMA approval of several checkpoint inhibitors as immunotherapic agents in clinical practice. Anti-CTLA-4, anti-PD-1, and anti-PDL-1 antibodies are becoming standard of care in advanced melanoma, as well as in relapsed or metastatic lung and kidney cancer, demonstrating higher and longer response compared to standard chemotherapy. These encouraging results have fostered the evaluation of these antibodies either alone or in combination with other therapies in several dozen clinical trials for the treatment of multiple tumor types. However, not all patients respond to immune checkpoint inhibitors, hence, specific biomarkers are necessary to guide and monitor therapy. The utility of PD-L1 expression as a biomarker has varied in different clinical trials, but, to date, no consensus has been reached on whether PD-L1 expression is an ideal marker for response and patient selection; approximately 20-25% of patients will respond to immunotherapy with checkpoint inhibitors despite a negative PD-L1 staining. On the other hand, major issues concern the evaluation of objective response in patients treated with immunotherapy. Pure morphological criteria as commonly used in solid tumors (i.e. RECIST) are not sufficient because change in size is not an early and reliable marker of tumor response to biological therapies. Thus, the scientific community has required a continuous adaptation of immune-related response criteria (irRC) to overcome the problem. In this context, metabolic information and antibody-based imaging with positron emission tomography (PET) have been investigated, providing a powerful approach for an optimal stratification of patients at staging and during the evaluation of the response to therapy. In the present review we provide an overview on the clinical characteristics of patient selection when using imaging

  13. Covering Resilience: A Recent Development for Binomial Checkpointing

    Walther, Andrea; Narayanan, Sri Hari Krishna

    2016-09-12

    In terms of computing time, adjoint methods offer a very attractive alternative to compute gradient information, required, e.g., for optimization purposes. However, together with this very favorable temporal complexity result comes a memory requirement that is in essence proportional with the operation count of the underlying function, e.g., if algorithmic differentiation is used to provide the adjoints. For this reason, checkpointing approaches in many variants have become popular. This paper analyzes an extension of the so-called binomial approach to cover also possible failures of the computing systems. Such a measure of precaution is of special interest for massive parallel simulations and adjoint calculations where the mean time between failure of the large scale computing system is smaller than the time needed to complete the calculation of the adjoint information. We describe the extensions of standard checkpointing approaches required for such resilience, provide a corresponding implementation and discuss first numerical results.

  14. Unique Contributions of Maternal Reading Proficiency to Predicting Children's Preschool Receptive Vocabulary and Reading Proficiency

    Phillips, Linda M.; Norris, Stephen P.; Hayward, Denyse V.; Lovell, Meridith A.

    2017-01-01

    This study investigated whether mothers' measured reading proficiency and their educational level predict, over and above each other, their children's receptive vocabulary and reading proficiency when confounding factors of speaking a minority language, ethnicity, number of children in the family, and marital and employment status are controlled.…

  15. Assessment of Preschoolers' Gross Motor Proficiency: Revisiting Bruininks-Oseretsky Test of Motor Proficiency

    Lam, Hazel Mei Yung

    2011-01-01

    Literature reveals that there are very few validated motor proficiency tests for young children. According to Gallahue and Ozmun, the Bruininks-Oseretsky Test of Motor Proficiency is a valid test. However, manipulative skills, which are classified as gross motor skills by most motor development specialists, are only tested in the Upper Limb…

  16. Implementing forward recovery using checkpointing in distributed systems

    Long, Junsheng; Fuchs, W. K.; Abraham, Jacob A.

    1991-01-01

    The paper describes the implementation of a forward recovery scheme using checkpoints and replicated tasks. The implementation is based on the concept of lookahead execution and rollback validation. In the experiment, two tasks are selected for the normal execution and one for rollback validation. It is shown that the recovery strategy has nearly error-free execution time and an average redundancy lower than TMR.

  17. Analysis of Drug Development Paradigms for Immune Checkpoint Inhibitors.

    Jardim, Denis L; de Melo Gagliato, Débora; Giles, Francis J; Kurzrock, Razelle

    2018-04-15

    Immune checkpoint inhibitors have unique toxicities and response kinetics compared with cytotoxic and gene-targeted anticancer agents. We investigated the impact of innovative/accelerated immunotherapy drug development/approval models on the accuracy of safety and efficacy assessments by searching the FDA website. Initial phase I trials for each agent were reviewed and safety and efficacy data compared with that found in later trials leading to regulatory approvals of the same agents. As of June 2017, the FDA approved six checkpoint inhibitors for a variety of cancer types. All checkpoint inhibitors received a priority review status and access to at least two additional FDA special access programs, more often breakthrough therapy designation and accelerated approval. Median clinical development time (investigational new drug application to approval) was 60.77 months [avelumab had the shortest timeline (52.33 months)]. Response rates during early phase I trials (median = 16%) are higher than for phase I trials of other agents (with the exception of gene-targeted agents tested with a biomarker). Doses approved were usually not identical to doses recommended on phase I trials. Approximately 50% of types of immune-related and 43% of types of clinically relevant toxicities from later trials were identified in early-phase trials. Even so, treatment-related mortality remains exceedingly low in later studies (0.33% of patients). In conclusion, efficacy and safety of immune checkpoint inhibitors appear to be reasonably predicted from the dose-finding portion of phase I trials, indicating that the fast-track development of these agents is safe and justified. Clin Cancer Res; 24(8); 1785-94. ©2017 AACR . ©2017 American Association for Cancer Research.

  18. Spindle assembly checkpoint acquisition at the mid-blastula transition.

    Maomao Zhang

    Full Text Available The spindle assembly checkpoint (SAC maintains the fidelity of chromosome segregation during mitosis. Nonpathogenic cells lacking the SAC are typically only found in cleavage stage metazoan embryos, which do not acquire functional checkpoints until the mid-blastula transition (MBT. It is unclear how proper SAC function is acquired at the MBT, though several models exist. First, SAC acquisition could rely on transcriptional activity, which increases dramatically at the MBT. Embryogenesis prior to the MBT relies primarily on maternally loaded transcripts, and if SAC signaling components are not maternally supplied, the SAC would depend on zygotic transcription at the MBT. Second, checkpoint acquisition could depend on the Chk1 kinase, which is activated at the MBT to elongate cell cycles and is required for the SAC in somatic cells. Third, SAC function could depend on a threshold nuclear to cytoplasmic (N:C ratio, which increases during pre-MBT cleavage cycles and dictates several MBT events like zygotic transcription and cell cycle remodeling. Finally, the SAC could by regulated by a timer mechanism that coincides with other MBT events but is independent of them. Using zebrafish embryos we show that SAC acquisition at the MBT is independent of zygotic transcription, indicating that the checkpoint program is maternally supplied. Additionally, by precociously lengthening cleavage cycles with exogenous Chk1 activity, we show that cell cycle lengthening and Chk1 activity are not sufficient for SAC acquisition. Furthermore, we find that SAC acquisition can be uncoupled from the N:C ratio. Together, our findings indicate that SAC acquisition is regulated by a maternally programmed developmental timer.

  19. The final checkpoint. Cancer as an adaptive evolutionary mechanism

    Rumena Petkova

    2016-05-01

    Full Text Available The mechanisms for identification of DNA damage and repair usually manage DNA damage very efficiently. If damaged cells manage to bypass the checkpoints where the integrity of the genome is assessed and the decisions whether to proceed with the cell cycle are made, they may evade the imperative to stop dividing and to die. As a result, cancer may develop. Warding off the potential sequence-altering effects of DNA damage during the life of the individual or the existence span of the species is controlled by a set of larger checkpoints acting on a progressively increasing scale, from systematic removal of damaged cells from the proliferative pool by means of repair of DNA damage/programmed cell death through ageing to, finally, cancer. They serve different purposes and act at different levels of the life cycle, safeguarding the integrity of the genetic backup of the individual, the genetic diversity of the population, and, finally, the survival of the species and of life on Earth. In the light of the theory that cancer is the final checkpoint or the nature's manner to prevent complex organisms from living forever at the expense of genetic stagnation, the eventual failure of modern anti-cancer treatments is only to be expected. Nevertheless, the medicine of today and the near future has enough potential to slow down the progression to terminal cancer so that the life expectancy and the quality of life of cancer-affected individuals may be comparable to those of healthy aged individuals.

  20. The Aurora B kinase in chromosome biorientation and spindle checkpoint signalling

    Veronica eKrenn

    2015-10-01

    Full Text Available Aurora B, a member of the Aurora family of serine/threonine protein kinases, is a key player in chromosome segregation. As part of a macromolecular complex known as the chromosome passenger complex, Aurora B concentrates early during mitosis in the proximity of centromeres and kinetochores, the sites of attachment of chromosomes to spindle microtubules. There, it contributes to a number of processes that impart fidelity to cell division, including kinetochore stabilization, kinetochore-microtubule attachment, and the regulation of a surveillance mechanism named the spindle assembly checkpoint. In the regulation of these processes, Aurora B is the fulcrum of a remarkably complex network of interactions that feed back on its localization and activation state. In this review we discuss the multiple roles of Aurora B during mitosis, focusing in particular on its role at centromeres and kinetochores. Many details of the network of interactions at these locations remain poorly understood, and we focus here on several crucial outstanding questions.

  1. Sobriety checkpoints in Thailand: a review of effectiveness and developments over time.

    Ditsuwan, Vallop; Veerman, J Lennert; Bertram, Melanie; Vos, Theo

    2015-03-01

    This review describes the legal basis for and implementation of sobriety checkpoints in Thailand and identifies factors that influenced their historical development and effectiveness. The first alcohol and traffic injury control law in Thailand was implemented in 1934. The 0.05 g/100 mL blood alcohol concentration limit was set in 1994. Currently, 3 types of sobriety checkpoints are used: general police checkpoints, selective breath testing, and special event sobriety checkpoints. The authors found few reports on the strategies, frequencies, and outcomes for any of these types of checkpoints, despite Thailand having devoted many resources to their implementation. In Thailand and other low-middle income countries, it is necessary to address the country-specific barriers to successful enforcement (including political and logistical issues, lack of equipment, and absence of other supportive alcohol harm reduction measures) before sobriety checkpoints can be expected to be as effective as reported in high-income countries. © 2011 APJPH.

  2. Association between pediatric asthma care quality and morbidity and English language proficiency in Ohio.

    Montgomery, Martha P; Allen, Elizabeth D; Thomas, Olivia; Robinson, Byron F; Clark, Donnie; Connelly, Ann; Mott, Joshua A; Conrey, Elizabeth

    2018-05-08

    Limited English proficiency can be a barrier to asthma care and is associated with poor outcomes. This study examines whether pediatric patients in Ohio with limited English proficiency experience lower asthma care quality or higher morbidity. We used electronic health records for asthma patients aged 2-17 years from a regional, urban, children's hospital in Ohio during 2011-2015. Community-level demographics were included from U.S. Census data. By using chi-square and t-tests, patients with limited English proficiency and bilingual English-speaking patients were compared with English-only patients. Five asthma outcomes-two quality and three morbidity measures-were modeled using generalized estimating equations. The study included 15 352 (84%) English-only patients, 1744 (10%) patients with limited English proficiency, and 1147 (6%) bilingual patients. Pulmonary function testing (quality measure) and multiple exacerbation visits (morbidity measure) did not differ by language group. Compared with English-only patients, bilingual patients had higher odds of ever having an exacerbation visit (morbidity measure) (adjusted odds ratio [aOR], 1.4; 95% confidence interval [CI], 1.2-1.6) but lower odds of admission to intensive care (morbidity measure) (aOR, 0.3; 95% CI, 0.2-0.7), while patients with limited English proficiency did not differ on either factor. Recommended follow-up after exacerbation (quality measure) was higher for limited English proficiency (aOR, 1.8; 95% CI, 1.4-2.3) and bilingual (aOR, 1.6; 95% CI, 1.3-2.1), compared with English-only patients. In this urban, pediatric population with reliable interpreter services, limited English proficiency was not associated with worse asthma care quality or morbidity.

  3. Emodnet Med Sea Check-Point - Indicators for decision- maker

    Besnard, Sophie; Claverie, Vincent; Blanc, Frédérique

    2015-04-01

    The Emodnet Checkpoint projects aim is to assess the cost-effectiveness, reliability and utility of the existing monitoring at the sea basin level. This involves the development of monitoring system indicators and a GIS Platform to perform the assessment and make it available. Assessment or production of Check-Point information is made by developing targeted products based on the monitoring data and determining whether the products are meeting the needs of industry and public authorities. Check-point users are the research community, the 'institutional' policy makers for IMP and MSFD implementation, the 'intermediate users', i.e., users capable to understand basic raw data but that benefit from seeing the Checkpoint targeted products and the assessment of the fitness for purpose. We define assessment criteria aimed to characterize/depict the input datasets in terms of 3 territories capable to show performance and gaps of the present monitoring system, appropriateness, availability and fitness for purpose. • Appropriateness: What is made available to users? What motivate/decide them to select this observation rather than this one. • Availability: How this is made available to the user? Place to understand the readiness and service performance of the EU infrastructure • Fitness for use / fitness for purpose: Ability for non-expert user to appreciate the data exploitability (feedback on efficiency & reliability of marine data) For each territory (appropriateness, Availability and Fitness for purpose / for use), we define several indicators. For example, for Availability we define Visibility, Accessibility and Performance. And Visibility is itself defined by "Easily found" and "EU service". So these indicators can be classified according to their territory and sub-territory as seen above, but also according to the complexity to build them. Indicators are built from raw descriptors in 3 stages:  Stage 1: to give a neutral and basic status directly computed from

  4. Beyond English Proficiency: Rethinking Immigrant Integration

    Akresh, Ilana Redstone; Massey, Douglas S.; Frank, Reanne

    2014-01-01

    We develop and test a conceptual model of English language acquisition and the strength of the latter in predicting social and cultural assimilation. We present evidence that the path to English proficiency begins with exposure to English in the home country and on prior U.S. trips. English proficiency, then, has direct links to the intermediate migration outcomes of occupational status in the U.S., the amount of time in the U.S. since the most recent trip, and the co-ethnic residential context in the U.S. In turn, pre-migration characteristics and the intermediate characteristics work in tandem with English proficiency to determine social assimilation in the U.S., while cultural assimilation is primarily determined by pre-migration habits. A shift in focus to English use is desirable in studies of immigrant integration. PMID:24576636

  5. The spindle assembly checkpoint: More than just keeping track of the spindle.

    Lawrence, KS; Engebrecht, J

    2015-01-01

    Genome stability is essential for cell proliferation and survival. Consequently, genome integrity is monitored by two major checkpoints, the DNA damage response (DDR) and the spindle assembly checkpoint (SAC). The DDR monitors DNA lesions in G1, S, and G2 stages of the cell cycle and the SAC ensures proper chromosome segregation in M phase. There have been extensive studies characterizing the roles of these checkpoints in response to the processes for which they are named; however, emerging e...

  6. The DNA replication checkpoint directly regulates MBF-dependent G1/S transcription.

    Dutta, Chaitali; Patel, Prasanta K; Rosebrock, Adam; Oliva, Anna; Leatherwood, Janet; Rhind, Nicholas

    2008-10-01

    The DNA replication checkpoint transcriptionally upregulates genes that allow cells to adapt to and survive replication stress. Our results show that, in the fission yeast Schizosaccharomyces pombe, the replication checkpoint regulates the entire G(1)/S transcriptional program by directly regulating MBF, the G(1)/S transcription factor. Instead of initiating a checkpoint-specific transcriptional program, the replication checkpoint targets MBF to maintain the normal G(1)/S transcriptional program during replication stress. We propose a mechanism for this regulation, based on in vitro phosphorylation of the Cdc10 subunit of MBF by the Cds1 replication-checkpoint kinase. Replacement of two potential phosphorylation sites with phosphomimetic amino acids suffices to promote the checkpoint transcriptional program, suggesting that Cds1 phosphorylation directly regulates MBF-dependent transcription. The conservation of MBF between fission and budding yeast, and recent results implicating MBF as a target of the budding yeast replication checkpoint, suggests that checkpoint regulation of the MBF transcription factor is a conserved strategy for coping with replication stress. Furthermore, the structural and regulatory similarity between MBF and E2F, the metazoan G(1)/S transcription factor, suggests that this checkpoint mechanism may be broadly conserved among eukaryotes.

  7. The DNA Replication Checkpoint Directly Regulates MBF-Dependent G1/S Transcription▿

    Dutta, Chaitali; Patel, Prasanta K.; Rosebrock, Adam; Oliva, Anna; Leatherwood, Janet; Rhind, Nicholas

    2008-01-01

    The DNA replication checkpoint transcriptionally upregulates genes that allow cells to adapt to and survive replication stress. Our results show that, in the fission yeast Schizosaccharomyces pombe, the replication checkpoint regulates the entire G1/S transcriptional program by directly regulating MBF, the G1/S transcription factor. Instead of initiating a checkpoint-specific transcriptional program, the replication checkpoint targets MBF to maintain the normal G1/S transcriptional program during replication stress. We propose a mechanism for this regulation, based on in vitro phosphorylation of the Cdc10 subunit of MBF by the Cds1 replication-checkpoint kinase. Replacement of two potential phosphorylation sites with phosphomimetic amino acids suffices to promote the checkpoint transcriptional program, suggesting that Cds1 phosphorylation directly regulates MBF-dependent transcription. The conservation of MBF between fission and budding yeast, and recent results implicating MBF as a target of the budding yeast replication checkpoint, suggests that checkpoint regulation of the MBF transcription factor is a conserved strategy for coping with replication stress. Furthermore, the structural and regulatory similarity between MBF and E2F, the metazoan G1/S transcription factor, suggests that this checkpoint mechanism may be broadly conserved among eukaryotes. PMID:18662996

  8. The correlation between motor proficiency and physical activity in ...

    Lizl-Louise van Niekerk

    eOseretsky Test of Motor Proficiency 2 (BOT-2) for motor proficiency, and the International. Physical Activity ... Pienaar, 2007; Malina, 2012). ..... sults of Hardy, Reinten-Reynolds, Espinel, Zask, and Okely .... Journal of Psychiatric and Mental.

  9. From Universal Access to Universal Proficiency.

    Lewis, Anne C.

    2003-01-01

    Panel of five education experts--Elliot Eisner, John Goodlad, Patricia Graham, Phillip Schlechty, and Warren Simons--answer questions related to recent school reform efforts, such as the No Child Left Behind Act, aimed at achieving universal educational proficiency. (PKP)

  10. Measuring receptive collocational competence across proficiency ...

    Kate H

    frequency bands. A proficiency measure and a collocation test were administered to English ... battery may negatively impact the test-takers' performance. ..... examples. The major finding is that raising learners' awareness constitutes the best way forward ..... Amsterdam: John Benjamins Publishing Company. Green, R.

  11. Foreign language proficiency and working memory capacity

    Noort, M.W.M.L. van den; Bosch, M.P.C.; Hugdahl, K.

    2006-01-01

    In this study, the hypothesis that working memory capacity interacts with (foreign) language proficiency was tested on multilinguals, who were native (L1) Dutch speakers, were fluent in their second (L2) language, German, and had recently started the acquisition of their third (L3) language,

  12. Proficiency test for paracitides in salmon muscle

    Elbers, I.J.W.

    2012-01-01

    The aim of this proficiency study was to give laboratories the possibility to evaluate or demonstrate their competence for the analysis of parasiticides in salmon muscle. This study also provided an evaluation of the methods applied for the quantitative analysis of parasiticides in salmon muscle.

  13. Proficiency Testing in Nondestructive Testing (NDT)

    Amry Amin Abbas; Suhairy Sani; Mohamad Pauzi Ismail; Abd Nassir Ibrahim

    2014-01-01

    Department of Standard Malaysia (DSM) launched myPTP programme on 31 December 2013 in accordance to ISO/IC 17043. The standard states the requirements for Proficiency Testing. The provider of these services is called Proficiency Testing Provider (PTP). The role of PTP is to compare the proficiency level between inspection bodies or laboratories. With the assistance of expert panel, the PTP will determine the assigned value as reference to be compared to the values obtained from the inspection bodies or laboratories. Quality wise, this services is important as participation will improve wuality of the inspection quality continuously and increase confidence level of client and improve safety level. Requirement of PT in NDT is mentioned in SC1.5- Specific Criteria for Accreditation of Mechanical Testing and Non-Destructive Testing (NDT) for MS ISO/IEC17025 and MTR2- MIBAS Technical Requirements for Accreditation of NDT. This paper explains and discusses the result of this proficiency test done on a number of NDT companies that participated. (author)

  14. It Really Works: Cultural Communication Proficiency.

    Bennett, Ruth, Ed.

    This paper describes the cultural communication proficiency method of indigenous language instruction, developed at Humboldt State University's Center for Indian Community Development (California), and demonstrates the method with five Hupa lesson plans. The method is based on three principles: that Native American students learn by doing, learn…

  15. The Oral Proficiency Interview: A Research Agenda

    Chalhoub-Deville, Micheline; Fulcher, Glenn

    2003-01-01

    Many researchers and practitioners maintain that ACTFL's efforts to improve instructional practices and promote proficiency assessments tied to descriptors of what learners can do in real life have contributed significantly to second language teaching and testing. Similar endeavors in the area of research, however, are critically needed. Focusing…

  16. 14 CFR 61.98 - Flight proficiency.

    2010-01-01

    ... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false Flight proficiency. 61.98 Section 61.98 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIRMEN...) Navigation; (viii) Slow flight and stalls; (ix) Emergency operations; and (x) Postflight procedures. (2) For...

  17. 14 CFR 61.107 - Flight proficiency.

    2010-01-01

    ... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false Flight proficiency. 61.107 Section 61.107 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIRMEN... reference maneuvers; (vii) Navigation; (viii) Slow flight and stalls; (ix) Basic instrument maneuvers; (x...

  18. 14 CFR 61.127 - Flight proficiency.

    2010-01-01

    ... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false Flight proficiency. 61.127 Section 61.127 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIRMEN...; (x) High-altitude operations; and (xi) Postflight procedures. (2) For an airplane category rating...

  19. Predictors of responses to immune checkpoint blockade in advanced melanoma

    Jacquelot, N; Roberti, M P; Enot, D P

    2017-01-01

    Immune checkpoint blockers (ICB) have become pivotal therapies in the clinical armamentarium against metastatic melanoma (MMel). Given the frequency of immune related adverse events and increasing use of ICB, predictors of response to CTLA-4 and/or PD-1 blockade represent unmet clinical needs....... Using a systems biology-based approach to an assessment of 779 paired blood and tumor markers in 37 stage III MMel patients, we analyzed association between blood immune parameters and the functional immune reactivity of tumor-infiltrating cells after ex vivo exposure to ICB. Based on this assay, we...

  20. Central Tolerance Blockade to Augment Checkpoint Immunotherapy in Melanoma

    2017-09-01

    expressed at higher levels in medullary thymic epithelial cells (mTECs) than in cortical thymic epithelial cells (cTECs), addition of anti-RANKL antibody...relative Aire expression by quantitative RT-PCR in cultured thymic tissue . 12-15 90% Subtask 3. Culture human thymus sections with OPG-Fc or vehicle...PCR in cultured thymic tissue . 15-18 90% ACURO approval 13-14 100% Major Task 1. Effect of concurrent anti-RANKL and checkpoint inhibitor

  1. 34 CFR 300.27 - Limited English proficient.

    2010-07-01

    ... 34 Education 2 2010-07-01 2010-07-01 false Limited English proficient. 300.27 Section 300.27... CHILDREN WITH DISABILITIES General Definitions Used in This Part § 300.27 Limited English proficient. Limited English proficient has the meaning given the term in section 9101(25) of the ESEA. (Authority: 20...

  2. A Validation Study of the Student Oral Proficiency Assessment (SOPA).

    Thompson, Lynn E.; Kenyon, Dorry M.; Rhodes, Nancy C.

    This study validated the Student Oral Proficiency Assessment (SOPA), an oral proficiency instrument designed for students in elementary foreign language programs. Elementary students who were tested with the SOPA were also administered other instruments designed to measure proficiency. These instruments included the Stanford Foreign Language Oral…

  3. Proverb Comprehension as a Function of Reading Proficiency in Preadolescents.

    Nippold, Marilyn A.; Allen, Melissa M.; Kirsch, Dixon I.

    2001-01-01

    Proverb comprehension through reading was examined in 42 preadolescent students, 24 of whom were identified as "proficient readers," and 18 as "less proficient readers." Comprehension on both unfamiliar concrete and abstract proverbs was associated with reading proficiency, word knowledge, and analogical reasoning. (Contains references.)…

  4. The Checkpoint Kinase 1 Inhibitor Prexasertib Induces Regression of Preclinical Models of Human Neuroblastoma.

    Lowery, Caitlin D; VanWye, Alle B; Dowless, Michele; Blosser, Wayne; Falcon, Beverly L; Stewart, Julie; Stephens, Jennifer; Beckmann, Richard P; Bence Lin, Aimee; Stancato, Louis F

    2017-08-01

    Purpose: Checkpoint kinase 1 (CHK1) is a key regulator of the DNA damage response and a mediator of replication stress through modulation of replication fork licensing and activation of S and G 2 -M cell-cycle checkpoints. We evaluated prexasertib (LY2606368), a small-molecule CHK1 inhibitor currently in clinical testing, in multiple preclinical models of pediatric cancer. Following an initial assessment of prexasertib activity, this study focused on the preclinical models of neuroblastoma. Experimental Design: We evaluated the antiproliferative activity of prexasertib in a panel of cancer cell lines; neuroblastoma cell lines were among the most sensitive. Subsequent Western blot and immunofluorescence analyses measured DNA damage and DNA repair protein activation. Prexasertib was investigated in several cell line-derived xenograft mouse models of neuroblastoma. Results: Within 24 hours, single-agent prexasertib promoted γH2AX-positive double-strand DNA breaks and phosphorylation of DNA damage sensors ATM and DNA-PKcs, leading to neuroblastoma cell death. Knockdown of CHK1 and/or CHK2 by siRNA verified that the double-strand DNA breaks and cell death elicited by prexasertib were due to specific CHK1 inhibition. Neuroblastoma xenografts rapidly regressed following prexasertib administration, independent of starting tumor volume. Decreased Ki67 and increased immunostaining of endothelial and pericyte markers were observed in xenografts after only 6 days of exposure to prexasertib, potentially indicating a swift reduction in tumor volume and/or a direct effect on tumor vasculature. Conclusions: Overall, these data demonstrate that prexasertib is a specific inhibitor of CHK1 in neuroblastoma and leads to DNA damage and cell death in preclinical models of this devastating pediatric malignancy. Clin Cancer Res; 23(15); 4354-63. ©2017 AACR . ©2017 American Association for Cancer Research.

  5. Laboratory competence evaluation through proficiency testing - mycotoxins in food

    Torović Ljilja D.

    2017-01-01

    Full Text Available Laboratory for analysis of mycotoxins in food at the Institute of Public Health of Vojvodina (Novi Sad, Serbia participated in 15 proficiency testing schemes in period 2012-2016, comprising 22 determinations of regulated mycotoxins: aflatoxins B1, B2, G1, G2 and M1, ochratoxin A, deoxynivalenone, zearalenone, fumonisins and patulin, in different food commodities: wheat, corn, barley, breakfast cereals, infant food, milk, wine and fruit juice. Analyses were carried out by high performance liquid chromatography with ultraviolet (patulin, deoxynivalenol or fluorescence detection (aflatoxin M1, ochratoxin A, zearalenone using o-phthalaldehyde precolumn derivatization (fumonisins or UV postcolumn derivatization (aflatoxins B1, B2, G1, G2, following clean-up on immunoaffinity columns with specific antibodies, except in case of patulin when solvent extraction and solid-phase C-18 clean-up were used. Laboratory performance assessed in terms of z scores showed all satisfactory results. In depth evaluation revealed following distribution of z scores (absolute values: 59.1% up to 0.5, 36.4% between 0.5 and 1.0, and 4.5% above 1.0. Analysis of trends performed for multiple determinations of individual mycotoxins showed several changes of z score to better or worse rank. Overall assessment of the performance in proficiency testing demonstrated laboratory competence for analysis of mycotoxins in food.

  6. Conformation-specific anti-Mad2 monoclonal antibodies for the dissection of checkpoint signaling

    Sedgwick, Garry G; Larsen, Marie Sofie Yoo; Lischetti, Tiziana

    2016-01-01

    The spindle assembly checkpoint (SAC) ensures accurate chromosome segregation during mitosis by delaying the activation of the anaphase-promoting complex/cyclosome (APC/C) in response to unattached kinetochores. The Mad2 protein is essential for a functional checkpoint because it binds directly t...

  7. Space Reclamation for Uncoordinated Checkpointing in Message-Passing Systems. Ph.D. Thesis

    Wang, Yi-Min

    1993-01-01

    Checkpointing and rollback recovery are techniques that can provide efficient recovery from transient process failures. In a message-passing system, the rollback of a message sender may cause the rollback of the corresponding receiver, and the system needs to roll back to a consistent set of checkpoints called recovery line. If the processes are allowed to take uncoordinated checkpoints, the above rollback propagation may result in the domino effect which prevents recovery line progression. Traditionally, only obsolete checkpoints before the global recovery line can be discarded, and the necessary and sufficient condition for identifying all garbage checkpoints has remained an open problem. A necessary and sufficient condition for achieving optimal garbage collection is derived and it is proved that the number of useful checkpoints is bounded by N(N+1)/2, where N is the number of processes. The approach is based on the maximum-sized antichain model of consistent global checkpoints and the technique of recovery line transformation and decomposition. It is also shown that, for systems requiring message logging to record in-transit messages, the same approach can be used to achieve optimal message log reclamation. As a final topic, a unifying framework is described by considering checkpoint coordination and exploiting piecewise determinism as mechanisms for bounding rollback propagation, and the applicability of the optimal garbage collection algorithm to domino-free recovery protocols is demonstrated.

  8. Immunotherapy targeting immune check-point(s) in brain metastases.

    Di Giacomo, Anna Maria; Valente, Monica; Covre, Alessia; Danielli, Riccardo; Maio, Michele

    2017-08-01

    Immunotherapy with monoclonal antibodies (mAb) directed to different immune check-point(s) is showing a significant clinical impact in a growing number of human tumors of different histotype, both in terms of disease response and long-term survival patients. In this rapidly changing scenario, treatment of brain metastases remains an high unmeet medical need, and the efficacy of immunotherapy in these highly dismal clinical setting remains to be largely demonstrated. Nevertheless, up-coming observations are beginning to suggest a clinical potential of cancer immunotherapy also in brain metastases, regardless the underlying tumor histotype. These observations remain to be validated in larger clinical trials eventually designed also to address the efficacy of therapeutic mAb to immune check-point(s) within multimodality therapies for brain metastases. Noteworthy, the initial proofs of efficacy on immunotherapy in central nervous system metastases are already fostering clinical trials investigating its therapeutic potential also in primary brain tumors. We here review ongoing immunotherapeutic approaches to brain metastases and primary brain tumors, and the foreseeable strategies to overcome their main biologic hurdles and clinical challenges. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Avelumab: combining immune checkpoint inhibition and antibody-dependent cytotoxicity.

    Hamilton, Gerhard; Rath, Barbara

    2017-04-01

    Immune checkpoint inhibition holds great promise for selected tumors. The human monoclonal antibody (mAB) avelumab is directed to programmed death ligand-1 (PD-L1) and is supposed to inhibit the immunosuppressive PD-L1/PD-1 interaction and, furthermore, effect antibody-dependent cytotoxicity (ADCC) lysis of tumor cells. Areas covered: This article presents an overview of the current means to activate the antitumor immune defense by targeting PD-1 or PD-L1 with mABs and their possible role in ADCC-mediated tumor cell elimination. Expert opinion: Avelumab contains a Fc region which can bind cognate receptors on immune effector cells and induce ADCC-mediated tumor cell lysis, in contrast to other mABs directed to PD-1/PD-L1 which lack the ability to trigger ADCC due to belonging to the IgG4 subclass or possessing a mutated Fc region. Preclinical and clinical data indicate that avelumab can be safely administered to cancer patients with a toxicity profile comparable to other mABs and without lysis of PD-L1-positive activated immune cells. This antibody yielded durable responses in a phase II trial in advanced Merkel cell carcinoma patients. Tumor cell lysis by avelumab prevents cells from resorting to alternative checkpoints as shown by targeting PD-1 and the upregulation of TIM-3.

  10. Cenp-meta is required for sustained spindle checkpoint

    Thomas Rubin

    2014-05-01

    Full Text Available Cenp-E is a kinesin-like motor protein required for efficient end-on attachment of kinetochores to the spindle microtubules. Cenp-E immunodepletion in Xenopus mitotic extracts results in the loss of mitotic arrest and massive chromosome missegregation, whereas its depletion in mammalian cells leads to chromosome segregation defects despite the presence of a functional spindle assembly checkpoint (SAC. Cenp-meta has previously been reported to be the Drosophila homolog of vertebrate Cenp-E. In this study, we show that cenp-metaΔ mutant neuroblasts arrest in mitosis when treated with colchicine. cenp-metaΔ mutant cells display a mitotic delay. Yet, despite the persistence of the two checkpoint proteins Mad2 and BubR1 on unattached kinetochores, these cells eventually enter anaphase and give rise to highly aneuploid daughter cells. Indeed, we find that cenp-metaΔ mutant cells display a slow but continuous degradation of cyclin B, which eventually triggers the mitotic exit observed. Thus, our data provide evidence for a role of Cenp-meta in sustaining the SAC response.

  11. Continuing global improvement in human papillomavirus DNA genotyping services: The 2013 and 2014 HPV LabNet international proficiency studies.

    Eklund, Carina; Forslund, Ola; Wallin, Keng-Ling; Dillner, Joakim

    2018-04-01

    Accurate and internationally comparable human papillomavirus (HPV) DNA detection and typing services are essential for HPV vaccine research and surveillance. This study assessed the proficiency of different HPV typing services offered routinely in laboratories worldwide. The HPV Laboratory Network (LabNet) has designed international proficiency panels that can be regularly issued. The HPV genotyping proficiency panels of 2013 and 2014 contained 43 and 41 coded samples, respectively, composed of purified plasmids of sixteen HPV types (HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68a and 68b) and 3 extraction controls. Proficient typing was defined as detection in both single and multiple infections of 50 International Units of HPV 16 and HPV 18 and 500 genome equivalents for the other 14 HPV types, with at least 97% specificity. Ninety-six laboratories submitted 136 datasets in 2013 and 121 laboratories submitted 148 datasets in 2014. Thirty-four different HPV genotyping assays were used, notably Linear Array, HPV Direct Flow-chip, GenoFlow HPV array, Anyplex HPV 28, Inno-LiPa, and PGMY-CHUV assays. A trend towards increased sensitivity and specificity was observed. In 2013, 59 data sets (44%) were 100% proficient compared to 86 data sets (59%) in 2014. This is a definite improvement compared to the first proficiency panel, issued in 2008, when only 19 data sets (26%) were fully proficient. The regularly issued global proficiency program has documented an ongoing worldwide improvement in comparability and reliability of HPV genotyping services. Copyright © 2018 Elsevier B.V. All rights reserved.

  12. Evaluation of Mycology Laboratory Proficiency Testing

    Reilly, Andrew A.; Salkin, Ira F.; McGinnis, Michael R.; Gromadzki, Sally; Pasarell, Lester; Kemna, Maggi; Higgins, Nancy; Salfinger, Max

    1999-01-01

    Changes over the last decade in overt proficiency testing (OPT) regulations have been ostensibly directed at improving laboratory performance on patient samples. However, the overt (unblinded) format of the tests and regulatory penalties associated with incorrect values allow and encourage laboratorians to take extra precautions with OPT analytes. As a result OPT may measure optimal laboratory performance instead of the intended target of typical performance attained during routine patient te...

  13. More Proficient vs. Less Proficient EFL Learners’ Perceptions of Teachers ‘Motivation Raising Strategies

    Nasrin Yousefi

    2022-09-01

    Full Text Available Motivation raising strategies are frequently used in English as a Foreign Language (EFL classes; nevertheless, learners’ perceptions of such strategies used by language teachers have not sufficiently been explored. Also, there are not enough studies on differences and similarities between more and less proficient EFL learners regarding this issue. To scrutinize this topic, a groups of more (No=50 and less proficient EFL learners (No=50 participated in this study by completing to a validated, researcher-made questionnaire with a five-point Likert type format. Non-parametric Mann-Whiteny U test was run in the SPSS ver. 23 to check the differences between the two groups. The results of the study verified that, regardless of each individual scale in the utilized questionnaire, overall, the more proficient ones manifested significantly less perceptions on teachers’ motivation raising strategies based on the total estimated mean ranks compared with the less proficient learners.  However, within the surveyed scales, only in the classroom atmosphere scale, the results showed that the less proficient learners were more mindful of teacher strategies for motivation raising. The findings from this study have implications for motivation raising strategy instructions for a language classroom.

  14. Genetic Control of the Trigger for the G2/M Checkpoint

    Hall, Eric J. [Columbia University; Smilenov, Lubomir B. [Columbia University; Young, Erik F. [Columbia University

    2013-10-01

    The work undertaken in this project addressed two seminal areas of low dose radiation biology that are poorly understood and controversial. These areas are the challenge to the linear-no-threshold (LNT) paradigm at low doses of radiation and, the fundamental elements of radiation bystander effect biology Genetic contributions to low dose checkpoint engagement: The LNT paradigm is an extrapolation of known, measured cancer induction endpoints. Importantly, data for lower doses is often not available. Debatably, radiation protection standards have been introduced which are prudently contingent on the adherence of cancer risk to the established trend seen at higher doses. Intriguing findings from other labs have hinted at separate DNA damage response programs that engage at low or high levels of radiation. Individual radiation sensitivity commensurate with hemizygosity for a radiation sensitivity gene has been estimated at 1-2% in the U.S.. Careful interrogation of the DNA damage response at low doses of radiation became important and served as the basis for this grant. Several genes were tested in combinations to determine if combined haploinsufficiency for multiple radiosensitizing genes could render a cell more sensitive to lower levels of acute radiation exposure. We measured a classical radiation response endpoint, cell cycle arrest prior to mitosis. Mouse embryo fibroblasts were used and provided a uniform, rapidly dividing and genetically manipulable population of study. Our system did not report checkpoint engagement at acute doses of gamma rays below 100 mGy. The system did report checkpoint engagement reproducibly at 500 mGy establishing a threshold for activation between 100 and 500 mGy. Engagement of the checkpoint was ablated in cells nullizygous for ATM but was otherwise unperturbed in cells combinatorially haploinsufficient for ATM and Rad9, ATM and PTEN or PTEN and Rad9. Taken together, these experiments tell us that, in a sensitive fibroblast culture

  15. A genetic screen identifies BRCA2 and PALB2 as key regulators of G2 checkpoint maintenance

    Menzel, Tobias; Nähse-Kumpf, Viola; Kousholt, Arne Nedergaard

    2011-01-01

    To identify key connections between DNA-damage repair and checkpoint pathways, we performed RNA interference screens for regulators of the ionizing radiation-induced G2 checkpoint, and we identified the breast cancer gene BRCA2. The checkpoint was also abrogated following depletion of PALB2......, an interaction partner of BRCA2. BRCA2 and PALB2 depletion led to premature checkpoint abrogation and earlier activation of the AURORA A-PLK1 checkpoint-recovery pathway. These results indicate that the breast cancer tumour suppressors and homologous recombination repair proteins BRCA2 and PALB2 are main...

  16. EMODnet MedSea Checkpoint for sustainable Blue Growth

    Moussat, Eric; Pinardi, Nadia; Manzella, Giuseppe; Blanc, Frederique

    2016-04-01

    The EMODNET checkpoint is a wide monitoring system assessment activity aiming to support the sustainable Blue Growth at the scale of the European Sea Basins by: 1) Clarifying the observation landscape of all compartments of the marine environment including Air, Water, Seabed, Biota and Human activities, pointing out to the existing programs, national, European and international 2) Evaluating fitness for use indicators that will show the accessibility and usability of observation and modeling data sets and their roles and synergies based upon selected applications by the European Marine Environment Strategy 3) Prioritizing the needs to optimize the overall monitoring Infrastructure (in situ and satellite data collection and assembling, data management and networking, modeling and forecasting, geo-infrastructure) and release recommendations for evolutions to better meet the application requirements in view of sustainable Blue Growth The assessment is designed for : - Institutional stakeholders for decision making on observation and monitoring systems - Data providers and producers to know how their data collected once for a given purpose could fit other user needs - End-users interested in a regional status and possible uses of existing monitoring data Selected end-user applications are of paramount importance for: (i) the blue economy sector (offshore industries, fisheries); (ii) marine environment variability and change (eutrophication, river inputs and ocean climate change impacts); (iii) emergency management (oil spills); and (iv) preservation of natural resources and biodiversity (Marine Protected Areas). End-user applications generate innovative products based on the existing observation landscape. The fitness for use assessment is made thanks to the comparison of the expected product specifications with the quality of the product derived from the selected data. This involves the development of checkpoint information and indicators based on Data quality and

  17. Acute inflammatory thyromegaly following checkpoint inhibition: A new imaging entity?

    Erik H. Middlebrooks, MD

    2018-02-01

    Full Text Available Immune checkpoint blockade (CPB utilizing such agents as ipilimumab, nivolumab, or pembrolizumab has revolutionized melanoma therapy and has seen continued utilization in numerous other malignancies in recent years. However, these agents come at the price of inflammatory immune-related adverse events. Despite the increasing recognition of biochemical thyroid dysfunction associated with CPB, information regarding potential imaging findings is sparse. We describe the first 2 cases of acute thyroiditis following CPB presenting as diffuse thyromegaly documented by computed tomography, ultrasound, and iodine uptake imaging. Given the rise in the use of CPB, it is important for radiologists to recognize potential imaging manifestations of therapy immune-related adverse events to avoid erroneous diagnosis and to prompt the biochemical investigation of thyroid function.

  18. The CD47-SIRPα signaling axis as an innate immune checkpoint in cancer.

    Matlung, Hanke L; Szilagyi, Katka; Barclay, Neil A; van den Berg, Timo K

    2017-03-01

    Immune checkpoint inhibitors, including those targeting CTLA-4/B7 and the PD-1/PD-L1 inhibitory pathways, are now available for clinical use in cancer patients, with other interesting checkpoint inhibitors being currently in development. Most of these have the purpose to promote adaptive T cell-mediated immunity against cancer. Here, we review another checkpoint acting to potentiate the activity of innate immune cells towards cancer. This innate immune checkpoint is composed of what has become known as the 'don't-eat me' signal CD47, which is a protein broadly expressed on normal cells and often overexpressed on cancer cells, and its counter-receptor, the myeloid inhibitory immunoreceptor SIRPα. Blocking CD47-SIRPα interactions has been shown to promote the destruction of cancer cells by phagocytes, including macrophages and neutrophils. Furthermore, there is growing evidence that targeting of the CD47-SIRPα axis may also promote antigen-presenting cell function and thereby stimulate adaptive T cell-mediated anti-cancer immunity. The development of CD47-SIRPα checkpoint inhibitors and the potential side effects that these may have are discussed. Collectively, this identifies the CD47-SIRPα axis as a promising innate immune checkpoint in cancer, and with data of the first clinical studies with CD47-SIRPα checkpoint inhibitors expected within the coming years, this is an exciting and rapidly developing field. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Role of Immune Checkpoint Inhibitors in Small Cell Lung Cancer.

    Cooper, Maryann R; Alrajhi, Abdullah M; Durand, Cheryl R

    Small cell lung cancer (SCLC) accounts for approximately 13% of all lung cancer diagnoses each year. SCLC is characterized by a rapid doubling time, early metastatic spread, and an unfavorable prognosis overall. Most patients with SCLC will respond to initial treatment; however, the majority will experience a disease recurrence and response to second-line therapies is poor. Immune checkpoint inhibitors may be an option given the success in other diseases. A literature search was conducted using Medline (1946-July week 1, 2017) and Embase (1996-2017 week 28) with the search terms small cell lung cancer combined with nivolumab or ipilimumab or pembrolizumab or atezolizumab or tremelimumab or durvalumab. Five clinical trials, including extended follow-up for 2, that evaluated immune checkpoint inhibitors in limited stage or extensive stage SCLC were included. In 2 phase 2 trials, ipilimumab was added to upfront chemotherapy. In both trials, an improvement in progression-free survival was seen. Toxicity, when combined with a platinum and etoposide, was significant. In a confirmatory phase 3 trial, ipilimumab did not prolong overall survival when added to first-line chemotherapy. Overall, response rates were similar between the placebo and ipilimumab groups. A phase 1/2 trial evaluated nivolumab alone or in combination with ipilimumab in recurrent SCLC. Results revealed that nivolumab monotherapy and the combination of nivolumab and ipilimumab were relatively safe and had antitumor activity. Pembrolizumab has been evaluated in a multicohort, phase 1b trial. Preliminary data showed a durable response in the second-line setting. Given the lack of overall survival data and significant toxicity associated with the combination of ipilimumab with first-line chemotherapy, this treatment is not a reasonable option at this time. Nivolumab alone or in combination with ipilimumab is a valid option for recurrent SCLC.

  20. Immigration, language proficiency, and autobiographical memories: Lifespan distribution and second-language access.

    Esposito, Alena G; Baker-Ward, Lynne

    2016-08-01

    This investigation examined two controversies in the autobiographical literature: how cross-language immigration affects the distribution of autobiographical memories across the lifespan and under what circumstances language-dependent recall is observed. Both Spanish/English bilingual immigrants and English monolingual non-immigrants participated in a cue word study, with the bilingual sample taking part in a within-subject language manipulation. The expected bump in the number of memories from early life was observed for non-immigrants but not immigrants, who reported more memories for events surrounding immigration. Aspects of the methodology addressed possible reasons for past discrepant findings. Language-dependent recall was influenced by second-language proficiency. Results were interpreted as evidence that bilinguals with high second-language proficiency, in contrast to those with lower second-language proficiency, access a single conceptual store through either language. The final multi-level model predicting language-dependent recall, including second-language proficiency, age of immigration, internal language, and cue word language, explained ¾ of the between-person variance and (1)/5 of the within-person variance. We arrive at two conclusions. First, major life transitions influence the distribution of memories. Second, concept representation across multiple languages follows a developmental model. In addition, the results underscore the importance of considering language experience in research involving memory reports.

  1. The pachytene checkpoint and its relationship to evolutionary patterns of polyploidization and hybrid sterility.

    Li, X C; Barringer, B C; Barbash, D A

    2009-01-01

    Sterility is a commonly observed phenotype in interspecific hybrids. Sterility may result from chromosomal or genic incompatibilities, and much progress has been made toward understanding the genetic basis of hybrid sterility in various taxa. The underlying mechanisms causing hybrid sterility, however, are less well known. The pachytene checkpoint is a meiotic surveillance system that many organisms use to detect aberrant meiotic products, in order to prevent the production of defective gametes. We suggest that activation of the pachytene checkpoint may be an important mechanism contributing to two types of hybrid sterility. First, the pachytene checkpoint may form the mechanistic basis of some gene-based hybrid sterility phenotypes. Second, the pachytene checkpoint may be an important mechanism that mediates chromosomal-based hybrid sterility phenotypes involving gametes with non-haploid (either non-reduced or aneuploid) chromosome sets. Studies in several species suggest that the strength of the pachytene checkpoint is sexually dimorphic, observations that warrant future investigation into whether such variation may contribute to differences in patterns of sterility between male and female interspecific hybrids. In addition, plants seem to lack the pachytene checkpoint, which correlates with increased production of unreduced gametes and a higher incidence of polyploid species in plants versus animals. Although the pachytene checkpoint occurs in many animals and in fungi, at least some of the genes that execute the pachytene checkpoint are different among organisms. This finding suggests that the penetrance of the pachytene checkpoint, and even its presence or absence can evolve rapidly. The surprising degree of evolutionary flexibility in this meiotic surveillance system may contribute to the observed variation in patterns of hybrid sterility and in rates of polyploidization.

  2. NDR1 modulates the UV-induced DNA-damage checkpoint and nucleotide excision repair

    Park, Jeong-Min; Choi, Ji Ye [Department of Biological Science, Dong-A University, Busan (Korea, Republic of); Yi, Joo Mi [Research Center, Dongnam Institute of Radiological & Medical Sciences, Busan (Korea, Republic of); Chung, Jin Woong; Leem, Sun-Hee; Koh, Sang Seok [Department of Biological Science, Dong-A University, Busan (Korea, Republic of); Kang, Tae-Hong, E-mail: thkang@dau.ac.kr [Department of Biological Science, Dong-A University, Busan (Korea, Republic of)

    2015-06-05

    Nucleotide excision repair (NER) is the sole mechanism of UV-induced DNA lesion repair in mammals. A single round of NER requires multiple components including seven core NER factors, xeroderma pigmentosum A–G (XPA–XPG), and many auxiliary effector proteins including ATR serine/threonine kinase. The XPA protein helps to verify DNA damage and thus plays a rate-limiting role in NER. Hence, the regulation of XPA is important for the entire NER kinetic. We found that NDR1, a novel XPA-interacting protein, modulates NER by modulating the UV-induced DNA-damage checkpoint. In quiescent cells, NDR1 localized mainly in the cytoplasm. After UV irradiation, NDR1 accumulated in the nucleus. The siRNA knockdown of NDR1 delayed the repair of UV-induced cyclobutane pyrimidine dimers in both normal cells and cancer cells. It did not, however, alter the expression levels or the chromatin association levels of the core NER factors following UV irradiation. Instead, the NDR1-depleted cells displayed reduced activity of ATR for some set of its substrates including CHK1 and p53, suggesting that NDR1 modulates NER indirectly via the ATR pathway. - Highlights: • NDR1 is a novel XPA-interacting protein. • NDR1 accumulates in the nucleus in response to UV irradiation. • NDR1 modulates NER (nucleotide excision repair) by modulating the UV-induced DNA-damage checkpoint response.

  3. NEK11: linking CHK1 and CDC25A in DNA damage checkpoint signaling

    Sørensen, Claus Storgaard; Melixetian, Marina; Klein, Ditte Kjaersgaard

    2010-01-01

    The DNA damage induced G(2)/M checkpoint is an important guardian of the genome that prevents cell division when DNA lesions are present. The checkpoint prevents cells from entering mitosis by degrading CDC25A, a key CDK activator. CDC25A proteolysis is controlled by direct phosphorylation events...... is required for beta-TrCP mediated CDC25A polyubiquitylation and degradation. The activity of NEK11 is in turn controlled by CHK1 that activates NEK11 via phosphorylation on serine 273. Since inhibition of NEK11 activity forces checkpoint-arrested cells into mitosis and cell death, NEK11 is, like CHK1...

  4. Proficiency and sentence constraint effects on second language word learning.

    Ma, Tengfei; Chen, Baoguo; Lu, Chunming; Dunlap, Susan

    2015-07-01

    This paper presents an experiment that investigated the effects of L2 proficiency and sentence constraint on semantic processing of unknown L2 words (pseudowords). All participants were Chinese native speakers who learned English as a second language. In the experiment, we used a whole sentence presentation paradigm with a delayed semantic relatedness judgment task. Both higher and lower-proficiency L2 learners could make use of the high-constraint sentence context to judge the meaning of novel pseudowords, and higher-proficiency L2 learners outperformed lower-proficiency L2 learners in all conditions. These results demonstrate that both L2 proficiency and sentence constraint affect subsequent word learning among second language learners. We extended L2 word learning into a sentence context, replicated the sentence constraint effects previously found among native speakers, and found proficiency effects in L2 word learning. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Checkpoint kinase 1-induced phosphorylation of O-linked β-N-acetylglucosamine transferase regulates the intermediate filament network during cytokinesis.

    Li, Zhe; Li, Xueyan; Nai, Shanshan; Geng, Qizhi; Liao, Ji; Xu, Xingzhi; Li, Jing

    2017-12-01

    Checkpoint kinase 1 (Chk1) is a kinase instrumental for orchestrating DNA replication, DNA damage checkpoints, the spindle assembly checkpoint, and cytokinesis. Despite Chk1's pivotal role in multiple cellular processes, many of its substrates remain elusive. Here, we identified O- linked β- N -acetylglucosamine ( O -GlcNAc)-transferase (OGT) as one of Chk1's substrates. We found that Chk1 interacts with and phosphorylates OGT at Ser-20, which not only stabilizes OGT, but also is required for cytokinesis. Phospho-specific antibodies of OGT-pSer-20 exhibited specific signals at the midbody of the cell, consistent with midbody localization of OGT as reported previously. Moreover, phospho-deficient OGT (S20A) cells attenuated cellular O -GlcNAcylation levels and also reduced phosphorylation of Ser-71 in the cytoskeletal protein vimentin, a modification critical for severing vimentin filament during cytokinesis. Consequently, elongated vimentin bridges were observed in cells depleted of OGT via an si OGT- based approach. Lastly, expression of plasmids resistant to si OGT efficiently rescued the vimentin bridge phenotype, but the OGT-S20A rescue plasmids did not. Our results suggest a Chk1-OGT-vimentin pathway that regulates the intermediate filament network during cytokinesis. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  6. What Is Lexical Proficiency? Some Answers from Computational Models of Speech Data

    Crossley, Scott A.; Salsbury, Tom; McNamara, Danielle S.; Jarvis, Scott

    2011-01-01

    Lexical proficiency, as a cognitive construct, is poorly understood. However, lexical proficiency is an important element of language proficiency and fluency, especially for second language (L2) learners. Lexical proficiency is also an important attribute of L2 academic achievement. Generally speaking, lexical proficiency comprises breadth of…

  7. Differences in Less Proficient and More Proficient ESL College Writing in the Philippine Setting

    Gustilo, Leah E.

    2016-01-01

    The present study aimed at characterizing what skilled or more proficient ESL college writing is in the Philippine setting through a contrastive analysis of three groups of variables identified from previous studies: resources, processes, and performance of ESL writers. Based on Chenoweth and Hayes' (2001; 2003) framework, the resource level…

  8. Developing English Writing Proficiency in Limited English Proficient College Students through Cooperative Learning Strategies.

    Gooden-Jones, Epsey M.; Carrasquillo, Angela L.

    A study followed ten limited-English-proficient (LEP) community college students who were taught English largely using a cooperative learning approach. For four months, the students worked together using brainstorming techniques and collaborative reading and writing tasks. Task emphasis was on development of thinking skills through collaboration…

  9. An origin-deficient yeast artificial chromosome triggers a cell cycle checkpoint.

    van Brabant, A J; Buchanan, C D; Charboneau, E; Fangman, W L; Brewer, B J

    2001-04-01

    Checkpoint controls coordinate entry into mitosis with the completion of DNA replication. Depletion of nucleotide precursors by treatment with the drug hydroxyurea triggers such a checkpoint response. However, it is not clear whether the signal for this hydroxyurea-induced checkpoint pathway is the presence of unreplicated DNA, or rather the persistence of single-stranded or damaged DNA. In a yeast artificial chromosome (YAC) we have engineered an approximately 170 kb region lacking efficient replication origins that allows us to explore the specific effects of unreplicated DNA on cell cycle progression. Replication of this YAC extends the length of S phase and causes cells to engage an S/M checkpoint. In the absence of Rad9 the YAC becomes unstable, undergoing deletions within the origin-free region.

  10. Top3 processes recombination intermediates and modulates checkpoint activity after DNA damage

    Mankouri, Hocine W; Hickson, Ian D

    2006-01-01

    Mutation of TOP3 in Saccharomyces cerevisiae causes poor growth, hyperrecombination, and a failure to fully activate DNA damage checkpoints in S phase. Here, we report that overexpression of a dominant-negative allele of TOP3, TOP3(Y356F), which lacks the catalytic (decatenation) activity of Top3......, the catalytic activity of Top3 is not required for DNA damage checkpoint activation, but it is required for normal S-phase progression after DNA damage. We also present evidence that the checkpoint-mediated cell cycle delay and persistence of X-shaped DNA molecules resulting from overexpression of TOP3(Y356F......) are downstream of Rad51 function. We propose that Top3 functions in S phase to both process homologous recombination intermediates and modulate checkpoint activity....

  11. An ATM-independent S-phase checkpoint response involves CHK1 pathway

    Zhou, Xiang-Yang; Wang, Xiang; Hu, Baocheng; Guan, Jun; Iliakis, George; Wang, Ya

    2002-01-01

    After exposure to genotoxic stress, proliferating cells actively slow down the DNA replication through a S-phase checkpoint to provide time for repair. We report that in addition to the ataxia-telangiectasia mutated (ATM)-dependent pathway that controls the fast response, there is an ATM-independent pathway that controls the slow response to regulate the S-phase checkpoint after ionizing radiation in mammalian cells. The slow response of S-phase checkpoint, which is resistant to wortmannin, sensitive to caffeine and UCN-01, and related to cyclin-dependent kinase phosphorylation, is much stronger in CHK1 overexpressed cells, and it could be abolished by Chk1 antisense oligonucleotides. These results provide evidence that the ATM-independent slow response of S-phase checkpoint involves CHK1 pathway.

  12. Immune-checkpoint inhibitors in the era of precision medicine: What radiologists should know

    Braschi-Amirfarzan, Marta; Tirumani, Sree Harsha; Hodi, Frank Stephan Jr; Nishno, Mizuki [Dept. of Radiology, Brigham and Women' s Hospital and Dana Farber Cancer Institute, Boston (United States)

    2017-01-15

    Over the past five years immune-checkpoint inhibitors have dramatically changed the therapeutic landscape of advanced solid and hematologic malignancies. The currently approved immune-checkpoint inhibitors include antibodies to cytotoxic T-lymphocyte antigen-4, programmed cell death (PD-1), and programmed cell death ligand (PD-L1 and PD-L2). Response to immune-checkpoint inhibitors is evaluated on imaging using the immune-related response criteria. Activation of immune system results in a unique toxicity profile termed immune-related adverse events. This article will review the molecular mechanism, clinical applications, imaging of immune-related response patterns and adverse events associated with immune-checkpoint inhibitors.

  13. Implication of the G2 checkpoint in the maintenance of genome integrity

    Piette, J.; Munoz, P.

    2000-01-01

    Checkpoints are surveillance mechanisms that block transitions, for instance in response to DNA damage. We summarize here here recent progress in the molecular characterization of the G 2 checkpoint which controls the entry into mitosis, and review new evidence which implicates de-regulated expression of checkpoint proteins and proteins involved in DNA damage repair in cancer development. These now exists good evidence that individuals who inherited mutations in genes involved in G 2 checkpoint and DNA damage repair are predisposed to the development of various types of cancer, their cells having a strong tendency to accumulate additional mutations. However, the occurrence of mutations of most of these genes in sporadic tumors has yet to be analysed more accurately. (authors)

  14. Immune-checkpoint inhibitors in the era of precision medicine: What radiologists should know

    Braschi-Amirfarzan, Marta; Tirumani, Sree Harsha; Hodi, Frank Stephan Jr; Nishno, Mizuki

    2017-01-01

    Over the past five years immune-checkpoint inhibitors have dramatically changed the therapeutic landscape of advanced solid and hematologic malignancies. The currently approved immune-checkpoint inhibitors include antibodies to cytotoxic T-lymphocyte antigen-4, programmed cell death (PD-1), and programmed cell death ligand (PD-L1 and PD-L2). Response to immune-checkpoint inhibitors is evaluated on imaging using the immune-related response criteria. Activation of immune system results in a unique toxicity profile termed immune-related adverse events. This article will review the molecular mechanism, clinical applications, imaging of immune-related response patterns and adverse events associated with immune-checkpoint inhibitors

  15. Is there a role for immune checkpoint blockade with ipilimumab in prostate cancer?

    Cha, Edward; Small, Eric J

    2013-01-01

    Treatment for advanced prostate cancer has and will continue to grow increasingly complex, owing to the introduction of multiple new therapeutic approaches with the potential to substantially improve outcomes for this disease. Agents that modulate the patient's immune system to fight prostate cancer – immunotherapeutics – are among the most exciting of these new approaches. The addition of antigen-specific immunotherapy to the treatment of castration-resistant prostate cancer (CRPC) has paved the way for additional research that seeks to augment the activity of the immune system itself. The monoclonal antibody ipilimumab, approved in over 40 countries to treat advanced melanoma and currently under phase 2 and 3 investigation in prostate cancer, is thought to act by augmenting immune responses to tumors through blockade of cytotoxic T-lymphocyte antigen 4, an inhibitory immune checkpoint molecule. Ipilimumab has been studied in seven phase 1 and 2 clinical trials that evaluated various doses, schedules, and combinations across the spectrum of patients with advanced prostate cancer. The CRPC studies of ipilimumab to date suggest that the agent is active in prostate cancer as monotherapy or in combination with radiotherapy, docetaxel, or other immunotherapeutics, and that the adverse event profile is as expected given the safety data in advanced melanoma. The ongoing phase 3 program will further characterize the risk/benefit profile of ipilimumab in chemotherapy-naïve and -pretreated CRPC

  16. Replicative stress and alterations in cell cycle checkpoint controls following acetaminophen hepatotoxicity restrict liver regeneration.

    Viswanathan, Preeti; Sharma, Yogeshwar; Gupta, Priya; Gupta, Sanjeev

    2018-03-05

    Acetaminophen hepatotoxicity is a leading cause of hepatic failure with impairments in liver regeneration producing significant mortality. Multiple intracellular events, including oxidative stress, mitochondrial damage, inflammation, etc., signify acetaminophen toxicity, although how these may alter cell cycle controls has been unknown and was studied for its significance in liver regeneration. Assays were performed in HuH-7 human hepatocellular carcinoma cells, primary human hepatocytes and tissue samples from people with acetaminophen-induced acute liver failure. Cellular oxidative stress, DNA damage and cell proliferation events were investigated by mitochondrial membrane potential assays, flow cytometry, fluorescence staining, comet assays and spotted arrays for protein expression after acetaminophen exposures. In experimental groups with acetaminophen toxicity, impaired mitochondrial viability and substantial DNA damage were observed with rapid loss of cells in S and G2/M and cell cycle restrictions or even exit in the remainder. This resulted from altered expression of the DNA damage regulator, ATM and downstream transducers, which imposed G1/S checkpoint arrest, delayed entry into S and restricted G2 transit. Tissues from people with acute liver failure confirmed hepatic DNA damage and cell cycle-related lesions, including restrictions of hepatocytes in aneuploid states. Remarkably, treatment of cells with a cytoprotective cytokine reversed acetaminophen-induced restrictions to restore cycling. Cell cycle lesions following mitochondrial and DNA damage led to failure of hepatic regeneration in acetaminophen toxicity but their reversibility offers molecular targets for treating acute liver failure. © 2018 John Wiley & Sons Ltd.

  17. The flavonoid eupatorin inactivates the mitotic checkpoint leading to polyploidy and apoptosis

    Salmela, Anna-Leena [VTT Technical Research Centre of Finland, Medical Biotechnology, P.O. Box 106, Turku (Finland); Turku Graduate School of Biomedical Sciences, Turku (Finland); Turku Centre for Biotechnology, P.O. Box 123, University of Turku (Finland); Pouwels, Jeroen; Kukkonen-Macchi, Anu [VTT Technical Research Centre of Finland, Medical Biotechnology, P.O. Box 106, Turku (Finland); Waris, Sinikka; Toivonen, Pauliina [Turku Centre for Biotechnology, P.O. Box 123, University of Turku (Finland); Jaakkola, Kimmo [VTT Technical Research Centre of Finland, Medical Biotechnology, P.O. Box 106, Turku (Finland); Maeki-Jouppila, Jenni [VTT Technical Research Centre of Finland, Medical Biotechnology, P.O. Box 106, Turku (Finland); Turku Centre for Biotechnology, P.O. Box 123, University of Turku (Finland); Drug Discovery Graduate School, University of Turku (Finland); Kallio, Lila, E-mail: lila.kallio@vtt.fi [VTT Technical Research Centre of Finland, Medical Biotechnology, P.O. Box 106, Turku (Finland); Kallio, Marko J. [VTT Technical Research Centre of Finland, Medical Biotechnology, P.O. Box 106, Turku (Finland); Turku Centre for Biotechnology, P.O. Box 123, University of Turku (Finland); Centre of Excellence for Translational Genome-Scale Biology, P.O. Box 106, Academy of Finland (Finland)

    2012-03-10

    The spindle assembly checkpoint (SAC) is a conserved mechanism that ensures the fidelity of chromosome distribution in mitosis by preventing anaphase onset until the correct bipolar microtubule-kinetochore attachments are formed. Errors in SAC function may contribute to tumorigenesis by inducing numerical chromosome anomalies (aneuploidy). On the other hand, total disruption of SAC can lead to massive genomic imbalance followed by cell death, a phenomena that has therapeutic potency. We performed a cell-based high-throughput screen with a compound library of 2000 bioactives for novel SAC inhibitors and discovered a plant-derived phenolic compound eupatorin (3 Prime ,5-dihydroxy-4 Prime ,6,7-trimethoxyflavone) as an anti-mitotic flavonoid. The premature override of the microtubule drug-imposed mitotic arrest by eupatorin is dependent on microtubule-kinetochore attachments but not interkinetochore tension. Aurora B kinase activity, which is essential for maintenance of normal SAC signaling, is diminished by eupatorin in cells and in vitro providing a mechanistic explanation for the observed forced mitotic exit. Eupatorin likely has additional targets since eupatorin treatment of pre-mitotic cells causes spindle anomalies triggering a transient M phase delay followed by impaired cytokinesis and polyploidy. Finally, eupatorin potently induces apoptosis in multiple cancer cell lines and suppresses cancer cell proliferation in organotypic 3D cell culture model.

  18. Adventures in Scaffold Morphing: Discovery of Fused Ring Heterocyclic Checkpoint Kinase 1 (CHK1) Inhibitors.

    Yang, Bin; Vasbinder, Melissa M; Hird, Alexander W; Su, Qibin; Wang, Haixia; Yu, Yan; Toader, Dorin; Lyne, Paul D; Read, Jon A; Breed, Jason; Ioannidis, Stephanos; Deng, Chun; Grondine, Michael; DeGrace, Nancy; Whitston, David; Brassil, Patrick; Janetka, James W

    2018-02-08

    Checkpoint kinase 1 (CHK1) inhibitors are potential cancer therapeutics that can be utilized for enhancing the efficacy of DNA damaging agents. Multiple small molecule CHK1 inhibitors from different chemical scaffolds have been developed and evaluated in clinical trials in combination with chemotherapeutics and radiation treatment. Scaffold morphing of thiophene carboxamide ureas (TCUs), such as AZD7762 (1) and a related series of triazoloquinolines (TZQs), led to the identification of fused-ring bicyclic CHK1 inhibitors, 7-carboxamide thienopyridines (7-CTPs), and 7-carboxamide indoles. X-ray crystal structures reveal a key intramolecular noncovalent sulfur-oxygen interaction in aligning the hinge-binding carboxamide group to the thienopyridine core in a coplanar fashion. An intramolecular hydrogen bond to an indole NH was also effective in locking the carboxamide in the preferred bound conformation to CHK1. Optimization on the 7-CTP series resulted in the identification of lead compound 44, which displayed respectable drug-like properties and good in vitro and in vivo potency.

  19. Orchestration of DNA Damage Checkpoint Dynamics across the Human Cell Cycle.

    Chao, Hui Xiao; Poovey, Cere E; Privette, Ashley A; Grant, Gavin D; Chao, Hui Yan; Cook, Jeanette G; Purvis, Jeremy E

    2017-11-22

    Although molecular mechanisms that prompt cell-cycle arrest in response to DNA damage have been elucidated, the systems-level properties of DNA damage checkpoints are not understood. Here, using time-lapse microscopy and simulations that model the cell cycle as a series of Poisson processes, we characterize DNA damage checkpoints in individual, asynchronously proliferating cells. We demonstrate that, within early G1 and G2, checkpoints are stringent: DNA damage triggers an abrupt, all-or-none cell-cycle arrest. The duration of this arrest correlates with the severity of DNA damage. After the cell passes commitment points within G1 and G2, checkpoint stringency is relaxed. By contrast, all of S phase is comparatively insensitive to DNA damage. This checkpoint is graded: instead of halting the cell cycle, increasing DNA damage leads to slower S phase progression. In sum, we show that a cell's response to DNA damage depends on its exact cell-cycle position and that checkpoints are phase-dependent, stringent or relaxed, and graded or all-or-none. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Evaluation of Mycology Laboratory Proficiency Testing

    Reilly, Andrew A.; Salkin, Ira F.; McGinnis, Michael R.; Gromadzki, Sally; Pasarell, Lester; Kemna, Maggi; Higgins, Nancy; Salfinger, Max

    1999-01-01

    Changes over the last decade in overt proficiency testing (OPT) regulations have been ostensibly directed at improving laboratory performance on patient samples. However, the overt (unblinded) format of the tests and regulatory penalties associated with incorrect values allow and encourage laboratorians to take extra precautions with OPT analytes. As a result OPT may measure optimal laboratory performance instead of the intended target of typical performance attained during routine patient testing. This study addresses this issue by evaluating medical mycology OPT and comparing its fungal specimen identification error rates to those obtained in a covert (blinded) proficiency testing (CPT) program. Identifications from 188 laboratories participating in the New York State mycology OPT from 1982 to 1994 were compared with the identifications of the same fungi recovered from patient specimens in 1989 and 1994 as part of the routine procedures of 88 of these laboratories. The consistency in the identification of OPT specimens was sufficient to make accurate predictions of OPT error rates. However, while the error rates in OPT and CPT were similar for Candida albicans, significantly higher error rates were found in CPT for Candida tropicalis, Candida glabrata, and other common pathogenic fungi. These differences may, in part, be due to OPT’s use of ideal organism representatives cultured under optimum growth conditions. This difference, as well as the organism-dependent error rate differences, reflects the limitations of OPT as a means of assessing the quality of routine laboratory performance in medical mycology. PMID:10364601

  1. Proficiency test in the accreditation system

    Legarda, F.; Herranz, M.; Idoeta, R.

    2008-01-01

    In the accreditation process of a radioactivity measurements laboratory, according to ISO standard 17025, proficiency tests play a fundamental role. These PTs constitute an irreplaceable tool for the validation of measuring methods. In the case of Spain, ENAC, which is the Spanish accreditation national body, requires that the laboratory has to take part in a PT for each one of the accredited measuring methods in the period of time between two reassessments of the accreditation, what happens every 4-5 years. In specific areas of determination procedures, among which radioactive measurements could be included, the number of methods which can be accredited is very large. The purpose of the present work is to establish a classification into families of the different radioactivity measurement procedures, as well as to establish complementary actions that guarantee that carrying out periodically proficiency-tests on any of the included procedures in each family, every measurement procedure include in that family is controlled, complying with the criteria established by ENAC

  2. Modeling the language learning strategies and English language proficiency of pre-university students in UMS: A case study

    Kiram, J. J.; Sulaiman, J.; Swanto, S.; Din, W. A.

    2015-10-01

    This study aims to construct a mathematical model of the relationship between a student's Language Learning Strategy usage and English Language proficiency. Fifty-six pre-university students of University Malaysia Sabah participated in this study. A self-report questionnaire called the Strategy Inventory for Language Learning was administered to them to measure their language learning strategy preferences before they sat for the Malaysian University English Test (MUET), the results of which were utilised to measure their English language proficiency. We attempted the model assessment specific to Multiple Linear Regression Analysis subject to variable selection using Stepwise regression. We conducted various assessments to the model obtained, including the Global F-test, Root Mean Square Error and R-squared. The model obtained suggests that not all language learning strategies should be included in the model in an attempt to predict Language Proficiency.

  3. [Effects of Korean proficiency and parent-child cohesion on self-esteem and acculturation among children from multicultural families].

    Kim, Mi Ye; Lim, Ji Young; Chung, Grace H

    2012-12-01

    There is evidence that parent-child cohesion is a potentially influential factor in children's self-esteem and acculturation. However, no research to date has examined cohesion with parents as a potential pathway between Korean proficiency and self-esteem or acculturation among children from multicultural families. This study was done to address these limitations by examining whether and to what extent cohesion with parents mediated the effect of Korean proficiency on self-esteem and acculturation among children from multicultural families. Data were collected from a sample of 138 mothers and their children living in Seoul, Daegu, Kyungi province, and Kyungpook province. Multiple regression analysis was used to examine the relationships between the variables of interest. Mediation effects of cohesion with parents were tested by following the procedure recommended by Baron and Kenny (1986). Cohesion with parents partially mediated the relationship between Korean proficiency and self-esteem. For children's acculturation, the effect of Korean proficiency was partially mediated through father-child cohesion. Mother-child cohesion completely mediated the relationship between Korean proficiency and acculturation. These findings suggest that to help children from multicultural families experiencing difficulties with self-esteem or acculturation, it might be useful to develop programs that are aimed at strengthen cohesion with parents.

  4. 76 FR 81958 - Notice of Submission of Proposed Information Collection to OMB; Limited English Proficiency...

    2011-12-29

    ... Proposed Information Collection to OMB; Limited English Proficiency Initiative (LEPI) Program AGENCY... that support the assistance of persons with limited English proficiency in utilizing the services...: Limited English Proficiency Initiative (LEPI) Program. OMB Approval Number: 2529-0051. Form Numbers...

  5. Resistance to checkpoint blockade therapy through inactivation of antigen presentation.

    Sade-Feldman, Moshe; Jiao, Yunxin J; Chen, Jonathan H; Rooney, Michael S; Barzily-Rokni, Michal; Eliane, Jean-Pierre; Bjorgaard, Stacey L; Hammond, Marc R; Vitzthum, Hans; Blackmon, Shauna M; Frederick, Dennie T; Hazar-Rethinam, Mehlika; Nadres, Brandon A; Van Seventer, Emily E; Shukla, Sachet A; Yizhak, Keren; Ray, John P; Rosebrock, Daniel; Livitz, Dimitri; Adalsteinsson, Viktor; Getz, Gad; Duncan, Lyn M; Li, Bo; Corcoran, Ryan B; Lawrence, Donald P; Stemmer-Rachamimov, Anat; Boland, Genevieve M; Landau, Dan A; Flaherty, Keith T; Sullivan, Ryan J; Hacohen, Nir

    2017-10-26

    Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients with metastatic melanoma, but the common mechanisms of primary and acquired resistance to these agents remain incompletely characterized and have yet to be validated in large cohorts. By analyzing longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB therapies, we observed point mutations, deletions or loss of heterozygosity (LOH) in beta-2-microglobulin (B2M), an essential component of MHC class I antigen presentation, in 29.4% of patients with progressing disease. In two independent cohorts of melanoma patients treated with anti-CTLA4 and anti-PD1, respectively, we find that B2M LOH is enriched threefold in non-responders (~30%) compared to responders (~10%) and associated with poorer overall survival. Loss of both copies of B2M is found only in non-responders. B2M loss is likely a common mechanism of resistance to therapies targeting CTLA4 or PD1.

  6. Identification of a novel EGF-sensitive cell cycle checkpoint

    Walker, Francesca; Zhang Huihua; Burgess, Antony W.

    2007-01-01

    The site of action of growth factors on mammalian cell cycle has been assigned to the boundary between the G1 and S phases. We show here that Epidermal Growth Factor (EGF) is also required for mitosis. BaF/3 cells expressing the EGFR (BaF/wtEGFR) synthesize DNA in response to EGF, but arrest in S-phase. We have generated a cell line (BaF/ERX) with defective downregulation of the EGFR and sustained activation of EGFR signalling pathways: these cells undergo mitosis in an EGF-dependent manner. The transit of BaF/ERX cells through G2/M strictly requires activation of EGFR and is abolished by AG1478. This phenotype is mimicked by co-expression of ErbB2 in BaF/wtEGFR cells, and abolished by inhibition of the EGFR kinase, suggesting that sustained signalling of the EGFR, through impaired downregulation of the EGFR or heterodimerization, is required for completion of the cycle. We have confirmed the role of EGFR signalling in the G2/M phase of the cell cycle using a human tumor cell line which overexpresses the EGFR and is dependent on EGFR signalling for growth. These findings unmask an EGF-sensitive checkpoint, helping to understand the link between sustained EGFR signalling, proliferation and the acquisition of a radioresistant phenotype in cancer cells

  7. Loss of the Greatwall Kinase Weakens the Spindle Assembly Checkpoint.

    M Kasim Diril

    2016-09-01

    Full Text Available The Greatwall kinase/Mastl is an essential gene that indirectly inhibits the phosphatase activity toward mitotic Cdk1 substrates. Here we show that although Mastl knockout (MastlNULL MEFs enter mitosis, they progress through mitosis without completing cytokinesis despite the presence of misaligned chromosomes, which causes chromosome segregation defects. Furthermore, we uncover the requirement of Mastl for robust spindle assembly checkpoint (SAC maintenance since the duration of mitotic arrest caused by microtubule poisons in MastlNULL MEFs is shortened, which correlates with premature disappearance of the essential SAC protein Mad1 at the kinetochores. Notably, MastlNULL MEFs display reduced phosphorylation of a number of proteins in mitosis, which include the essential SAC kinase MPS1. We further demonstrate that Mastl is required for multi-site phosphorylation of MPS1 as well as robust MPS1 kinase activity in mitosis. In contrast, treatment of MastlNULL cells with the phosphatase inhibitor okadaic acid (OKA rescues the defects in MPS1 kinase activity, mislocalization of phospho-MPS1 as well as Mad1 at the kinetochore, and premature SAC silencing. Moreover, using in vitro dephosphorylation assays, we demonstrate that Mastl promotes persistent MPS1 phosphorylation by inhibiting PP2A/B55-mediated MPS1 dephosphorylation rather than affecting Cdk1 kinase activity. Our findings establish a key regulatory function of the Greatwall kinase/Mastl->PP2A/B55 pathway in preventing premature SAC silencing.

  8. Loss of the Greatwall Kinase Weakens the Spindle Assembly Checkpoint.

    Diril, M Kasim; Bisteau, Xavier; Kitagawa, Mayumi; Caldez, Matias J; Wee, Sheena; Gunaratne, Jayantha; Lee, Sang Hyun; Kaldis, Philipp

    2016-09-01

    The Greatwall kinase/Mastl is an essential gene that indirectly inhibits the phosphatase activity toward mitotic Cdk1 substrates. Here we show that although Mastl knockout (MastlNULL) MEFs enter mitosis, they progress through mitosis without completing cytokinesis despite the presence of misaligned chromosomes, which causes chromosome segregation defects. Furthermore, we uncover the requirement of Mastl for robust spindle assembly checkpoint (SAC) maintenance since the duration of mitotic arrest caused by microtubule poisons in MastlNULL MEFs is shortened, which correlates with premature disappearance of the essential SAC protein Mad1 at the kinetochores. Notably, MastlNULL MEFs display reduced phosphorylation of a number of proteins in mitosis, which include the essential SAC kinase MPS1. We further demonstrate that Mastl is required for multi-site phosphorylation of MPS1 as well as robust MPS1 kinase activity in mitosis. In contrast, treatment of MastlNULL cells with the phosphatase inhibitor okadaic acid (OKA) rescues the defects in MPS1 kinase activity, mislocalization of phospho-MPS1 as well as Mad1 at the kinetochore, and premature SAC silencing. Moreover, using in vitro dephosphorylation assays, we demonstrate that Mastl promotes persistent MPS1 phosphorylation by inhibiting PP2A/B55-mediated MPS1 dephosphorylation rather than affecting Cdk1 kinase activity. Our findings establish a key regulatory function of the Greatwall kinase/Mastl->PP2A/B55 pathway in preventing premature SAC silencing.

  9. Teaching English through English: Proficiency, Pedagogy and Performance

    Richards, Jack C.

    2017-01-01

    Most of the world's English language teachers speak English as a second or third language rather than as their first language. For many, their level of proficiency in English may not reach benchmarks established by their employers, raising the issue that is the focus of this article, namely, what kind of proficiency in English is necessary to be…

  10. The Nevada Proficiency Examination Program: Evaluating the Writing Samples.

    Howard, Edward H.

    Writing tests are part of the mandated statewide proficiency examination in Nevada. The ninth-grade screening test and the eleventh-grade diploma-certifying test require that a student write a paragraph and a business letter, each on an assigned topic and each at an acceptable level of proficiency. Pilot tests, extended discussion, and statistical…

  11. Reconnecting Proficiency, Literacy, and Culture: From Theory to Practice

    Warford, Mark K.; White, William L.

    2012-01-01

    What does it mean to capably communicate across languages? This article introduces two theoretical models and a lesson plan format designed to facilitate the integration of proficiency, literacy, and culture teaching in foreign language teaching. The Second Symbolic Competencies Model configures proficiency and literacy as subordinate clusters of…

  12. 5 CFR 9901.364 - Foreign language proficiency pay.

    2010-01-01

    ... 5 Administrative Personnel 3 2010-01-01 2010-01-01 false Foreign language proficiency pay. 9901... NATIONAL SECURITY PERSONNEL SYSTEM (NSPS) Pay and Pay Administration Premium Pay § 9901.364 Foreign language proficiency pay. (a) General provisions. (1) This section applies to employees who may be paid...

  13. Proficiency testing for sensory profile panels : measuring panel performance

    Mcewan, J.A.; Hunter, E.A.; Gemert, L.J. van; Lea, P.

    2002-01-01

    Proficiency testing in sensory analysis is an important step towards demonstrating that results from one sensory panel are consistent with the results of other sensory panels. The uniqueness of sensory analysis poses some specific problems for measuring the proficiency of the human instrument

  14. English Proficiency and Participation in Online Discussion for Learning

    Leung, Steve

    2013-01-01

    Does English proficiency affect participation in online discussion? This study polled 14 students from a postgraduate online course that require online discussion. The students are divided into groups according to their home language spoken and self-assessed English proficiency, and measure against their participation level in the required…

  15. Proficiency test for tropane alkaloids in food en feed

    Pereboom-de Fauw, D.P.K.H.; Elbers, I.J.W.; Mulder, P.P.J.; Nijs, de W.C.M.

    2014-01-01

    Proficiency testing is conducted to provide laboratories with a powerful tool to evaluate and demonstrate the reliability of the data that are produced. Next to validation and accreditation, proficiency testing is an important requirement of the EU Additional Measures Directive 93/99/EEC [1] and is

  16. The correlation between motor proficiency and physical activity in ...

    Background: One of the risks associated with low physical activity levels is the insufficient development of motor proficiency, which in turn has an impact on participation in physical activity and sport during adolescence. Objectives: To determine the relationship between motor proficiency and physical activity levels in ...

  17. Proficiency test for heavy metals in compound feed

    Pereboom, D.P.K.H.; Elbers, I.J.W.; Jong, de J.; Lee, van der M.K.; Nijs, de W.C.M.

    2016-01-01

    The here described proficiency test for heavy metals in compound feed was organised by RIKILT, Wageningen UR in accordance with ISO 17043. RIKILT Wageningen UR has an ISO/IEC 17043 accreditation for proficiency tests of residues in products of animal origin. However, this specific test is not part

  18. The Prediction of Training Proficiency in Firefighters: A Study of Predictive Validity in Spain

    Alfredo Berges

    2018-02-01

    Full Text Available The present study provides results of criterion validity in the selection of firefighters in Spain. The predictors were cognitive skills, job knowledge, and physical aptitudes, and the criterion was training proficiency. The process involves 639 candidates, but only 44 complete successfully the selection process. Our results support previous evidence showing that general cognitive ability is the best predictor of training proficiency, with an operational validity of .57. With respect to the other predictors, job knowledge presented an operational validity of .55 and physical tests of .49. In addition, multiple regression analysis showed that cognitive aptitude explains 33% of the variance, but when physical aptitudes are included the explained variance increases to 50%. If we also add job knowledge, explained variance increases to 55%. Our study offers recent results of criterion validity in a barely investigated job, gathered in a country other than the one where prior research had been carried out.

  19. The Rating of Direct and Semi-Direct Oral Proficiency Interviews: Comparing Performance at Lower Proficiency Levels.

    Kenyon, Dorry M.; Tschirner, Erwin

    2000-01-01

    Reports on a study comparing student performances and test reliabilities for the German Speaking Test, a semi-direct tape-mediated oral proficiency test (GST) developed by the Center for Applied Linguistics, and the American Council on the Teaching of Foreign Languages Oral Proficiency Interviews. (Author/VWL)

  20. Smurf2 as a novel mitotic regulator: From the spindle assembly checkpoint to tumorigenesis

    Moore Finola E

    2009-07-01

    Full Text Available Abstract The execution of the mitotic program with high fidelity is dependent upon precise spatiotemporal regulation of posttranslational protein modifications. For example, the timely polyubiquitination of critical mitotic regulators by Anaphase Promoting Complex/Cyclosome (APC/C is essential for the metaphase to anaphase transition and mitotic exit. The spindle assembly checkpoint prevents unscheduled activity of APC/C-Cdc20 in early mitosis, allowing bipolar attachment of kinetochores to mitotic spindle and facilitating equal segregation of sister chromatids. The critical effector of the spindle checkpoint, Mitotic arrest deficient 2 (Mad2, is recruited to unattached kinetochores forming a complex with other regulatory proteins to efficiently and cooperatively inhibit APC/C-Cdc20. A weakened and/or dysfunctional spindle checkpoint has been linked to the development of genomic instability in both cell culture and animal models, and evidence suggests that aberrant regulation of the spindle checkpoint plays a critical role in human carcinogenesis. Recent studies have illuminated a network of both degradative and non-degradative ubiquitination events that regulate the metaphase to anaphase transition and mitotic exit. Within this context, our recent work showed that the HECT (Homologous to E6-AP C-terminus-family E3 ligase Smurf2 (Smad specific ubiquitin regulatory factor 2, known as a negative regulator of transforming growth factor-beta (TGF-β signaling, is required for a functional spindle checkpoint by promoting the functional localization and stability of Mad2. Here we discuss putative models explaining the role of Smurf2 as a new regulator in the spindle checkpoint. The dynamic mitotic localization of Smurf2 to the centrosome and other critical mitotic structures provides implications about mitotic checkpoint control dependent on various ubiquitination events. Finally, deregulated Smurf2 activity may contribute to carcinogenesis by

  1. Bir1 Deletion Causes Malfunction of the Spindle Assembly Checkpoint and Apoptosis in Yeast

    Ren, Qun; Liou, Liang-Chun; Gao, Qiuqiang; Bao, Xiaoming; Zhang, Zhaojie

    2012-01-01

    Cell division in yeast is a highly regulated and well studied event. Various checkpoints are placed throughout the cell cycle to ensure faithful segregation of sister chromatids. Unexpected events, such as DNA damage or oxidative stress, cause the activation of checkpoint(s) and cell cycle arrest. Malfunction of the checkpoints may induce cell death. We previously showed that under oxidative stress, the budding yeast cohesin Mcd1, a homolog of human Rad21, was cleaved by the caspase-like protease Esp1. The cleaved Mcd1 C-terminal fragment was then translocated to mitochondria, causing apoptotic cell death. In the present study, we demonstrated that Bir1 plays an important role in spindle assembly checkpoint and cell death. Similar to H 2 O 2 treatment, deletion of BIR1 using a BIR1-degron strain caused degradation of the securin Pds1, which binds and inactivates Esp1 until metaphase-anaphase transition in a normal cell cycle. BIR1 deletion caused an increase level of ROS and mis-location of Bub1, a major protein for spindle assembly checkpoint. In wild type, Bub1 was located at the kinetochores, but was primarily in the cytoplasm in bir1 deletion strain. When BIR1 was deleted, addition of nocodazole was unable to retain the Bub1 localization on kinetochores, further suggesting that Bir1 is required to activate and maintain the spindle assembly checkpoint. Our study suggests that the BIR1 function in cell cycle regulation works in concert with its anti-apoptosis function.

  2. Proficiency-based cervical cancer brachytherapy training.

    Zhao, Sherry; Francis, Louise; Todor, Dorin; Fields, Emma C

    2018-04-25

    Although brachytherapy increases the local control rate for cervical cancer, there has been a progressive decline in its use. Furthermore, the training among residency programs for gynecologic brachytherapy varies considerably, with some residents receiving little to no training. This trend is especially concerning given the association between poor applicator placement and decline in local control. Considering the success of proficiency-based training in other procedural specialties, we developed and implemented a proficiency-based cervical brachytherapy training curriculum for our residents. Each resident placed tandem and ovoid applicators with attending guidance and again alone 2 weeks later using a pelvic model that was modified to allow for cervical brachytherapy. Plain films were taken of the pelvic model, and applicator placement quality was evaluated. Other evaluated metrics included retention of key procedural details, the time taken for each procedure and presession and postsession surveys to assess confidence. During the initial session, residents on average met 4.5 of 5 placement criteria, which improved to 5 the second session. On average, residents were able to remember 7.6 of the 8 key procedural steps. Execution time decreased by an average of 10.5%. Resident confidence with the procedure improved dramatically, from 2.6 to 4.6 of 5. Residents who had previously never performed a tandem and ovoid procedure showed greater improvements in these criteria than those who had. All residents strongly agreed that the training was helpful and wanted to participate again the following year. Residents participating in this simulation training had measurable improvements in the time to perform the procedure, applicator placement quality, and confidence. This curriculum is easy to implement and is of great value for training residents, and would be particularly beneficial in programs with low volume of cervical brachytherapy cases. Simulation programs could

  3. Aberrant PO2 values in proficiency testing.

    Fonzi, C E; Clausen, J L; Mahoney, J

    1993-03-01

    We prospectively determined the frequency of aberrant vials of fluorocarbon/buffer used for proficiency testing of measurements of pH, PCO2, and PO2, using 20 duplicate vials from 12 lots of fluorocarbon/buffer and two arterial blood gas analyzers in eight reference laboratories. We defined aberrant vials as vials for which both duplicate measurements differed from the mean value of repeated measurements for the specific instrument (for each lot of testing materials) by > 0.04 for pH, > 10% of the mean or 3.0 mm Hg, whichever was greater, for PCO2; or > 10% of the mean or 6 mm Hg, whichever was greater, for PO2. Four of 1620 vials (0.25%) were aberrant, all based on PO2 measurements (range of mean values: pH, 7.181-7.631; PCO2, 12.7-65.9; PO2, 32.5-150.1) were 0.0055 for pH, 0.67 mm Hg for PCO2, and 1.65 mm Hg for PO2. Deliberate contamination of the fluorocarbon emulsion with room air, as might occur during sampling from the vial, indicated that only minor increases in PO2 (e.g., 1.0 mm Hg at PO2 of 56 mm Hg) occur when samples are aspirated. Larger increases in PO2 (mean 7.1 mm Hg at a PO2 of 66 mm Hg) occurred when the syringe samples were contaminated with room air. We conclude that isolated aberrant measurements of PO2 in blood gas proficiency testing attributable to vial contents can occur, but the frequency is very low.

  4. The amount of DNA damage needed to activate the radiation-induced G2 checkpoint varies between single cells

    Tkacz-Stachowska, Kinga; Lund-Andersen, Christin; Velissarou, Angeliki; Myklebust, June H.; Stokke, Trond; Syljuåsen, Randi G.

    2011-01-01

    Background and purpose: The radiation-induced G2 checkpoint helps facilitate DNA repair before cell division. However, recent work has revealed that human cells often escape the G2 checkpoint with unrepaired DNA breaks. The purpose was to explore whether G2 checkpoint activation occurs according to a threshold level of DNA damage. Materials and methods: G2 checkpoint activation was assayed at 75–90 min and 24–48 h after X-ray irradiation of BJ diploid fibroblasts and U2OS osteosarcoma cells. Multiparameter flow cytometry with pacific blue barcoding, and flow cytometry-based sorting of phospho-H3 positive cells to microscope slides, were used to examine the DNA damage marker γ-H2AX in individual mitotic cells that had escaped the G2 checkpoint. Results: For all radiation doses and times tested, the number of γ-H2AX foci varied between individual mitotic cells. At 75 min the median levels of γ-H2AX in mitotic cells increased with higher radiation doses. At 24–48 h, following a prolonged G2 checkpoint, cells were more resistant to checkpoint re-activation by a second dose of radiation. Conclusion: Our results suggest that different amounts of DNA damage are needed to activate the G2 checkpoint in individual cells. Such single cell variation in checkpoint activation may potentially contribute to radiation-induced genomic instability.

  5. Asynchronous Two-Level Checkpointing Scheme for Large-Scale Adjoints in the Spectral-Element Solver Nek5000

    Schanen, Michel; Marin, Oana; Zhang, Hong; Anitescu, Mihai

    2016-01-01

    Adjoints are an important computational tool for large-scale sensitivity evaluation, uncertainty quantification, and derivative-based optimization. An essential component of their performance is the storage/recomputation balance in which efficient checkpointing methods play a key role. We introduce a novel asynchronous two-level adjoint checkpointing scheme for multistep numerical time discretizations targeted at large-scale numerical simulations. The checkpointing scheme combines bandwidth-limited disk checkpointing and binomial memory checkpointing. Based on assumptions about the target petascale systems, which we later demonstrate to be realistic on the IBM Blue Gene/Q system Mira, we create a model of the expected performance of our checkpointing approach and validate it using the highly scalable Navier-Stokes spectralelement solver Nek5000 on small to moderate subsystems of the Mira supercomputer. In turn, this allows us to predict optimal algorithmic choices when using all of Mira. We also demonstrate that two-level checkpointing is significantly superior to single-level checkpointing when adjoining a large number of time integration steps. To our knowledge, this is the first time two-level checkpointing had been designed, implemented, tuned, and demonstrated on fluid dynamics codes at large scale of 50k+ cores.

  6. Casein kinase II is required for the spindle assembly checkpoint by regulating Mad2p in fission yeast

    Shimada, Midori; Yamamoto, Ayumu; Murakami-Tonami, Yuko; Nakanishi, Makoto; Yoshida, Takashi; Aiba, Hirofumi; Murakami, Hiroshi

    2009-01-01

    The spindle checkpoint is a surveillance mechanism that ensures the fidelity of chromosome segregation in mitosis. Here we show that fission yeast casein kinase II (CK2) is required for this checkpoint function. In the CK2 mutants mitosis occurs in the presence of a spindle defect, and the spindle checkpoint protein Mad2p fails to localize to unattached kinetochores. The CK2 mutants are sensitive to the microtubule depolymerising drug thiabendazole, which is counteracted by ectopic expression of mad2 + . The level of Mad2p is low in the CK2 mutants. These results suggest that CK2 has a role in the spindle checkpoint by regulating Mad2p.

  7. In-silico modeling of the mitotic spindle assembly checkpoint.

    Bashar Ibrahim

    2008-02-01

    Full Text Available The Mitotic Spindle Assembly Checkpoint ((MSAC is an evolutionary conserved mechanism that ensures the correct segregation of chromosomes by restraining cell cycle progression from entering anaphase until all chromosomes have made proper bipolar attachments to the mitotic spindle. Its malfunction can lead to cancer.We have constructed and validated for the human (MSAC mechanism an in silico dynamical model, integrating 11 proteins and complexes. The model incorporates the perspectives of three central control pathways, namely Mad1/Mad2 induced Cdc20 sequestering based on the Template Model, MCC formation, and APC inhibition. Originating from the biochemical reactions for the underlying molecular processes, non-linear ordinary differential equations for the concentrations of 11 proteins and complexes of the (MSAC are derived. Most of the kinetic constants are taken from literature, the remaining four unknown parameters are derived by an evolutionary optimization procedure for an objective function describing the dynamics of the APC:Cdc20 complex. MCC:APC dissociation is described by two alternatives, namely the "Dissociation" and the "Convey" model variants. The attachment of the kinetochore to microtubuli is simulated by a switching parameter silencing those reactions which are stopped by the attachment. For both, the Dissociation and the Convey variants, we compare two different scenarios concerning the microtubule attachment dependent control of the dissociation reaction. Our model is validated by simulation of ten perturbation experiments.Only in the controlled case, our models show (MSAC behaviour at meta- to anaphase transition in agreement with experimental observations. Our simulations revealed that for (MSAC activation, Cdc20 is not fully sequestered; instead APC is inhibited by MCC binding.

  8. Acute symptomatic hypocalcemia from immune checkpoint therapy-induced hypoparathyroidism.

    Win, Myint Aung; Thein, Kyaw Zin; Qdaisat, Aiham; Yeung, Sai-Ching Jim

    2017-07-01

    Ipilimumab (a monoclonal antibody against CTLA-4) and nivolumab (a humanized antibody against PD-1) target these immune checkpoint pathways and are used for treatment of melanoma and an increasing number of other cancers. However, they may cause immune-related adverse effects (IRAEs). Although many endocrinopathies are known to be IRAEs, primary hypoparathyroidism with severe hypocalcemia has never been reported. This is the first case of hypoparathyroidism as an IRAE presenting to an Emergency Department with acute hypocalcemia. A 73-year-old man with metastatic melanoma presented to the Emergency Department for the chief complaints of imbalance, general muscle weakness, abdominal pain and tingling in extremities. He had wide spread metastasis, and begun immunotherapy with concurrent ipilimumab and nivolumab 1.5months ago. At presentation, he had ataxia, paresthesia in the hands and feet, and abdominal cramping. Magnetic resonance imaging of the brain was unremarkable. He was found to be hypocalcemic with undetectable plasma parathyroid hormone. He was admitted for treatment of symptomatic hypocalcemia and was diagnosed with primary hypoparathyroidism. Shortly afterwards, he had thyrotoxicosis manifesting as tachycardia and anxiety, followed by development of primary hypothyroidism. At 4months after the Emergency Department visit, his parathyroid function and thyroid function had not recovered, and required continued thyroid hormone replacement and calcium and vitamin D treatment for hypocalcemia. Primary hypoparathyroidism caused by ipilimumab and nivolumab may acute manifest with severe symptomatic hypocalcemia. Emergency care providers should be aware of hypoparathyroidism as a new IRAE in this new era of immuno-oncology. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Calreticulin reveals a critical Ca2+ checkpoint in cardiac myofibrillogenesis

    Li, Jian; Pucéat, Michel; Perez-Terzic, Carmen; Mery, Annabelle; Nakamura, Kimitoshi; Michalak, Marek; Krause, Karl-Heinz; Jaconi, Marisa E.

    2002-01-01

    Calreticulin (crt) is an ubiquitously expressed and multifunctional Ca2+-binding protein that regulates diverse vital cell functions, including Ca2+ storage in the ER and protein folding. Calreticulin deficiency in mice is lethal in utero due to defects in heart development and function. Herein, we used crt − / − embryonic stem (ES) cells differentiated in vitro into cardiac cells to investigate the molecular mechanisms underlying heart failure of knockout embryos. After 8 d of differentiation, beating areas were prominent in ES-derived wild-type (wt) embryoid bodies (EBs), but not in ES-derived crt − / − EBs, despite normal expression levels of cardiac transcription factors. Crt − / − EBs exhibited a severe decrease in expression and a lack of phosphorylation of ventricular myosin light chain 2 (MLC2v), resulting in an impaired organization of myofibrils. Crt − / − phenotype could be recreated in wt cells by chelating extracellular or cytoplasmic Ca2+ with EGTA or BAPTA, or by inhibiting Ca2+/calmodulin-dependent kinases (CaMKs). An imposed ionomycin-triggered cystolic-free Ca2+ concentration ([Ca2+]c) elevation restored the expression, phosphorylation, and insertion of MLC2v into sarcomeric structures and in turn the myofibrillogenesis. The transcription factor myocyte enhancer factor C2 failed to accumulate into nuclei of crt − / − cardiac cells in the absence of ionomycin-triggered [Ca2+]c increase. We conclude that the absence of calreticulin interferes with myofibril formation. Most importantly, calreticulin deficiency revealed the importance of a Ca2+-dependent checkpoint critical for early events during cardiac myofibrillogenesis. PMID:12105184

  10. The organizational effects of pubertal testosterone on sexual proficiency in adult male Syrian hamsters.

    De Lorme, Kayla C; Sisk, Cheryl L

    2016-10-15

    Social proficiency requires making appropriate behavioral adaptations as a result of social experience. For example, male rodents become sexually proficient with experience as demonstrated by a reduction in ectopic (misdirected) mounts, mount-to-intromission ratio, and latency to ejaculation. We previously found that over a series of timed tests with a receptive female, male hamsters deprived of testosterone specifically during puberty (NoT@P) have overall lower levels of sexual behavior and continue to display high levels of ectopic mounts, compared with males that experienced endogenous testosterone during puberty (T@P). These results suggested that pubertal testosterone programs sexual proficiency in adulthood, but because NoT@P males engaged in less sexual behavior than T@P males in these tests, the amount of sexual experience may have been insufficient to improve sexual proficiency. To more rigorously test the hypothesis that pubertal testosterone is necessary for social proficiency in adulthood, the present study compared the behavior of NoT@P and T@P males in a series of 4 trials with a 48-h interval between each trial. Sexual experience was equated by limiting each trial to 5 intromissions. Sexually-naïve males were either gonadectomized prepubertally (NoT@P) or in adulthood (T@P) and received subcutaneous testosterone capsules four weeks later. Two weeks after testosterone replacement, these groups and a group of adult gonad-intact controls began sexual behavior testing. We found that NoT@P males had more ectopic mounts/min across all four tests compared to gonad-intact and T@P males. Moreover, both gonad-intact and T@P males, but not NoT@P males, showed an increase in the number of mounts and intromissions/min between trials 1 and 3. Unexpectedly, both gonad-intact and T@P, but not NoT@P, males showed a decrease in sexual behaviors during trial 4. Thus, T@P males display multiple behavioral adaptations to sexual experience that are not observed in No

  11. Caffeine stabilizes Cdc25 independently of Rad3 in S chizosaccharomyces pombe contributing to checkpoint override

    Alao, John P; Sjölander, Johanna J; Baar, Juliane; Özbaki-Yagan, Nejla; Kakoschky, Bianca; Sunnerhagen, Per

    2014-01-01

    Cdc25 is required for Cdc2 dephosphorylation and is thus essential for cell cycle progression. Checkpoint activation requires dual inhibition of Cdc25 and Cdc2 in a Rad3-dependent manner. Caffeine is believed to override activation of the replication and DNA damage checkpoints by inhibiting Rad3-related proteins in both S chizosaccharomyces pombe and mammalian cells. In this study, we have investigated the impact of caffeine on Cdc25 stability, cell cycle progression and checkpoint override. Caffeine induced Cdc25 accumulation in S . pombe independently of Rad3. Caffeine delayed cell cycle progression under normal conditions but advanced mitosis in cells treated with replication inhibitors and DNA-damaging agents. In the absence of Cdc25, caffeine inhibited cell cycle progression even in the presence of hydroxyurea or phleomycin. Caffeine induces Cdc25 accumulation in S . pombe by suppressing its degradation independently of Rad3. The induction of Cdc25 accumulation was not associated with accelerated progression through mitosis, but rather with delayed progression through cytokinesis. Caffeine-induced Cdc25 accumulation appears to underlie its ability to override cell cycle checkpoints. The impact of Cdc25 accumulation on cell cycle progression is attenuated by Srk1 and Mad2. Together our findings suggest that caffeine overrides checkpoint enforcement by inducing the inappropriate nuclear localization of Cdc25. PMID:24666325

  12. Relationship between phonological awareness and spelling proficiency in first-grade students

    Nasibe Soltaninejad

    2014-12-01

    Full Text Available Background and Aim: Phonological awareness (consisting of phoneme, syllable and intra-syllable awareness is an important part of receptive and expressive language; it facilitates reading and writing skills through phonological re-coding. Multiple studies in several languages have studied the relationship between phonological awareness and dictation. This research is based on a study of the relationship between phonological skill and spelling score in first-grade Persian students.Methods: Four hundred first-grade students participated in the study, including 209 girls and 191 boys. A phonological awareness test was individually administered for each student and then a spelling exam was administered in groups. The correlation between the two tests was studied using a simple regression model. The comparison of mean scores of girls and boys was evaluated employing an independent t-test.Results: A correlation coefficient of 0.82 was obtained between phonological awareness and spelling proficiency (p<0.001. Phonological skill sub-tests also showed a significant correlation with spelling proficiency (highest for phoneme awareness r=0.34 and lowest for rhyme awareness r=0.12. The mean scores of girls and boys differed significantly (p<0.05.Conclusion: There is a strong positive association between phonological awareness and spelling proficiency. Therefore, if phonological skill is improved, spelling score can be enhanced.

  13. Observed hierarchy of student proficiency with period, frequency, and angular frequency

    Nicholas T. Young

    2018-01-01

    Full Text Available In the context of a generic harmonic oscillator, we investigated students’ accuracy in determining the period, frequency, and angular frequency from mathematical and graphical representations. In a series of studies including interviews, free response tests, and multiple choice tests developed in an iterative process, we assessed students in both algebra-based and calculus-based, traditionally instructed university-level introductory physics courses. Using the results, we categorized nine skills necessary for proficiency in determining period, frequency, and angular frequency. Overall results reveal that, postinstruction, proficiency is quite low: only about 20%–40% of students mastered most of the nine skills. Next, we used a semiquantitative, intuitive method to investigate the hierarchical structure of the nine skills. We also employed the more formal item tree analysis method to verify this structure and found that the skills form a multilevel, nonlinear hierarchy, with mastery of some skills being prerequisite for mastery in other skills. Finally, we implemented a targeted, 30-min group-work activity to improve proficiency in these skills and found a 1 standard deviation gain in accuracy. Overall, the results suggest that many students currently lack these essential skills, targeted practice may lead to required mastery, and that the observed hierarchical structure in the skills suggests that instruction should especially attend to the skills lower in the hierarchy.

  14. READING COMPREHENSION EXERCISES ONLINE: THE EFFECTS OF FEEDBACK, PROFICIENCY AND INTERACTION

    Philip Murphy

    2007-02-01

    Full Text Available This paper describes an ongoing project to create an online version of a reading programme, a custom-designed English language proficiency course at a university in Japan. Following an interactionist view of second language acquisition, it was hypothesised that comprehension of a reading passage could be enhanced by online materials promoting interaction between students as they completed a multiple-choice reading comprehension exercise. Interaction was promoted: (a through pair work at a single computer and (b by providing Elaborative feedback in the form of hints about incorrect answers as a means of stimulating discussion about corrections. Students were randomly selected from upper and lower levels of English proficiency, as determined by the Kanda English Proficiency Test (Bonk & Ockey, 2003, to receive either Elaborative feedback or Knowledge of Correct Response feedback (which supplies the correct answers. Within these groups, some students worked in pairs and some alone. Quantitative results show that the interaction between Type of feedback and Manner of study (individual or pair work was statistically significant; students performed best on a follow-up comprehension exercise when in pairs and having been provided with Elaborative feedback. Furthermore, qualitative analysis of transcribed interactions also shows that Elaborative feedback was conducive to quality interaction.

  15. Television viewing in low-income latino children: variation by ethnic subgroup and English proficiency.

    Thompson, Darcy A; Matson, Pamela A; Ellen, Jonathan M

    2013-02-01

    Television viewing is associated with an increased risk for obesity in children. Latino children are at high risk for obesity and yet little is known about differences in television viewing habits within this population. The purpose of this study is to determine if hours of television viewed by young children with low-income Latina mothers differs by maternal ethnic subgroup and English language proficiency. This was a cross-sectional analysis of data from the Welfare, Children, & Families: A Three City Study. Participants were 422 low-income Latina mothers of Mexican and Puerto Rican descent with children ages 0-4 years old. The dependent variable was hours of daily television viewed by the child. The independent variable was maternal ethnic subgroup and English language proficiency. Analyses involved the use of multiple negative binomial regression models, which were adjusted for demographic variables. Multivariable regression analyses showed that compared to children with mothers of Mexican descent, children of mothers of Puerto Rican descent watch more daily television (child television viewing (IRR=1.29, 95% CI 1.04, 1.61). No relationship was found for children of Puerto Rican descent. Child television viewing varies in low-income Latino children by maternal ethnic subgroup and English language proficiency. Interventionists must consider the varying sociocultural contexts of Latino children and their influence on television viewing.

  16. Television Viewing in Low-Income Latino Children: Variation by Ethnic Subgroup and English Proficiency

    Matson, Pamela A.; Ellen, Jonathan M.

    2013-01-01

    Abstract Background Television viewing is associated with an increased risk for obesity in children. Latino children are at high risk for obesity and yet little is known about differences in television viewing habits within this population. The purpose of this study is to determine if hours of television viewed by young children with low-income Latina mothers differs by maternal ethnic subgroup and English language proficiency. Methods This was a cross-sectional analysis of data from the Welfare, Children, & Families: A Three City Study. Participants were 422 low-income Latina mothers of Mexican and Puerto Rican descent with children ages 0–4 years old. The dependent variable was hours of daily television viewed by the child. The independent variable was maternal ethnic subgroup and English language proficiency. Analyses involved the use of multiple negative binomial regression models, which were adjusted for demographic variables. Results Multivariable regression analyses showed that compared to children with mothers of Mexican descent, children of mothers of Puerto Rican descent watch more daily television (television viewing (IRR=1.29, 95% CI 1.04, 1.61). No relationship was found for children of Puerto Rican descent. Conclusions Child television viewing varies in low-income Latino children by maternal ethnic subgroup and English language proficiency. Interventionists must consider the varying sociocultural contexts of Latino children and their influence on television viewing. PMID:23301653

  17. DW-MRI as a Predictive Biomarker of Radiosensitization of GBM through Targeted Inhibition of Checkpoint Kinases.

    Williams, Terence M; Galbán, Stefanie; Li, Fei; Heist, Kevin A; Galbán, Craig J; Lawrence, Theodore S; Holland, Eric C; Thomae, Tami L; Chenevert, Thomas L; Rehemtulla, Alnawaz; Ross, Brian D

    2013-04-01

    The inherent treatment resistance of glioblastoma (GBM) can involve multiple mechanisms including checkpoint kinase (Chk1/2)-mediated increased DNA repair capability, which can attenuate the effects of genotoxic chemotherapies and radiation. The goal of this study was to evaluate diffusion-weighted magnetic resonance imaging (DW-MRI) as a biomarker for Chk1/2 inhibitors in combination with radiation for enhancement of treatment efficacy in GBM. We evaluated a specific small molecule inhibitor of Chk1/2, AZD7762, in combination with radiation using in vitro human cell lines and in vivo using a genetically engineered GBM mouse model. DW-MRI and T1-contrast MRI were used to follow treatment effects on intracranial tumor cellularity and growth rates, respectively. AZD7762 inhibited clonal proliferation in a panel of GBM cell lines and increased radiosensitivity in p53-mutated GBM cell lines to a greater extent compared to p53 wild-type cells. In vivo efficacy of AZD7762 demonstrated a dose-dependent inhibitory effect on GBM tumor growth rate and a reduction in tumor cellularity based on DW-MRI scans along with enhancement of radiation efficacy. DW-MRI was found to be a useful imaging biomarker for the detection of radiosensitization through inhibition of checkpoint kinases. Chk1/2 inhibition resulted in antiproliferative activity, prevention of DNA damage-induced repair, and radiosensitization in preclinical GBM tumor models, both in vitro and in vivo. The effects were found to be maximal in p53-mutated GBM cells. These results provide the rationale for integration of DW-MRI in clinical translation of Chk1/2 inhibition with radiation for the treatment of GBM.

  18. Gender impacts on motor skill proficiency-physical activity relationship in children

    Diana Samara

    2015-12-01

    Full Text Available BACKGROUND Physical activity is the greatest contributor to achievement of adequate physical activity. Children performing adequate daily physical activity will get positive benefits from their activity. Several studies indicate a difference in motor skills between boys and girls. To understand the development of motor skill proficiency and physical activity in boys and girls, a study was conducted to determine the role of gender on motor skill proficiency and physical activity in children aged 6-12 years. METHODS A cross-sectional observational study was conducted and a total of 162 children were included at a primary school in the Grogol area, West Jakarta. Data collection was by questionnaire-based interviews, covering age, gender, and physical activity (watching TV, playing games, and outdoor play. Assessment of motor skills was performed using the Bruininks-Oseretsky Test–Second Edition (BOT-2. Data analysis was performed using SPSS for Windows release 17.0 and level of significance was set at 0.05. RESULTS Multiple linear regression results showed that in boys the strength subset was the most influential factor on TV watching activity, with the higher scores for strength indicating a lower TV watching activity (â=-0.125;p=0.021. Age was the most influential factor on outdoor playing activity in girls, with older girls having lower outdoor playing activity (â=-0.375;p=0.016. CONCLUSIONS This study revealed that gender difference impacts on motor skills and physical activity in children. Higher motor proficiency increases outdoor playing activity only in boys. Primary school pupils should be given opportunities for performing outdoor playing activities to improve their motor proficiency.

  19. Gender impacts on motor skill proficiency-physical activity relationship in children

    Diana Samara

    2012-12-01

    Full Text Available Background Physical activity is the greatest contributor to achievement of adequate physical activity. Children performing adequate daily physical activity will get positive benefits from their activity. Several studies indicate a difference in motor skills between boys and girls. To understand the development of motor skill proficiency and physical activity in boys and girls, a study was conducted to determine the role of gender on motor skill proficiency and physical activity in children aged 6-12 years. Methods A cross-sectional observational study was conducted and a total of 162 children were included at a primary school in the Grogol area, West Jakarta. Data collection was by questionnaire-based interviews, covering age, gender, and physical activity (watching TV, playing games, and outdoor play. Assessment of motor skills was performed using the Bruininks-Oseretsky Test–Second Edition (BOT-2. Data analysis was performed using SPSS for Windows release 17.0 and level of significance was set at 0.05. Results Multiple linear regression results showed that in boys the strength subset was the most influential factor on TV watching activity, with the higher scores for strength indicating a lower TV watching activity (â=-0.125;p=0.021. Age was the most influential factor on outdoor playing activity in girls, with older girls having lower outdoor playing activity (â=-0.375;p=0.016. Conclusions This study revealed that gender difference impacts on motor skills and physical activity in children. Higher motor proficiency increases outdoor playing activity only in boys. Primary school pupils should be given opportunities for performing outdoor playing activities to improve their motor proficiency.

  20. Blocking CHK1 Expression Induces Apoptosis and Abrogates the G2 Checkpoint Mechanism

    Yan Luo

    2001-01-01

    Full Text Available Checkpoint kinase 1 (Chki is a checkpoint gene that is activated after DNA damage. It phosphorylates and inactivates the Cdc2 activating phosphatase Cdc25C. This in turn inactivates Cdc2, which leads to G2/M arrest. We report that blocking Chki expression by antisense or ribozymes in mammalian cells induces apoptosis and interferes with the G2/M arrest induced by adriamycin. The Chki inhibitor UCN-01 also blocks the G2 arrest after DNA damage and renders cells more susceptible to adriamycin. These results indicate that Chki is an essential gene for the checkpoint mechanism during normal cell proliferation as well as in the DNA damage response.

  1. A tumor suppressor role of the Bub3 spindle checkpoint protein after apoptosis inhibition

    Moutinho-Santos, Tatiana

    2013-01-01

    Most solid tumors contain aneuploid cells, indicating that the mitotic checkpoint is permissive to the proliferation of chromosomally aberrant cells. However, mutated or altered expression of mitotic checkpoint genes accounts for a minor proportion of human tumors. We describe a Drosophila melanogaster tumorigenesis model derived from knocking down spindle assembly checkpoint (SAC) genes and preventing apoptosis in wing imaginal discs. Bub3-deficient tumors that were also deficient in apoptosis displayed neoplastic growth, chromosomal aneuploidy, and high proliferative potential after transplantation into adult flies. Inducing aneuploidy by knocking down CENP-E and preventing apoptosis does not induce tumorigenesis, indicating that aneuploidy is not sufficient for hyperplasia. In this system, the aneuploidy caused by a deficient SAC is not driving tumorigenesis because preventing Bub3 from binding to the kinetochore does not cause hyperproliferation. Our data suggest that Bub3 has a nonkinetochore-dependent function that is consistent with its role as a tumor suppressor. PMID:23609535

  2. The Feasibility and Safety of Surgery in Patients Receiving Immune Checkpoint Inhibitors: A Retrospective Study

    Alexandra W. Elias

    2017-06-01

    Full Text Available Immune checkpoint inhibitors (ICI are revolutionizing care for cancer patients. The list of malignancies for which the Food and Drug Administration is granting approval is rapidly increasing. Furthermore, there is a concomitant increase in clinical trials incorporating ICI. However, the safety of ICI in patients undergoing surgery remains unclear. Herein, we assessed the safety of ICI in the perioperative setting at a single center. We conducted a retrospective review of patients who underwent planned surgery while receiving ICI in the perioperative setting from 2012 to 2016. We collected 30-day postoperative morbidity and mortality utilizing the Clavien–Dindo classification system. We identified 17 patients who received perioperative ICI in 22 operations. Patients were diagnosed with melanoma (n = 14, renal cell carcinoma (n = 2, and urothelial carcinoma (n = 1. Therapies included pembrolizumab (n = 10, ipilimumab (n = 5, atezolizumab (n = 5, and ipilimumab/nivolumab (n = 2. Procedures included cutaneous/subcutaneous resection (n = 6, lymph node resection (n = 5, small bowel resection (n = 5, abdominal wall resection (n = 3, other abdominal surgery (n = 3, orthopedic surgery (n = 1, hepatic resection (n = 1, and neurosurgery (n = 2. There were no Grade III–IV Clavien–Dindo complications. There was one death secondary to ventricular fibrillation in the setting of coronary artery disease. ICI appear safe in the perioperative setting, involving multiple different types of surgery, and likely do not need to be stopped in the perioperative setting. Further studies are warranted to confirm these findings.

  3. MK3 modulation affects BMI1-dependent and independent cell cycle check-points.

    Peggy Prickaerts

    Full Text Available Although the MK3 gene was originally found deleted in some cancers, it is highly expressed in others. The relevance of MK3 for oncogenesis is currently not clear. We recently reported that MK3 controls ERK activity via a negative feedback mechanism. This prompted us to investigate a potential role for MK3 in cell proliferation. We here show that overexpression of MK3 induces a proliferative arrest in normal diploid human fibroblasts, characterized by enhanced expression of replication stress- and senescence-associated markers. Surprisingly, MK3 depletion evokes similar senescence characteristics in the fibroblast model. We previously identified MK3 as a binding partner of Polycomb Repressive Complex 1 (PRC1 proteins. In the current study we show that MK3 overexpression results in reduced cellular EZH2 levels and concomitant loss of epigenetic H3K27me3-marking and PRC1/chromatin-occupation at the CDKN2A/INK4A locus. In agreement with this, the PRC1 oncoprotein BMI1, but not the PCR2 protein EZH2, bypasses MK3-induced senescence in fibroblasts and suppresses P16INK4A expression. In contrast, BMI1 does not rescue the MK3 loss-of-function phenotype, suggesting the involvement of multiple different checkpoints in gain and loss of MK3 function. Notably, MK3 ablation enhances proliferation in two different cancer cells. Finally, the fibroblast model was used to evaluate the effect of potential tumorigenic MK3 driver-mutations on cell proliferation and M/SAPK signaling imbalance. Taken together, our findings support a role for MK3 in control of proliferation and replicative life-span, in part through concerted action with BMI1, and suggest that the effect of MK3 modulation or mutation on M/SAPK signaling and, ultimately, proliferation, is cell context-dependent.

  4. THE BANGLADESHI EMPLOYMENT SECTOR: EMPLOYER PERSPECTIVES CONCERNING ENGLISH PROFICIENCY

    Rubina Khan

    2012-07-01

    Full Text Available Abstract: This paper presents a brief summary of a study which was carried out to investigate how employers representing major employment sectors in the Bangladeshi Industry view the skills and English proficiency level of the current employees. Opinions were also solicited on what skills are required for fresh recruits. Semi-structured interviews were conducted with 30 employers representing the major employment sectors in Bangladeshi Industry. Results revealed the importance of English as an indispensible means of communication in the Bangladeshi corporate sector and showed that the business enterprises use extensive amounts of English. It also highlighted that the existent English proficiency of the employees was far below the required proficiency level. Recommendations were made to address the gap and prepare the youth to meet the demands of the global market. Keywords: English proficiency, competency, employability skills, global literacy skills

  5. The anaphase inhibitor of Saccharomyces cerevisiae Pds1p is a target of the DNA damage checkpoint pathway

    Cohen-Fix, O.; Koshland, D.

    1997-01-01

    Inhibition of DNA replication and physical DNA damage induce checkpoint responses that arrest cell cycle progression at two different stages. In Saccharomyces cerevisiae, the execution of both checkpoint responses requires the Mec1 and Rad53 proteins. This observation led to the suggestion that these checkpoint responses are mediated through a common signal transduction pathway. However, because the checkpoint-induced arrests occur at different cell cycle stages, the downstream effectors mediating these arrests are likely to be distinct. We have previously shown that the S. cerevisiae protein Pds1p is an anaphase inhibitor and is essential for cell cycle arrest in mitosis in the presence DNA damage. Herein we show that DNA damage, but not inhibition of DNA replication, induces the phosphorylation of Pds1p. Analyses of Pds1p phosphorylation in different checkpoint mutants reveal that in the presence of DNA damage, Pds1p is phosphorylated in a Mec1p- and Rad9p-dependent hut Rad53p-independent manner. Our data place Pds1p and Rad53p on parallel branches of the DNA damage checkpoint pathway. We suggest that Pds1p is a downstream target of the DNA damage checkpoint pathway and that it is involved in implementing the DNA damage checkpoint arrest specifically in mitosis

  6. Use of common time base for checkpointing and rollback recovery in a distributed system

    Ramanathan, Parameswaran; Shin, Kang G.

    1993-01-01

    An approach to checkpointing and rollback recovery in a distributed computing system using a common time base is proposed. A common time base is established in the system using a hardware clock synchronization algorithm. This common time base is coupled with the idea of pseudo-recovery points to develop a checkpointing algorithm that has the following advantages: reduced wait for commitment for establishing recovery lines, fewer messages to be exchanged, and less memory requirement. These advantages are assessed quantitatively by developing a probabilistic model.

  7. Cyclin F suppresses B-Myb activity to promote cell cycle checkpoint control

    Klein, Ditte Kjærsgaard; Hoffmann, Saskia; Ahlskog, Johanna K

    2015-01-01

    an important role in checkpoint control following ionizing radiation. Cyclin F-depleted cells initiate checkpoint signalling after ionizing radiation, but fail to maintain G2 phase arrest and progress into mitosis prematurely. Importantly, cyclin F suppresses the B-Myb-driven transcriptional programme...... that promotes accumulation of crucial mitosis-promoting proteins. Cyclin F interacts with B-Myb via the cyclin box domain. This interaction is important to suppress cyclin A-mediated phosphorylation of B-Myb, a key step in B-Myb activation. In summary, we uncover a regulatory mechanism linking the F-box protein...

  8. Interprofessional Collaboration with Immune Checkpoint Inhibitor Therapy: the Roles of Gastroenterology, Endocrinology and Neurology.

    Seery, Virginia

    2017-11-01

    To discuss immune checkpoint inhibitor therapy and identify opportunities for interprofessional collaboration in the management of toxicities in the areas of gastroenterology, endocrinology, and neurology. Published research and education articles in oncology, nursing, and various specialties. The use of immune checkpoint inhibitors is expanding; timely management of toxicity is critical for positive patient outcomes. There are many opportunities for interprofessional collaboration in the diagnosis and treatment of immune-related adverse events. Nurses play key roles in recognizing immune-related adverse events, providing patient education, and helping to facilitate interprofessional collaboration. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Trainee-Associated Factors and Proficiency at Percutaneous Nephrolithotomy

    Seyed Mohammad Kazem Aghamir

    2017-09-01

    Full Text Available Percutaneous nephrolithotomy (PNL is a complicated procedure for urology trainees. This study was designed to investigate the effect of trainees’ ages and previous experience, as well as the number of operated cases, on proficiency at PNL by using patient outcomes. A cross sectional observational study was designed during a five-year period. Trainees in PNL fellowship programs were included. At the end of the program, the trainees’ performance in PNL was assessed regarding five competencies and scored 1-5. If the overall score was 4 or above, the trainee was considered as proficient. The trainees’ age at the beginning of the program and the years passed from their residency graduation were asked and recorded. Also, the number of PNL cases operated by each trainee was obtained via their logbooks. The age, years passed from graduation, and number of operated cases were compared between two groups of proficient and non-proficient trainees. Univariate and multivariate binary logistic regression analysis was applied to estimate the effect of aforementioned variables on the occurrence of the proficiency. Forty-two trainees were included in the study. The mean and standard deviation for the overall score were 3.40 (out of 5 and 0.67, respectively. Eleven trainees (26.2% recognized as proficient in performing PNL. Univariate regression analysis indicated that each of three variables (age, years passed from graduation and number of operated cases had statistically significant effect on proficiency. However, the multivariate regression analysis revealed that just the number of cases had significant effect on achieving proficiency. Although it might be assumed that trainees’ age negatively correlates with their scores, in fact, it is their amount of practice that makes a difference. A certain number of cases is required to be operated by a trainee in order to reach the desired competency in PNL.

  10. Trainee-Associated Factors and Proficiency at Percutaneous Nephrolithotomy.

    Aghamir, Seyed Mohammad Kazem; Behtash, Negar; Hamidi, Morteza; Farahmand, Hasan; Salavati, Alborz; Mortaz Hejri, Sara

    2017-07-01

    Percutaneous nephrolithotomy (PNL) is a complicated procedure for urology trainees. This study was designed to investigate the effect of trainees' ages and previous experience, as well as the number of operated cases, on proficiency at PNL by using patient outcomes. A cross sectional observational study was designed during a five-year period. Trainees in PNL fellowship programs were included. At the end of the program, the trainees' performance in PNL was assessed regarding five competencies and scored 1-5. If the overall score was 4 or above, the trainee was considered as proficient. The trainees' age at the beginning of the program and the years passed from their residency graduation were asked and recorded. Also, the number of PNL cases operated by each trainee was obtained via their logbooks. The age, years passed from graduation, and number of operated cases were compared between two groups of proficient and non-proficient trainees. Univariate and multivariate binary logistic regression analysis was applied to estimate the effect of aforementioned variables on the occurrence of the proficiency. Forty-two trainees were included in the study. The mean and standard deviation for the overall score were 3.40 (out of 5) and 0.67, respectively. Eleven trainees (26.2%) recognized as proficient in performing PNL. Univariate regression analysis indicated that each of three variables (age, years passed from graduation and number of operated cases) had statistically significant effect on proficiency. However, the multivariate regression analysis revealed that just the number of cases had significant effect on achieving proficiency. Although it might be assumed that trainees' age negatively correlates with their scores, in fact, it is their amount of practice that makes a difference. A certain number of cases is required to be operated by a trainee in order to reach the desired competency in PNL.

  11. Language proficiency and the international postgraduate student experience

    Weaver, M

    2016-01-01

    In an increasingly competitive environment, with reduced government funding, full fee-paying international students are an important source of revenue for higher education institutions (HEIs). Although many previous studies have focused on the role of English language proficiency on academic success, there is little known about the extent to which levels of English language proficiency affect these non-native English speaking students’ overall course experience. There have been a wealth of st...

  12. STRATEGIES OF MAINTAINING PROFICIENCY BY TEACHERS OF ENGLISH IN INDONESIA

    Junaidi Mistar, Alfan Zuhairini

    2011-10-01

    Full Text Available The objectives of the present study are four-fold: (1 to identify the types of strategies to maintain proficiency used by teachers of English in Indonesia, (2 to know the intensity of use of the obtained strategy types, (3 to measure the inter-correlation in the use of the obtained strategy types, and (4 to investigate the effect of proficiency level on the use of maintaining strategies. The subjects were 93 teachers applying for S2 degree in 2010/2011 at the postgraduate program of the Islamic University of Malang. They were given two sets of instrument, a Likert-scale questionnaire of English proficiency maintaining strategies and a TOEFL test. Then, a factor analysis identified nine strategy categories, including language focusing, metacognitive and affective developing, reading and writing activating, language resource utilizing, cognitive processing, culture learning, social communicating, text analyzing, and radio listening strategies. These strategy types explained 63.84% of variances of maintaining strategies and they were used at high level of intensity. Moreover, the use of the nine strategy types were found to be inter-correlated with one another. Finally, no significant effect of proficiency level on strategy use was found, indicating that teachers with different level of proficiency reported using the same strategies of maintaining their proficiency.

  13. Commutability of food microbiology proficiency testing samples.

    Abdelmassih, M; Polet, M; Goffaux, M-J; Planchon, V; Dierick, K; Mahillon, J

    2014-03-01

    Food microbiology proficiency testing (PT) is a useful tool to assess the analytical performances among laboratories. PT items should be close to routine samples to accurately evaluate the acceptability of the methods. However, most PT providers distribute exclusively artificial samples such as reference materials or irradiated foods. This raises the issue of the suitability of these samples because the equivalence-or 'commutability'-between results obtained on artificial vs. authentic food samples has not been demonstrated. In the clinical field, the use of noncommutable PT samples has led to erroneous evaluation of the performances when different analytical methods were used. This study aimed to provide a first assessment of the commutability of samples distributed in food microbiology PT. REQUASUD and IPH organized 13 food microbiology PTs including 10-28 participants. Three types of PT items were used: genuine food samples, sterile food samples and reference materials. The commutability of the artificial samples (reference material or sterile samples) was assessed by plotting the distribution of the results on natural and artificial PT samples. This comparison highlighted matrix-correlated issues when nonfood matrices, such as reference materials, were used. Artificially inoculated food samples, on the other hand, raised only isolated commutability issues. In the organization of a PT-scheme, authentic or artificially inoculated food samples are necessary to accurately evaluate the analytical performances. Reference materials, used as PT items because of their convenience, may present commutability issues leading to inaccurate penalizing conclusions for methods that would have provided accurate results on food samples. For the first time, the commutability of food microbiology PT samples was investigated. The nature of the samples provided by the organizer turned out to be an important factor because matrix effects can impact on the analytical results. © 2013

  14. Genetic variation in the major mitotic checkpoint genes associated with chromosomal aberrations in healthy humans

    Försti, A.; Frank, Ch.; Smolková, B.; Kazimírová, A.; Barančoková, M.; Vymetálková, Veronika; Kroupa, M.; Naccarati, Alessio; Vodičková, Ludmila; Buchancová, J.; Dusinská, M.; Musak, L.; Vodička, Pavel; Hemminki, K.

    2016-01-01

    Roč. 380, č. 2 (2016), s. 442-446 ISSN 0304-3835 R&D Projects: GA ČR(CZ) GA15-14789S Institutional support: RVO:68378041 Keywords : chromosomal integrity * cytogenetics * spindle checkpoint Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 6.375, year: 2016

  15. Synthesis of Fault-Tolerant Embedded Systems with Checkpointing and Replication

    Izosimov, Viacheslav; Pop, Paul; Eles, Petru

    2006-01-01

    We present an approach to the synthesis of fault-tolerant hard real-time systems for safety-critical applications. We use checkpointing with rollback recovery and active replication for tolerating transient faults. Processes are statically scheduled and communications are performed using the time...

  16. Constitutive Cdk2 activity promotes aneuploidy while altering the spindle assembly and tetraploidy checkpoints

    Jahn, Stephan C; Corsino, Patrick E; Davis, Bradley J

    2013-01-01

    instability. Expression of these complexes in the MCF10A cell line leads to retinoblastoma protein (Rb) hyperphosphorylation, a subsequent increase in proliferation rate, and increased expression of the spindle assembly checkpoint protein Mad2. This results in a strengthening of the spindle assembly...

  17. A phospho-proteomic screen identifies substrates of the checkpoint kinase Chk1

    Blasius, Melanie; Forment, Josep V; Thakkar, Neha

    2011-01-01

    BACKGROUND: The cell-cycle checkpoint kinase Chk1 is essential in mammalian cells due to its roles in controlling processes such as DNA replication, mitosis and DNA-damage responses. Despite its paramount importance, how Chk1 controls these functions remains unclear, mainly because very few Chk1...

  18. Localization of spindle checkpoint proteins in cells undergoing mitosis with unreplicated genomes.

    Johnson, Mary Kathrine; Cooksey, Amanda M; Wise, Dwayne A

    2008-11-01

    CHO cells can be arrested with hydoxyurea at the beginning of the DNA synthesis phase of the cell cycle. Subsequent treatment with the xanthine, caffeine, induces cells to bypass the S-phase checkpoint and enter unscheduled mitosis [Schlegel and Pardee,1986, Science 232:1264-1266]. These treated cells build a normal spindle and distribute kinetochores, unattached to chromosomes, to their daughter cells [Brinkley et al.,1988, Nature 336:251-254; Zinkowski et al.,1991, J Cell Biol 113:1091-1110; Wise and Brinkley,1997, Cell Motil Cytoskeleton 36:291-302; Balczon et al.,2003, Chromosoma 112:96-102]. To investigate how these cells distribute kinetochores to daughter cells, we analyzed the spindle checkpoint components, Mad2, CENP-E, and the 3F3 phosphoepitope, using immunofluorescence and digital microscopy. Even though the kinetochores were unpaired and DNA was fragmented, the tension, alignment, and motor components of the checkpoint were found to be present and localized as predicted in prometaphase and metaphase. This unusual mitosis proves that a cell can successfully localize checkpoint proteins and divide even when kinetochores are unpaired and fragmented. (c) 2008 Wiley-Liss, Inc.

  19. The point of no return: The poly(A)-associated elongation checkpoint.

    Tellier, Michael; Ferrer-Vicens, Ivan; Murphy, Shona

    2016-01-01

    Cyclin-dependent kinases play critical roles in transcription by RNA polymerase II (pol II) and processing of the transcripts. For example, CDK9 regulates transcription of protein-coding genes, splicing, and 3' end formation of the transcripts. Accordingly, CDK9 inhibitors have a drastic effect on the production of mRNA in human cells. Recent analyses indicate that CDK9 regulates transcription at the early-elongation checkpoint of the vast majority of pol II-transcribed genes. Our recent discovery of an additional CDK9-regulated elongation checkpoint close to poly(A) sites adds a new layer to the control of transcription by this critical cellular kinase. This novel poly(A)-associated checkpoint has the potential to powerfully regulate gene expression just before a functional polyadenylated mRNA is produced: the point of no return. However, many questions remain to be answered before the role of this checkpoint becomes clear. Here we speculate on the possible biological significance of this novel mechanism of gene regulation and the players that may be involved.

  20. The point of no return: The poly(A)-associated elongation checkpoint

    Tellier, Michael; Ferrer-Vicens, Ivan; Murphy, Shona

    2016-01-01

    abstract Cyclin-dependent kinases play critical roles in transcription by RNA polymerase II (pol II) and processing of the transcripts. For example, CDK9 regulates transcription of protein-coding genes, splicing, and 3′ end formation of the transcripts. Accordingly, CDK9 inhibitors have a drastic effect on the production of mRNA in human cells. Recent analyses indicate that CDK9 regulates transcription at the early-elongation checkpoint of the vast majority of pol II-transcribed genes. Our recent discovery of an additional CDK9-regulated elongation checkpoint close to poly(A) sites adds a new layer to the control of transcription by this critical cellular kinase. This novel poly(A)-associated checkpoint has the potential to powerfully regulate gene expression just before a functional polyadenylated mRNA is produced: the point of no return. However, many questions remain to be answered before the role of this checkpoint becomes clear. Here we speculate on the possible biological significance of this novel mechanism of gene regulation and the players that may be involved. PMID:26853452

  1. Immune Checkpoint Inhibitors in the Treatment of Patients with Neuroendocrine Neoplasia.

    Weber, Matthias M; Fottner, Christian

    2018-01-01

    Well-differentiated neuroendocrine neoplasms (NENs) are usually controlled by antiproliferative, local ablative and/or radionuclide therapies, whereas poorly differentiated NENs generally require cytotoxic chemotherapy. However, treatment options for patients with advanced/metastatic high-grade NENs remain limited. Review of the literature and international congress abstracts on the efficacy and safety of immunotherapy by checkpoint inhibition in advanced/metastatic NENs. Evidence points to an important role of immune phenomena in the pathogenesis and treatment of neuroendocrine tumors (NETs). Programmed cell death 1 (PD-1) protein and its ligand are mainly expressed in poorly differentiated NENs. Microsatellite instability and high mutational load are more pronounced in high-grade NENs and may predict response to immunotherapy. Clinical experience of immune checkpoint blockade mainly exists for Merkel cell carcinoma, a high-grade cutaneous neuroendocrine carcinoma (NEC), which has led to approval of the anti-PD-1 antibody avelumab. In addition, there is anecdotal evidence for the efficacy of checkpoint inhibitors in large-cell lung NECs, ovarian NECs and others, including gastroenteropancreatic NENs. Currently, phase II studies investigate PDR001, pembrolizumab, combined durvalumab and tremelimumab, and avelumab treatment in patients with advanced/metastatic NENs. Immune checkpoint inhibitors are a promising therapeutic option, especially in progressive NECs or high-grade NETs with high tumor burden, microsatellite instability, and/or mutational load. © 2018 S. Karger GmbH, Freiburg.

  2. Cells bearing chromosome aberrations lacking one telomere are selectively blocked at the G2/M checkpoint

    Rodriguez, Pilar [Unitat de Biologia Cel.lular, Departament de Biologia Cel.lular, Fisiologia i Immunologia, Universitat Autonoma de Barcelona, 08193 Bellaterra (Spain); Barquinero, Joan Francesc [Unitat d' Antropologia Biologica, Departament de Biologia Animal, Biologia Vegetal i Ecologia, Universitat Autonoma de Barcelona, 08193 Bellaterra (Spain); Duran, Assumpta [Unitat de Biologia Cel.lular, Departament de Biologia Cel.lular, Fisiologia i Immunologia, Universitat Autonoma de Barcelona, 08193 Bellaterra (Spain); Caballin, Maria Rosa [Unitat d' Antropologia Biologica, Departament de Biologia Animal, Biologia Vegetal i Ecologia, Universitat Autonoma de Barcelona, 08193 Bellaterra (Spain); Ribas, Montserrat [Servei de Radiofisica i Radioproteccio de l' Hospital de la Santa Creu i Sant Pau, 08025 Barcelona (Spain); Barrios, Leonardo, E-mail: Lleonard.Barrios@uab.cat [Unitat de Biologia Cel.lular, Departament de Biologia Cel.lular, Fisiologia i Immunologia, Universitat Autonoma de Barcelona, 08193 Bellaterra (Spain)

    2009-11-02

    Cell cycle checkpoints are part of the cellular mechanisms to maintain genomic integrity. After ionizing radiation exposure, the cells can show delay or arrest in their progression through the cell cycle, as well as an activation of the DNA repair machinery in order to reduce the damage. The G2/M checkpoint prevents G2 cells entering mitosis until the DNA damage has been reduced. The present study evaluates which G0 radiation-induced chromosome aberrations are negatively selected in the G2/M checkpoint. For this purpose, peripheral blood samples were irradiated at 1 and 3 Gy of {gamma}-rays, and lymphocytes were cultured for 48 h. Calyculin-A and Colcemid were used to analyze, in the same slide, cells in G2 and M. Chromosome spreads were consecutively analyzed by solid stain, pancentromeric and pantelomeric FISH and mFISH. The results show that the frequency of incomplete chromosome elements, those lacking a telomeric signal at one end, decreases abruptly from G2 to M. This indicates that cells with incomplete chromosome elements can progress from G0 to G2, but at the G2/M checkpoint suffer a strong negative selection.

  3. Cells bearing chromosome aberrations lacking one telomere are selectively blocked at the G2/M checkpoint

    Rodriguez, Pilar; Barquinero, Joan Francesc; Duran, Assumpta; Caballin, Maria Rosa; Ribas, Montserrat; Barrios, Leonardo

    2009-01-01

    Cell cycle checkpoints are part of the cellular mechanisms to maintain genomic integrity. After ionizing radiation exposure, the cells can show delay or arrest in their progression through the cell cycle, as well as an activation of the DNA repair machinery in order to reduce the damage. The G2/M checkpoint prevents G2 cells entering mitosis until the DNA damage has been reduced. The present study evaluates which G0 radiation-induced chromosome aberrations are negatively selected in the G2/M checkpoint. For this purpose, peripheral blood samples were irradiated at 1 and 3 Gy of γ-rays, and lymphocytes were cultured for 48 h. Calyculin-A and Colcemid were used to analyze, in the same slide, cells in G2 and M. Chromosome spreads were consecutively analyzed by solid stain, pancentromeric and pantelomeric FISH and mFISH. The results show that the frequency of incomplete chromosome elements, those lacking a telomeric signal at one end, decreases abruptly from G2 to M. This indicates that cells with incomplete chromosome elements can progress from G0 to G2, but at the G2/M checkpoint suffer a strong negative selection.

  4. Myasthenia triggered by immune checkpoint inhibitors: New case and literature review.

    Gonzalez, Natalia L; Puwanant, Araya; Lu, Angela; Marks, Stanley M; Živković, Saša A

    2017-03-01

    Immune checkpoint molecules are potent regulators of immunologic homeostasis that prevent the development of autoimmunity while maintaining self-tolerance. Inhibitors of immune checkpoint molecules are used as immunotherapy in the treatment of melanoma and different types of refractory cancer, and can trigger various autoimmune complications including myositis and myasthenia gravis. We describe a case of generalized myasthenia gravis induced by pembrolizumab and review 11 other cases. Five patients also had elevated serum CK levels ranging from 1200 to 8729 IU/L, and biopsy showed myositis in one. Severity was highly variable as symptoms normalized spontaneously in one patient, but three others developed myasthenic crisis (including two with fatal outcomes). Steroids have been recommended as a preferred treatment of autoimmune complications of immune-checkpoint inhibitors. Myasthenia gravis should be considered when weakness, diplopia or bulbar symptoms are seen after treatment with immune checkpoint inhibitors, and additional studies are needed to characterize association with hyperCKemia. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. rad-Dependent response of the chk1-encoded protein kinase at the DNA damage checkpoint

    Walworth, N.C.; Bernards, R.A.

    1996-01-01

    Exposure of eukaryotic cells to agents that generate DNA damage results in transient arrest of progression through the cell cycle. In fission yeast, the DNA damage checkpoint associated with cell cycle arrest before mitosis requires the protein kinase p56chk1. DNA damage induced by ultraviolet

  6. Differential impact of diverse anticancer chemotherapeutics on the Cdc25A-degradation checkpoint pathway

    Agner, Jeppe; Falck, Jacob; Lukas, Jiri; Bartek, Jiri

    2005-01-01

    When exposed to DNA-damaging insults such as ionizing radiation (IR) or ultraviolet light (UV), mammalian cells activate checkpoint pathways to halt cell cycle progression or induce cell death. Here we examined the ability of five commonly used anticancer drugs with different mechanisms of action to activate the Chk1/Chk2-Cdc25A-CDK2/cyclin E cell cycle checkpoint pathway, previously shown to be induced by IR or UV. Whereas exposure of human cells to topoisomerase inhibitors camptothecin, etoposide, or adriamycin resulted in rapid (within 1 h) activation of the pathway including degradation of the Cdc25A phosphatase and inhibition of cyclin E/CDK2 kinase activity, taxol failed to activate this checkpoint even after a prolonged treatment. Unexpectedly, although the alkylating agent cisplatin also induced degradation of Cdc25A (albeit delayed, after 8-12 h), cyclin E/CDK2 activity was elevated and DNA synthesis continued, a phenomena that correlated with increased E2F1 protein levels and consequently enhanced expression of cyclin E. These results reveal a differential impact of various classes of anticancer chemotherapeutics on the Cdc25A-degradation pathway, and indicate that the kinetics of checkpoint induction, and the relative balance of key components within the DNA damage response network may dictate whether the treated cells arrest their cell cycle progression

  7. Immunogenic Chemotherapy Sensitizes Renal Cancer to Immune Checkpoint Blockade Therapy in Preclinical Models.

    Cui, Shujin

    2017-07-11

    BACKGROUND Renal cell carcinoma (RCC) is among the most common malignant cancers of males worldwide. For advanced RCC patients, there still is no effective therapy. Immune checkpoint blockade therapies have shown benefits for many cancers, but previous clinical trials of immune checkpoint blockade therapies in RCC patients achieved only modest results. MATERIAL AND METHODS We explored the effects of combining chemotherapy with immune checkpoint blockade therapy in RCC xenograft mouse models. We also studied the potential mechanisms by which chemotherapy might enhance the efficacy of immune checkpoint blockade therapy, both in vitro and in vivo. RESULTS Our results showed that many commonly used chemotherapy agents can induce immunogenic marker release in RCC cell lines. Importantly, the RCC xenograft mouse model mice who received the combination treatment of 5-fluorouracil (5-FU) and anti-programmed cell death-ligand 1 (PD-L1) antibodies (Abs) had longer survival times compared to those who received 5-FU or anti-PD-L1 Abs alone. Also, increased key cytokines that promote tumor immunity, such as IL-2, IFN-γ, and TNF-α, as well as tumor-infiltrating cytotoxic T cells, were also increased after the combination treatment. CONCLUSIONS We conclude that 5-FU can sensitize RCC to anti-PD-L1 treatment by releasing the immune suppression in the tumor microenvironment.

  8. English language proficiency and smoking prevalence among California's Asian Americans.

    Tang, Hao; Shimizu, Robin; Chen, Moon S

    2005-12-15

    The authors documented California's tobacco control initiatives for Asian Americans and the current tobacco use status among Asian subgroups and provide a discussion of the challenges ahead. The California Tobacco Control Program has employed a comprehensive approach to decrease tobacco use in Asian Americans, including ethnic-specific media campaigns, culturally competent interventions, and technical assistance and training networks. Surveillance of tobacco use among Asian Americans and the interpretation of the results have always been a challenge. Data from the 2001 The California Health Interview Survey (CHIS) were analyzed to provide smoking prevalence estimates for all Asian Americans and Asian-American subgroups, including Korean, Filipino, Japanese, South Asian, Chinese, and Vietnamese. Current smoking prevalence was analyzed by gender and by English proficiency level. Cigarette smoking prevalence among Asian males in general was almost three times of that among Asian females. Korean and Vietnamese males had higher cigarette smoking prevalence rates than males in other subgroups. Although Asian females in general had low smoking prevalence rates, significant differences were found among Asian subgroups, from 1.1% (Vietnamese) to 12.7% (Japanese). Asian men who had high English proficiency were less likely to be smokers than men with lower English proficiency. Asian women with high English proficiency were more likely to be smokers than women with lower English proficiency. Smoking prevalence rates among Asian Americans in California differed significantly on the basis of ethnicity, gender, and English proficiency. English proficiency seemed to have the effect of reducing smoking prevalence rates among Asian males but had just the opposite effect among Asian females. Cancer 2005. (c) 2005 American Cancer Society.

  9. Mechanism-based screen for G1/S checkpoint activators identifies a selective activator of EIF2AK3/PERK signalling.

    Stockwell, Simon R; Platt, Georgina; Barrie, S Elaine; Zoumpoulidou, Georgia; Te Poele, Robert H; Aherne, G Wynne; Wilson, Stuart C; Sheldrake, Peter; McDonald, Edward; Venet, Mathilde; Soudy, Christelle; Elustondo, Frédéric; Rigoreau, Laurent; Blagg, Julian; Workman, Paul; Garrett, Michelle D; Mittnacht, Sibylle

    2012-01-01

    Human cancers often contain genetic alterations that disable G1/S checkpoint control and loss of this checkpoint is thought to critically contribute to cancer generation by permitting inappropriate proliferation and distorting fate-driven cell cycle exit. The identification of cell permeable small molecules that activate the G1/S checkpoint may therefore represent a broadly applicable and clinically effective strategy for the treatment of cancer. Here we describe the identification of several novel small molecules that trigger G1/S checkpoint activation and characterise the mechanism of action for one, CCT020312, in detail. Transcriptional profiling by cDNA microarray combined with reverse genetics revealed phosphorylation of the eukaryotic initiation factor 2-alpha (EIF2A) through the eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3/PERK) as the mechanism of action of this compound. While EIF2AK3/PERK activation classically follows endoplasmic reticulum (ER) stress signalling that sets off a range of different cellular responses, CCT020312 does not trigger these other cellular responses but instead selectively elicits EIF2AK3/PERK signalling. Phosphorylation of EIF2A by EIF2A kinases is a known means to block protein translation and hence restriction point transit in G1, but further supports apoptosis in specific contexts. Significantly, EIF2AK3/PERK signalling has previously been linked to the resistance of cancer cells to multiple anticancer chemotherapeutic agents, including drugs that target the ubiquitin/proteasome pathway and taxanes. Consistent with such findings CCT020312 sensitizes cancer cells with defective taxane-induced EIF2A phosphorylation to paclitaxel treatment. Our work therefore identifies CCT020312 as a novel small molecule chemical tool for the selective activation of EIF2A-mediated translation control with utility for proof-of-concept applications in EIF2A-centered therapeutic approaches, and as a chemical starting point for

  10. The emerging role of immune checkpoint based approaches in AML and MDS.

    Boddu, Prajwal; Kantarjian, Hagop; Garcia-Manero, Guillermo; Allison, James; Sharma, Padmanee; Daver, Naval

    2018-04-01

    The development of immune checkpoint inhibitors represents a major breakthrough in the field of cancer therapeutics. Pursuant to their success in melanoma and numerous solid tumor malignancies, these agents are being investigated in hematological malignancies including acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS). Although AML/MDS have traditionally been considered to be less immunogenic than solid tumor malignancies, recent pre-clinical models suggest a therapeutic role for immune checkpoint inhibition in these diseases. CTLA-4 inhibition may be especially effective in treating late post-allogeneic stem cell transplant relapse of AML in patients with limited or no graft versus host disease. Immune checkpoint inhibition, specifically PD-1 inhibition, demonstrated limited single agent efficacy in patients with relapsed AML and with MDS post-hypomethylating therapy. Rationally designed combinations of PD-1 inhibitors with standard anti-leukemic therapy are needed. Hypomethylating agents such as azacitidine, up-regulate PD-1, PD-L1, and PD-L2 in patients with AML/MDS and up-regulation of these genes was associated with the emergence of resistance. The combination of azacitidine and PD-1/PD-L1 inhibition may be a potential mechanism to prevent or overcome resistance to 5-azacitidine. A number of such combinations are being evaluated in clinical trials with early encouraging results. Immune checkpoint inhibition is also an attractive option to improve relapse-free survival or eliminate minimal residual disease post induction and consolidation by enhancing T-cell surveillance in patients with high-risk AML. The ongoing clinical trials with checkpoint inhibitors in AML/MDS will improve our understanding of the immunobiology of these diseases and guide us to the most appropriate application of these agents in the therapy of AML/MDS.

  11. [Sea urchin embryo, DNA-damaged cell cycle checkpoint and the mechanisms initiating cancer development].

    Bellé, Robert; Le Bouffant, Ronan; Morales, Julia; Cosson, Bertrand; Cormier, Patrick; Mulner-Lorillon, Odile

    2007-01-01

    Cell division is an essential process for heredity, maintenance and evolution of the whole living kingdom. Sea urchin early development represents an excellent experimental model for the analysis of cell cycle checkpoint mechanisms since embryonic cells contain a functional DNA-damage checkpoint and since the whole sea urchin genome is sequenced. The DNA-damaged checkpoint is responsible for an arrest in the cell cycle when DNA is damaged or incorrectly replicated, for activation of the DNA repair mechanism, and for commitment to cell death by apoptosis in the case of failure to repair. New insights in cancer biology lead to two fundamental concepts about the very first origin of cancerogenesis. Cancers result from dysfunction of DNA-damaged checkpoints and cancers appear as a result of normal stem cell (NCS) transformation into a cancer stem cell (CSC). The second aspect suggests a new definition of "cancer", since CSC can be detected well before any clinical evidence. Since early development starts from the zygote, which is a primary stem cell, sea urchin early development allows analysis of the early steps of the cancerization process. Although sea urchins do not develop cancers, the model is alternative and complementary to stem cells which are not easy to isolate, do not divide in a short time and do not divide synchronously. In the field of toxicology and incidence on human health, the sea urchin experimental model allows assessment of cancer risk from single or combined molecules long before any epidemiologic evidence is available. Sea urchin embryos were used to test the worldwide used pesticide Roundup that contains glyphosate as the active herbicide agent; it was shown to activate the DNA-damage checkpoint of the first cell cycle of development. The model therefore allows considerable increase in risk evaluation of new products in the field of cancer and offers a tool for the discovery of molecular markers for early diagnostic in cancer biology

  12. Caenorhabditis elegans histone methyltransferase MET-2 shields the male X chromosome from checkpoint machinery and mediates meiotic sex chromosome inactivation.

    Paula M Checchi

    2011-09-01

    Full Text Available Meiosis is a specialized form of cellular division that results in the precise halving of the genome to produce gametes for sexual reproduction. Checkpoints function during meiosis to detect errors and subsequently to activate a signaling cascade that prevents the formation of aneuploid gametes. Indeed, asynapsis of a homologous chromosome pair elicits a checkpoint response that can in turn trigger germline apoptosis. In a heterogametic germ line, however, sex chromosomes proceed through meiosis with unsynapsed regions and are not recognized by checkpoint machinery. We conducted a directed RNAi screen in Caenorhabditis elegans to identify regulatory factors that prevent recognition of heteromorphic sex chromosomes as unpaired and uncovered a role for the SET domain histone H3 lysine 9 histone methyltransferase (HMTase MET-2 and two additional HMTases in shielding the male X from checkpoint machinery. We found that MET-2 also mediates the transcriptional silencing program of meiotic sex chromosome inactivation (MSCI but not meiotic silencing of unsynapsed chromatin (MSUC, suggesting that these processes are distinct. Further, MSCI and checkpoint shielding can be uncoupled, as double-strand breaks targeted to an unpaired, transcriptionally silenced extra-chromosomal array induce checkpoint activation in germ lines depleted for met-2. In summary, our data uncover a mechanism by which repressive chromatin architecture enables checkpoint proteins to distinguish between the partnerless male X chromosome and asynapsed chromosomes thereby shielding the lone X from inappropriate activation of an apoptotic program.

  13. The Pch2 AAA+ ATPase promotes phosphorylation of the Hop1 meiotic checkpoint adaptor in response to synaptonemal complex defects.

    Herruzo, Esther; Ontoso, David; González-Arranz, Sara; Cavero, Santiago; Lechuga, Ana; San-Segundo, Pedro A

    2016-09-19

    Meiotic cells possess surveillance mechanisms that monitor critical events such as recombination and chromosome synapsis. Meiotic defects resulting from the absence of the synaptonemal complex component Zip1 activate a meiosis-specific checkpoint network resulting in delayed or arrested meiotic progression. Pch2 is an evolutionarily conserved AAA+ ATPase required for the checkpoint-induced meiotic block in the zip1 mutant, where Pch2 is only detectable at the ribosomal DNA array (nucleolus). We describe here that high levels of the Hop1 protein, a checkpoint adaptor that localizes to chromosome axes, suppress the checkpoint defect of a zip1 pch2 mutant restoring Mek1 activity and meiotic cell cycle delay. We demonstrate that the critical role of Pch2 in this synapsis checkpoint is to sustain Mec1-dependent phosphorylation of Hop1 at threonine 318. We also show that the ATPase activity of Pch2 is essential for its checkpoint function and that ATP binding to Pch2 is required for its localization. Previous work has shown that Pch2 negatively regulates Hop1 chromosome abundance during unchallenged meiosis. Based on our results, we propose that, under checkpoint-inducing conditions, Pch2 also possesses a positive action on Hop1 promoting its phosphorylation and its proper distribution on unsynapsed chromosome axes. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

  14. Mismatch repair proficiency is not required for radioenhancement by gemcitabine

    Bree, Chris van; Rodermond, Hans M.; Vos, Judith de; Haveman, Jaap; Franken, Nicolaas

    2005-01-01

    Purpose: Mismatch repair (MMR) proficiency has been reported to either increase or decrease radioenhancement by 24-h incubations with gemcitabine. This study aimed to establish the importance of MMR for radioenhancement by gemcitabine after short-exposure, high-dose treatment and long-exposure, low-dose treatment. Methods and Materials: Survival of MMR-deficient HCT116 and MMR-proficient HCT116 + 3 cells was analyzed by clonogenic assays. Mild, equitoxic gemcitabine treatments (4 h, 0.1 μM vs. 24 h, 6 nM) were combined with γ-irradiation to determine the radioenhancement with or without recovery. Gemcitabine metabolism and cell-cycle effects were evaluated by high-performance liquid chromatography analysis and bivariate flow cytometry. Results: Radioenhancement after 4 h of 0.1 μM of gemcitabine was similar in both cell lines, but the radioenhancement after 24 h of 6 nM of gemcitabine was reduced in MMR-proficient cells. No significant differences between both cell lines were observed in the gemcitabine metabolism or cell-cycle effects after these treatments. Gemcitabine radioenhancement after recovery was also lower in MMR-proficient cells than in MMR-deficient cells. Conclusion: Mismatch repair proficiency decreases radioenhancement by long incubations of gemcitabine but does not affect radioenhancement by short exposures to a clinically relevant gemcitabine dose. Our data suggest that MMR contributes to the recovery from gemcitabine treatment

  15. The proficiency testing of determination of dioxins in food

    Matsuda, R.; Tsutsumi, T.; Maitani, T. [National Institute of Health Sciences, Tokyo (Japan); Toyoda, M. [Jissen Womens Univ., Hino (Japan)

    2004-09-15

    Food intake is the main route of human dioxin exposure, making the determination of dioxins in food indispensable for risk assessment and risk management of dioxins. The uncertainty of analytical results, however, can be very great because of the low concentration of the analytes and complicated cleanup procedures. The risk assessment of dioxins based on analytical results also suffers from a similar degree of uncertainty. The Ministry of Health, Labor and Welfare of Japan has published ''Guideline for the Determination of Dioxins in Food'' to standardize the analytical procedures. The guideline contains the quality assurance procedures to obtain reliable analytical results and recommends participation in the relevant proficiency testing scheme. The proficiency testing provides the fair evaluation of the analytical results. The central science laboratory in England and the food and drug safety center in Japan offer the proficiency testing on food. The National Institute of Health Sciences of Japan (NIHS) also has carried out proficiency testing of dioxins in food since 1998 to assure the quality of analytical results for dioxins. In this presentation we will show the results of 5 rounds of proficiency testing.

  16. Participation of SRM5/CDC28, SRM8/NET1 and SRM12/HF11 genes in activation of checkpoints of Yeast Saccharomyces Cerevisiae

    Kadyshevskaya, E.Yu.; Koltovaya, N.A.

    2007-01-01

    It is known that there are about twenty checkpoint genes in yeast Saccharomyces cerevisiae. We study participation of SRM genes selected as genes affecting genetic stability and radiosensitivity. It has been shown that srm5/cdc28-srm, srm8/net1-srm, srm12/hfil-srm mutations prevent checkpoint activation by DNA damage, particularly G0/S-checkpoint (srm5, srm8), G1/S-checkpoint (srm5, srm8, srm12), S-checkpoint (srm5, srm12) and G2-checkpoint (srm5). These data indicate, at least in budding yeast, CDC28/SRM5, HF11/ADA1/SRM12 and NET1/SRM8 genes mediate cellular response induced by DNA damage including checkpoint control

  17. Parallel reorganization of protein function in the spindle checkpoint pathway through evolutionary paths in the fitness landscape that appear neutral in laboratory experiments.

    Alex N Nguyen Ba

    2017-04-01

    Full Text Available Regulatory networks often increase in complexity during evolution through gene duplication and divergence of component proteins. Two models that explain this increase in complexity are: 1 adaptive changes after gene duplication, such as resolution of adaptive conflicts, and 2 non-adaptive processes such as duplication, degeneration and complementation. Both of these models predict complementary changes in the retained duplicates, but they can be distinguished by direct fitness measurements in organisms with short generation times. Previously, it has been observed that repeated duplication of an essential protein in the spindle checkpoint pathway has occurred multiple times over the eukaryotic tree of life, leading to convergent protein domain organization in its duplicates. Here, we replace the paralog pair in S. cerevisiae with a single-copy protein from a species that did not undergo gene duplication. Surprisingly, using quantitative fitness measurements in laboratory conditions stressful for the spindle-checkpoint pathway, we find no evidence that reorganization of protein function after gene duplication is beneficial. We then reconstruct several evolutionary intermediates from the inferred ancestral network to the extant one, and find that, at the resolution of our assay, there exist stepwise mutational paths from the single protein to the divergent pair of extant proteins with no apparent fitness defects. Parallel evolution has been taken as strong evidence for natural selection, but our results suggest that even in these cases, reorganization of protein function after gene duplication may be explained by neutral processes.

  18. Clinical pharmacology quality assurance program: models for longitudinal analysis of antiretroviral proficiency testing for international laboratories.

    DiFrancesco, Robin; Rosenkranz, Susan L; Taylor, Charlene R; Pande, Poonam G; Siminski, Suzanne M; Jenny, Richard W; Morse, Gene D

    2013-10-01

    Among National Institutes of Health HIV Research Networks conducting multicenter trials, samples from protocols that span several years are analyzed at multiple clinical pharmacology laboratories (CPLs) for multiple antiretrovirals. Drug assay data are, in turn, entered into study-specific data sets that are used for pharmacokinetic analyses, merged to conduct cross-protocol pharmacokinetic analysis, and integrated with pharmacogenomics research to investigate pharmacokinetic-pharmacogenetic associations. The CPLs participate in a semiannual proficiency testing (PT) program implemented by the Clinical Pharmacology Quality Assurance program. Using results from multiple PT rounds, longitudinal analyses of recovery are reflective of accuracy and precision within/across laboratories. The objectives of this longitudinal analysis of PT across multiple CPLs were to develop and test statistical models that longitudinally: (1) assess the precision and accuracy of concentrations reported by individual CPLs and (2) determine factors associated with round-specific and long-term assay accuracy, precision, and bias using a new regression model. A measure of absolute recovery is explored as a simultaneous measure of accuracy and precision. Overall, the analysis outcomes assured 97% accuracy (±20% of the final target concentration of all (21) drug concentration results reported for clinical trial samples by multiple CPLs). Using the Clinical Laboratory Improvement Act acceptance of meeting criteria for ≥2/3 consecutive rounds, all 10 laboratories that participated in 3 or more rounds per analyte maintained Clinical Laboratory Improvement Act proficiency. Significant associations were present between magnitude of error and CPL (Kruskal-Wallis P Kruskal-Wallis P < 0.001).

  19. First year evaluation of EPA's radon contractor proficiency (RCP) program

    Salmon, G.L.

    1990-01-01

    This paper reports that the Environmental Protection Agency (EPA) has developed a voluntary program to evaluate radon reduction contractors and provide this information to the public, as part of activities mandated by the Indoor Radon Abatement Act (IRAA) of 1988. The Radon Contractor Proficiency Program consists of several elements that collectively help to ensure the proficiency of radon mitigators and give the public greater confidence in their capability. Contractors who participate in the program must pass a written examination, adhere to mitigation guidelines, keep records of work, meet continuing education requirements and pass a re-examination every two years. Upon meeting the program's requirements, mitigators are listed in EPA's National RCP Proficiency Report. The first Report released on May 15, 1990 listed 636 contractors. The second Report, to be release in August, will list 895 contractors, representing an increase of 40 per cent

  20. Physical activity and movement skills proficiency of young Filipino children.

    Capio, Catherine M; Sit, Cindy H P; Eguia, Kathlynne F; Abernethy, Bruce

    2014-08-01

    Recent reports indicate an increasing prevalence of overweight among Filipino children. Considering the known association of physical activity (PA) with obesity, this study reports the findings of an objective monitoring of PA in a sample of Filipino children. The study also explores the relationship of PA with fundamental movement skills (FMS) proficiency. Thirty-two children (6.54 ± 2.45 years old) wore an accelerometer for 7 days of PA monitoring and were assessed on five FMS (throw, catch, kick, run, jump). The children met the World Health Organization's recommendation of 60 min of PA per day, with more active time being accrued during weekdays than weekends. Children with greater FMS proficiency were found to spend more time in PA than those who were less skillful during weekends. Further research is recommended to examine PA and FMS proficiency associations, exploring the role of social interactions on weekends and weekdays. © 2014 Japan Pediatric Society.

  1. Casein kinase II is required for the spindle assembly checkpoint by regulating Mad2p in fission yeast

    Shimada, Midori [Department of Biochemistry and Cell Biology, Graduate School of Medicine, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Yamamoto, Ayumu [Department of Chemistry, Shizuoka University, 836 Ohya, Suruga-ku, Sizuoka 422-8529 (Japan); Murakami-Tonami, Yuko; Nakanishi, Makoto; Yoshida, Takashi [Department of Biochemistry and Cell Biology, Graduate School of Medicine, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Aiba, Hirofumi [Laboratory of Molecular Microbiology, School of Agriculture, Nagoya University, Chikusa-ku, Nagoya 464-8601 (Japan); Murakami, Hiroshi, E-mail: hmura@med.nagoya-cu.ac.jp [Department of Biochemistry and Cell Biology, Graduate School of Medicine, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan)

    2009-10-23

    The spindle checkpoint is a surveillance mechanism that ensures the fidelity of chromosome segregation in mitosis. Here we show that fission yeast casein kinase II (CK2) is required for this checkpoint function. In the CK2 mutants mitosis occurs in the presence of a spindle defect, and the spindle checkpoint protein Mad2p fails to localize to unattached kinetochores. The CK2 mutants are sensitive to the microtubule depolymerising drug thiabendazole, which is counteracted by ectopic expression of mad2{sup +}. The level of Mad2p is low in the CK2 mutants. These results suggest that CK2 has a role in the spindle checkpoint by regulating Mad2p.

  2. Leptin Regulation of Gonadotrope Gonadotropin-Releasing Hormone Receptors As a Metabolic Checkpoint and Gateway to Reproductive Competence

    Angela K. Odle

    2018-01-01

    Full Text Available The adipokine leptin signals the body’s nutritional status to the brain, and particularly, the hypothalamus. However, leptin receptors (LEPRs can be found all throughout the body and brain, including the pituitary. It is known that leptin is permissive for reproduction, and mice that cannot produce leptin (Lep/Lep are infertile. Many studies have pinpointed leptin’s regulation of reproduction to the hypothalamus. However, LEPRs exist at all levels of the hypothalamic–pituitary–gonadal axis. We have previously shown that deleting the signaling portion of the LEPR specifically in gonadotropes impairs fertility in female mice. Our recent studies have targeted this regulation to the control of gonadotropin releasing hormone receptor (GnRHR expression. The hypotheses presented here are twofold: (1 cyclic regulation of pituitary GnRHR levels sets up a target metabolic checkpoint for control of the reproductive axis and (2 multiple checkpoints are required for the metabolic signaling that regulates the reproductive axis. Here, we emphasize and explore the relationship between the hypothalamus and the pituitary with regard to the regulation of GnRHR. The original data we present strengthen these hypotheses and build on our previous studies. We show that we can cause infertility in 70% of female mice by deleting all isoforms of LEPR specifically in gonadotropes. Our findings implicate activin subunit (InhBa mRNA as a potential leptin target in gonadotropes. We further show gonadotrope-specific upregulation of GnRHR protein (but not mRNA levels following leptin stimulation. In order to try and understand this post-transcriptional regulation, we tested candidate miRNAs (identified with in silico analysis that may be binding the Gnrhr mRNA. We show significant upregulation of one of these miRNAs in our gonadotrope-Lepr-null females. The evidence provided here, combined with our previous work, lay the foundation for metabolically regulated post

  3. RNA interference regulates the cell cycle checkpoint through the RNA export factor, Ptr1, in fission yeast

    Iida, Tetsushi, E-mail: tiida@nig.ac.jp [Division of Cytogenetics, National Institute of Genetics, Mishima, 1111 Yata, Mishima 411-8540 (Japan); The Graduate University for Advanced Studies, Sokendai, Mishima, 1111 Yata, Mishima 411-8540 (Japan); Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), 4-1-8, Honcho, Kawaguchi-shi, Saitama 332-0012 (Japan); Iida, Naoko [Division of Mutagenesis, National Institute of Genetics, Mishima, 1111 Yata, Mishima 411-8540 (Japan); Tsutsui, Yasuhiro [Department of Life Science, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Nagatsuda-cho, Midori-ku, Yokohama 226-8501 (Japan); Yamao, Fumiaki [Division of Mutagenesis, National Institute of Genetics, Mishima, 1111 Yata, Mishima 411-8540 (Japan); The Graduate University for Advanced Studies, Sokendai, Mishima, 1111 Yata, Mishima 411-8540 (Japan); Kobayashi, Takehiko [Division of Cytogenetics, National Institute of Genetics, Mishima, 1111 Yata, Mishima 411-8540 (Japan); The Graduate University for Advanced Studies, Sokendai, Mishima, 1111 Yata, Mishima 411-8540 (Japan)

    2012-10-12

    Highlights: Black-Right-Pointing-Pointer RNAi is linked to the cell cycle checkpoint in fission yeast. Black-Right-Pointing-Pointer Ptr1 co-purifies with Ago1. Black-Right-Pointing-Pointer The ptr1-1 mutation impairs the checkpoint but does not affect gene silencing. Black-Right-Pointing-Pointer ago1{sup +} and ptr1{sup +} regulate the cell cycle checkpoint via the same pathway. Black-Right-Pointing-Pointer Mutations in ago1{sup +} and ptr1{sup +} lead to the nuclear accumulation of poly(A){sup +} RNAs. -- Abstract: Ago1, an effector protein of RNA interference (RNAi), regulates heterochromatin silencing and cell cycle arrest in fission yeast. However, the mechanism by which Ago1 controls cell cycle checkpoint following hydroxyurea (HU) treatment has not been elucidated. In this study, we show that Ago1 and other RNAi factors control cell cycle checkpoint following HU treatment via a mechanism independent of silencing. While silencing requires dcr1{sup +}, the overexpression of ago1{sup +} alleviated the cell cycle defect in dcr1{Delta}. Ago1 interacted with the mRNA export factor, Ptr1. The ptr1-1 mutation impaired cell cycle checkpoint but gene silencing was unaffected. Genetic analysis revealed that the regulation of cell cycle checkpoint by ago1{sup +} is dependent on ptr1{sup +}. Nuclear accumulation of poly(A){sup +} RNAs was detected in mutants of ago1{sup +} and ptr1{sup +}, suggesting there is a functional link between the cell cycle checkpoint and RNAi-mediated RNA quality control.

  4. Histone dosage regulates DNA damage sensitivity in a checkpoint-independent manner by the homologous recombination pathway

    Liang, Dun; Burkhart, Sarah Lyn; Singh, Rakesh Kumar; Kabbaj, Marie-Helene Miquel; Gunjan, Akash

    2012-01-01

    In eukaryotes, multiple genes encode histone proteins that package genomic deoxyribonucleic acid (DNA) and regulate its accessibility. Because of their positive charge, ‘free’ (non-chromatin associated) histones can bind non-specifically to the negatively charged DNA and affect its metabolism, including DNA repair. We have investigated the effect of altering histone dosage on DNA repair in budding yeast. An increase in histone gene dosage resulted in enhanced DNA damage sensitivity, whereas deletion of a H3–H4 gene pair resulted in reduced levels of free H3 and H4 concomitant with resistance to DNA damaging agents, even in mutants defective in the DNA damage checkpoint. Studies involving the repair of a HO endonuclease-mediated DNA double-strand break (DSB) at the MAT locus show enhanced repair efficiency by the homologous recombination (HR) pathway on a reduction in histone dosage. Cells with reduced histone dosage experience greater histone loss around a DSB, whereas the recruitment of HR factors is concomitantly enhanced. Further, free histones compete with the HR machinery for binding to DNA and associate with certain HR factors, potentially interfering with HR-mediated repair. Our findings may have important implications for DNA repair, genomic stability, carcinogenesis and aging in human cells that have dozens of histone genes. PMID:22850743

  5. Immune Checkpoint Inhibitors: A New Opportunity in the Treatment of Ovarian Cancer?

    Gloria Mittica

    2016-07-01

    Full Text Available Epithelial ovarian cancer (EOC is the leading cause of death for gynecological cancer. The standard treatment for advanced stage is the combination of optimal debulking surgery and platinum-based chemotherapy. Nevertheless, recurrence is frequent (around 70% and prognosis is globally poor. New therapeutic agents are needed to improve survival. Since EOC is strongly immunogenic, immune checkpoint inhibitors are under evaluation for their capacity to contrast the “turn off” signals expressed by the tumor to escape the immune system and usually responsible for self-tolerance maintenance. This article reviews the literature on anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies in EOC and highlights their possible lines of development. Further studies are needed to better define the prognostic role of the immune checkpoint inhibitors, to identify predictors of response and the optimal clinical setting in EOC.

  6. Immune Checkpoint Inhibitors: An Innovation in Immunotherapy for the Treatment and Management of Patients with Cancer.

    Dine, Jennifer; Gordon, RuthAnn; Shames, Yelena; Kasler, Mary Kate; Barton-Burke, Margaret

    2017-01-01

    Cancer survival rates are generally increasing in the United States. These trends have been partially attributed to improvement in therapeutic strategies. Cancer immunotherapy is an example of one of the newer strategies used to fight cancer, which primes or activates the immune system to produce antitumor effects. The first half of this review paper concisely describes the cell mechanisms that control antitumor immunity and the major immunotherapeutic strategies developed to target these mechanisms. The second half of the review discusses in greater depth immune checkpoint inhibitors that have recently demonstrated tremendous promise for the treatment of diverse solid tumor types, including melanoma, non-small cell lung cancer, and others. More specifically, the mechanisms of action, side effects, and patient and family management and education concerns are discussed to provide oncology nurses up-to-date information relevant to caring for cancer-affected patients treated with immune checkpoint inhibitors. Future directions for cancer immunotherapy are considered.

  7. The fission yeast spindle orientation checkpoint: a model that generates tension?

    Gachet, Yannick; Reyes, Céline; Goldstone, Sherilyn; Tournier, Sylvie

    2006-10-15

    In all eukaryotes, the alignment of the mitotic spindle with the axis of cell polarity is essential for accurate chromosome segregation as well as for the establishment of cell fate, and thus morphogenesis, during development. Studies in invertebrates, higher eukaryotes and yeast suggest that astral microtubules interact with the cell cortex to position the spindle. These microtubules are thought to impose pushing or pulling forces on the spindle poles to affect the rotation or movement of the spindle. In the fission yeast model, where cell division is symmetrical, spindle rotation is dependent on the interaction of astral microtubules with the cortical actin cytoskeleton. In these cells, a bub1-dependent mitotic checkpoint, the spindle orientation checkpoint (SOC), is activated when the spindles fail to align with the cell polarity axis. In this paper we review the mechanism that orientates the spindle during mitosis in fission yeast, and discuss the consequences of misorientation on metaphase progression. Copyright 2006 John Wiley & Sons, Ltd.

  8. Cloud object store for checkpoints of high performance computing applications using decoupling middleware

    Bent, John M.; Faibish, Sorin; Grider, Gary

    2016-04-19

    Cloud object storage is enabled for checkpoints of high performance computing applications using a middleware process. A plurality of files, such as checkpoint files, generated by a plurality of processes in a parallel computing system are stored by obtaining said plurality of files from said parallel computing system; converting said plurality of files to objects using a log structured file system middleware process; and providing said objects for storage in a cloud object storage system. The plurality of processes may run, for example, on a plurality of compute nodes. The log structured file system middleware process may be embodied, for example, as a Parallel Log-Structured File System (PLFS). The log structured file system middleware process optionally executes on a burst buffer node.

  9. A Comprehensive Review of US FDA-Approved Immune Checkpoint Inhibitors in Urothelial Carcinoma

    Fu-Shun Hsu

    2017-01-01

    Full Text Available Few effective treatment options are available for patients with advanced or metastatic urothelial carcinoma (UC after unsuccessful first-line platinum-based chemotherapy. To date, immune checkpoint inhibitors are novel therapeutic agents for UC treatment. From May 2016 to May 2017, five anti-PD-1/PD-L1 monoclonal antibodies received accelerated or regular approval from the US Food and Drug Administration (FDA for the treatment of patients with locally advanced or metastatic UC. The present comprehensive review presents the background information of these five US FDA-approved anticancer agents to provide a basic but concise understanding of these agents for advanced studies. We summarize their immune checkpoint mechanisms, clinical efficacy, recommended usage protocols, adverse events, and the limitations of the PD-L1 biomarker assays.

  10. Dynein Light Intermediate Chain 2 Facilitates the Metaphase to Anaphase Transition by Inactivating the Spindle Assembly Checkpoint.

    Sagar P Mahale

    Full Text Available The multi-functional molecular motor cytoplasmic dynein performs diverse essential roles during mitosis. The mechanistic importance of the dynein Light Intermediate Chain homologs, LIC1 and LIC2 is unappreciated, especially in the context of mitosis. LIC1 and LIC2 are believed to exist in distinct cytoplasmic dynein complexes as obligate subunits. LIC1 had earlier been reported to be required for metaphase to anaphase progression by inactivating the kinetochore-microtubule attachment-sensing arm of the spindle assembly checkpoint (SAC. However, the functional importance of LIC2 during mitosis remains elusive. Here we report prominent novel roles for the LIC2 subunit of cytoplasmic dynein in regulating the spindle assembly checkpoint. LIC2 depletion in mammalian cells led to prolonged metaphase arrest in the presence of an active SAC and also to stretched kinetochores, thus implicating it in SAC inactivation. Quantitative fluorescence microscopy of SAC components revealed accumulation of both attachment- and tension-sensing checkpoint proteins at metaphase kinetochores upon LIC2 depletion. These observations support a stronger and more diverse role in checkpoint inactivation for LIC2 in comparison to its close homolog LIC1. Our study uncovers a novel functional hierarchy during mitotic checkpoint inactivation between the closely related but homologous LIC subunits of cytoplasmic dynein. These subtle functional distinctions between dynein subpopulations could be exploited to study specific aspects of the spindle assembly checkpoint, which is a key mediator of fidelity in eukaryotic cell division.

  11. A novel ATM-dependent checkpoint defect distinct from loss of function mutation promotes genomic instability in melanoma.

    Spoerri, Loredana; Brooks, Kelly; Chia, KeeMing; Grossman, Gavriel; Ellis, Jonathan J; Dahmer-Heath, Mareike; Škalamera, Dubravka; Pavey, Sandra; Burmeister, Bryan; Gabrielli, Brian

    2016-05-01

    Melanomas have high levels of genomic instability that can contribute to poor disease prognosis. Here, we report a novel defect of the ATM-dependent cell cycle checkpoint in melanoma cell lines that promotes genomic instability. In defective cells, ATM signalling to CHK2 is intact, but the cells are unable to maintain the cell cycle arrest due to elevated PLK1 driving recovery from the arrest. Reducing PLK1 activity recovered the ATM-dependent checkpoint arrest, and over-expressing PLK1 was sufficient to overcome the checkpoint arrest and increase genomic instability. Loss of the ATM-dependent checkpoint did not affect sensitivity to ionizing radiation demonstrating that this defect is distinct from ATM loss of function mutations. The checkpoint defective melanoma cell lines over-express PLK1, and a significant proportion of melanomas have high levels of PLK1 over-expression suggesting this defect is a common feature of melanomas. The inability of ATM to impose a cell cycle arrest in response to DNA damage increases genomic instability. This work also suggests that the ATM-dependent checkpoint arrest is likely to be defective in a higher proportion of cancers than previously expected. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  12. Lyn tyrosine kinase promotes silencing of ATM-dependent checkpoint signaling during recovery from DNA double-strand breaks

    Fukumoto, Yasunori; Kuki, Kazumasa; Morii, Mariko; Miura, Takahito; Honda, Takuya; Ishibashi, Kenichi; Hasegawa, Hitomi; Kubota, Sho; Ide, Yudai; Yamaguchi, Noritaka; Nakayama, Yuji; Yamaguchi, Naoto

    2014-01-01

    Highlights: • Inhibition of Src family kinases decreased γ-H2AX signal. • Inhibition of Src family increased ATM-dependent phosphorylation of Chk2 and Kap1. • shRNA-mediated knockdown of Lyn increased phosphorylation of Kap1 by ATM. • Ectopic expression of Src family kinase suppressed ATM-mediated Kap1 phosphorylation. • Src is involved in upstream signaling for inactivation of ATM signaling. - Abstract: DNA damage activates the DNA damage checkpoint and the DNA repair machinery. After initial activation of DNA damage responses, cells recover to their original states through completion of DNA repair and termination of checkpoint signaling. Currently, little is known about the process by which cells recover from the DNA damage checkpoint, a process called checkpoint recovery. Here, we show that Src family kinases promote inactivation of ataxia telangiectasia mutated (ATM)-dependent checkpoint signaling during recovery from DNA double-strand breaks. Inhibition of Src activity increased ATM-dependent phosphorylation of Chk2 and Kap1. Src inhibition increased ATM signaling both in G2 phase and during asynchronous growth. shRNA knockdown of Lyn increased ATM signaling. Src-dependent nuclear tyrosine phosphorylation suppressed ATM-mediated Kap1 phosphorylation. These results suggest that Src family kinases are involved in upstream signaling that leads to inactivation of the ATM-dependent DNA damage checkpoint

  13. Disruption of spindle checkpoint function in rats following 28 days of repeated administration of renal carcinogens.

    Kimura, Masayuki; Mizukami, Sayaka; Watanabe, Yousuke; Hasegawa-Baba, Yasuko; Onda, Nobuhiko; Yoshida, Toshinori; Shibutani, Makoto

    2016-02-01

    We previously reported that 28-day exposure to hepatocarcinogens that facilitate cell proliferation specifically alters the expression of G1/S checkpoint-related genes and proteins, induces aberrant early expression of ubiquitin D (UBD) at the G2 phase, and increases apoptosis in the rat liver, indicating G1/S and spindle checkpoint dysfunction. The present study aimed to determine the time of onset of carcinogen-specific cell-cycle disruption after repeated administration of renal carcinogens for up to 28 days. Rats were orally administered the renal carcinogens nitrofurantoin (NFT), 1-amino-2,4-dibromoantraquinone (ADAQ), and 1,2,3-trichloropropane (TCP) or the non-carcinogenic renal toxicants 1-chloro-2-propanol, triamterene, and carboxin for 3, 7 or 28 days. Both immunohistochemical single-molecule analysis and real-time RT-PCR analysis revealed that carcinogen-specific expression changes were not observed after 28 days of administration. However, the renal carcinogens ADAQ and TCP specifically reduced the number of cells expressing phosphorylated-histone H3 at Ser10 in both UBD(+) cells and proliferating cells, suggestive of insufficient UBD expression at the M phase and early transition of proliferating cells from the M phase, without increasing apoptosis, after 28 days of administration. In contrast, NFT, which has marginal carcinogenic potential, did not induce such cellular responses. These results suggest that it may take 28 days to induce spindle checkpoint dysfunction by renal carcinogens; however, induction of apoptosis may not be essential. Thus, induction of spindle checkpoint dysfunction may be dependent on carcinogenic potential of carcinogen examined, and marginal carcinogens may not exert sufficient responses even after 28 days of administration.

  14. CDC28, NETI, and HFII are required for checkpoints in Saccharomyces cerevisiae

    Koltovaya, N.A.; Kadyshevskaya, E.Yu.; Roshina, M.P.; Devin, A.B.

    2009-01-01

    The involvement of SRM genes selected as genes affecting genetic stability and radiosensitivity in a cell cycle arrest under the action of damaging agents was studied. It was shown that the srm5/cdc28-srm, srm8/netI-srm, and srmI2/hfiI-srm mutations prevent checkpoint activation by DNA damage, particularly the G 0 /S (srm5, srm8), G 1 /S (srm5, srm8, srm12), S (srm8, srm12) and S/G 2 (srm5) checkpoints. It seems that in budding yeast the CDC28, HFII/ADAI, and NETI genes mediate cellular response induced by DNA damage with checkpoint control. The well-known checkpoint-genes RAD9, RAD17, RAD24, and RAD53, and the genes CDC28, and NETI have been found to belong to one epistasis group named RAD9-group as regards cell sensitivity to γ radiation. An analysis of the radiosensitivity of double mutants has revealed that the mutation cdc-28-srm is hypostatic to each of mutations rad9Δ, and rad24Δ, and additive to rad17Δ. The mutation netI-srm is hypostatic to the mutations rad9Δ but additive to rad17Δ, rad24Δ, and rad53. The mutation hfiI-srm has an additive effect in compound with the mutations rad24Δ and rad9Δ. So, investigations of epistatic interactions have demonstrated a branched RAD9-dependent pathway. The analyzed genes can also participate in a minor mechanism involved in determining cell radiation sensitivity independently of the mentioned RAD9-dependent pathway

  15. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints

    Bartkova, Jirina; Rezaei, Nousin; Liontos, Michalis

    2006-01-01

    Recent studies have indicated the existence of tumorigenesis barriers that slow or inhibit the progression of preneoplastic lesions to neoplasia. One such barrier involves DNA replication stress, which leads to activation of the DNA damage checkpoint and thereby to apoptosis or cell cycle arrest...... and senescence markers cosegregate closely. Thus, senescence in human preneoplastic lesions is a manifestation of oncogene-induced DNA replication stress and, together with apoptosis, provides a barrier to malignant progression....

  16. SPARC: Demonstrate burst-buffer-based checkpoint/restart on ATS-1.

    Oldfield, Ron A. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Ulmer, Craig D. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Widener, Patrick [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Ward, H. Lee [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

    2018-01-01

    Recent high-performance computing (HPC) platforms such as the Trinity Advanced Technology System (ATS-1) feature burst buffer resources that can have a dramatic impact on an application’s I/O performance. While these non-volatile memory (NVM) resources provide a new tier in the storage hierarchy, developers must find the right way to incorporate the technology into their applications in order to reap the benefits. Similar to other laboratories, Sandia is actively investigating ways in which these resources can be incorporated into our existing libraries and workflows without burdening our application developers with excessive, platform-specific details. This FY18Q1 milestone summaries our progress in adapting the Sandia Parallel Aerodynamics and Reentry Code (SPARC) in Sandia’s ATDM program to leverage Trinity’s burst buffers for checkpoint/restart operations. We investigated four different approaches with varying tradeoffs in this work: (1) simply updating job script to use stage-in/stage out burst buffer directives, (2) modifying SPARC to use LANL’s hierarchical I/O (HIO) library to store/retrieve checkpoints, (3) updating Sandia’s IOSS library to incorporate the burst buffer in all meshing I/O operations, and (4) modifying SPARC to use our Kelpie distributed memory library to store/retrieve checkpoints. Team members were successful in generating initial implementation for all four approaches, but were unable to obtain performance numbers in time for this report (reasons: initial problem sizes were not large enough to stress I/O, and SPARC refactor will require changes to our code). When we presented our work to the SPARC team, they expressed the most interest in the second and third approaches. The HIO work was favored because it is lightweight, unobtrusive, and should be portable to ATS-2. The IOSS work is seen as a long-term solution, and is favored because all I/O work (including checkpoints) can be deferred to a single library.

  17. Online Assessment of Oral Proficiency for Intercultural Professional Communication

    Rusman, Ellen; Stoyanov, Slavi

    2012-01-01

    Rusman, E., & Stoyanov, S. (2011, 18 May). Online Assessment of Oral Proficiency for Intercultural Professional Communication. Presentation about the CEFcult project (www.cefcult.eu) at the workshop ‘Crossing borders’ organised by the Talenacademie, Heerlen, The Netherlands: Open University in the

  18. Cultutal Factors Affecting English Proficiency in Rural Areas

    Ler, Ee Chop

    2012-01-01

    The purpose of this study is to investigate the rural "cultural" problems and to determine their effect on the learning of English. Twenty students from different ethnic backgrounds and English language proficiency in six rural schools in Terengganu, Malaysia were interviewed. In addition the teachers also from different rural schools…

  19. Predicting the Proficiency Level of Language Learners Using Lexical Indices

    Crossley, Scott A.; Salsbury, Tom; McNamara, Danielle S.

    2012-01-01

    This study explores how second language (L2) texts written by learners at various proficiency levels can be classified using computational indices that characterize lexical competence. For this study, 100 writing samples taken from 100 L2 learners were analyzed using lexical indices reported by the computational tool Coh-Metrix. The L2 writing…

  20. Pathways from Toddler Information Processing to Adolescent Lexical Proficiency

    Rose, Susan A.; Feldman, Judith F.; Jankowski, Jeffery J.

    2015-01-01

    This study examined the relation of 3-year core information-processing abilities to lexical growth and development. The core abilities covered four domains--memory, representational competence (cross-modal transfer), processing speed, and attention. Lexical proficiency was assessed at 3 and 13 years with the Peabody Picture Vocabulary Test (PPVT)…

  1. Determinants of Second Language Proficiency among Refugees in the Netherlands

    van Tubergen, Frank

    2010-01-01

    Little is known about the language acquisition of refugees in Western countries. This study examines how pre- and post-migration characteristics of refugees are related to their second language proficiency. Data are from a survey of 3,500 refugees, who were born in Afghanistan, Iran, Iraq, former Yugoslavia and Somalia, and who resided in the…

  2. Proficiency test on incurred and spiked pesticide residues in cereals

    Poulsen, Mette Erecius; Christensen, Hanne Bjerre; Herrmann, Susan Strange

    2009-01-01

    A proficiency test on incurred and spiked pesticide residues in wheat was organised in 2008. The test material was grown in 2007 and treated in the field with 14 pesticides formulations containing the active substances, alpha-cypermethrin, bifentrin, carbendazim, chlormequat, chlorpyrifos...

  3. Reading Processing Skills among EFL Learners in Different Proficiency Levels

    Dhanapala, Kusumi Vasantha; Yamada, Jun

    2015-01-01

    This study aims to understand how EFL learners in different reading proficiency levels comprehend L2 texts, using five-component skills involving measures of (1) vocabulary knowledge, (2) drawing inferences and predictions, (3) knowledge of text structure and discourse organization, (4) identifying the main idea and summarizing skills, and (5)…

  4. Determinants of second language proficiency among refugees in the Netherlands

    Tubergen, F.A. van

    2010-01-01

    Little is known about the language acquisition of refugees in Western countries. This study examines how pre- and post-migration characteristics of refugees are related to their second language proficiency. Data are from a survey of 3,500 refugees, who were born in Afghanistan, Iran, Iraq, former

  5. A new role of proficiency testing in nuclear analytical work

    Heydorn, Kaj

    2008-01-01

    The most recent definition of measurement result requires a statement of uncertainty whenever results obtained by nuclear or other quantitative methods of analysis are reported. Proficiency testing (PT) therefore must include the ability of laboratories to present not only unbiased quantity values...

  6. The Effects of Elementary Departmentalization on Mathematics Proficiency

    Taylor-Buckner, Nicole C.

    2014-01-01

    Mathematics education in the elementary schools has experienced many changes in recent decades. With the curriculum becoming more complex as a result of each modification, immense pressure has been put on schools to increase student proficiency. The Common Core State Standards is the latest example of this. These revisions to the mathematics…

  7. Motor proficiency and physical fitness in active and inactive girls ...

    In modern day society physical activity levels diminish rapidly among girls and may be a direct consequence of girls experiencing motor difficulties. Therefore the aim of the study was to compare motor proficiency levels and physical fitness levels among active and inactive girls (N=97), aged 12 to 13 years. The BOTMP ...

  8. Beyond Host Language Proficiency: Coping Resources Predicting International Students' Satisfaction

    Mak, Anita S.; Bodycott, Peter; Ramburuth, Prem

    2015-01-01

    As international students navigate in a foreign educational environment, having higher levels of coping or stress-resistance resources--both internal and external--could be related to increased satisfaction with personal and university life. The internal coping resources examined in this study were host language proficiency, self-esteem,…

  9. Developing Autonomous Learning for Oral Proficiency Using Digital Storytelling

    Kim, SoHee

    2014-01-01

    Since online educational technology can support a ubiquitous language learning environment, there are many ways to develop English learners' autonomy through self-access learning. This study investigates whether English as a second language (ESL) learners can improve their oral proficiency through independent study by using online self-study…

  10. Advisory Working Alliance, Perceived English Proficiency, and Acculturative Stress

    Wei, Meifen; Tsai, Pei-Chun; Chao, Ruth Chu-Lien; Du, Yi; Lin, Shu-Ping

    2012-01-01

    The aim of this study was to examine the moderators of (a) general or cross-cultural advisory working alliances and (b) perceived English proficiency on the association between acculturative stress and psychological distress. A total of 143 East Asian international students completed an online survey. Results from a hierarchical regression…

  11. The Education Consequences of Language Proficiency for Young Children

    Yao, Yuxin; Ohinata, Asako; van Ours, Jan

    2016-01-01

    This paper studies the educational consequences of language proficiency by investigating the relationship between dialect-speaking and academic performance of 5-6 year old children in the Netherlands. We find that dialect-speaking has a modestly negative effect on boys' language test scores. In

  12. The educational consequences of language proficiency for young children

    Yao, Yuxin; Ohinata, Asako; van Ours, Jan

    2016-01-01

    Our paper studies the educational consequences of language proficiency by investigating the relationship between dialect-speaking and academic performance of 5–6 year old children in the Netherlands. We find that dialect-speaking has a modestly negative effect on boys’ language test scores. In

  13. Teaching Mathematical Problem Solving to Students with Limited English Proficiency.

    Kaplan, Rochelle G.; Patino, Rodrigo A.

    Many mainstreamed students with limited English proficiency continue to face the difficulty of learning English as a second language (ESL) while studying mathematics and other content areas framed in the language of native speakers. The difficulty these students often encounter in mathematics classes and their poor performance on subsequent…

  14. Naming Abilities in Low-Proficiency Second Language Learners

    Borodkin, Katy; Faust, Miriam

    2014-01-01

    Difficulties in second language (L2) learning are often associated with recognizable learning difficulties in native language (L1), such as in dyslexia. However, some individuals have low L2 proficiency but intact L1 reading skills. These L2 learners experience frequent tip-of-the-tongue states while naming in L1, which indicates that they have a…

  15. Differential Effects of Learning Games on Mathematics Proficiency

    Chang, Mido; Evans, Michael A.; Kim, Sunha; Norton, Anderson; Samur, Yavuz

    2015-01-01

    This study examined the effects of a learning game, [The Math App] on the mathematics proficiency of middle school students. For the study, researchers recruited 306 students, Grades 6-8, from two schools in rural southwest Virginia. Over a nine-week period, [The Math App] was deployed as an intervention for investigation. Students were assigned…

  16. Listening and Reading Proficiency Levels of College Students

    Tschirner, Erwin

    2016-01-01

    This article examines listening and reading proficiency levels of U.S. college foreign language students at major milestones throughout their undergraduate career. Data were collected from more than 3,000 participants studying seven languages at 21 universities and colleges across the United States. The results show that while listening…

  17. Impact of English Proficiency on Academic Performance of International Students

    Martirosyan, Nara M.; Hwang, Eunjin; Wanjohi, Reubenson

    2015-01-01

    Using an ex-post facto, non-experimental approach, this research examined the impact of English language proficiency and multilingualism on the academic performance of international students enrolled in a four-year university located in north central Louisiana in the United States. Data were collected through a self-reported questionnaire from 59…

  18. Linguistic Proficiency and Strategies on Reading Performance in English

    Talebi, Seyed Hassan

    2015-01-01

    General English (L2) proficiency and reading strategies are believed to be highly effective in successful reading performance. However, available studies rarely investigated the combined effects of these two variables on successful reading. To fill this gap, 78 university students were divided into four groups of different degrees of these two…

  19. Music Teachers in Turkey: Their Proficiency, Working Environments and Problems

    Otacioglu, Sena Gursen

    2008-01-01

    The aim of this study was the collection of data concerning Turkish music teachers' proficiency and their place in the primary and secondary education system. In addition, information was collected regarding the teachers' working environment and professional complications. A total of 200 music teachers' opinions were compiled for the determination…

  20. Planes, Politics and Oral Proficiency: Testing International Air Traffic Controllers

    Moder, Carol Lynn; Halleck, Gene B.

    2009-01-01

    This study investigates the variation in oral proficiency demonstrated by 14 Air Traffic Controllers across two types of testing tasks: work-related radio telephony-based tasks and non-specific English tasks on aviation topics. Their performance was compared statistically in terms of level ratings on the International Civil Aviation Organization…

  1. Foreign Language Teachers' Language Proficiency and Their Language Teaching Practice

    Richards, Heather; Conway, Clare; Roskvist, Annelies; Harvey, Sharon

    2013-01-01

    Teachers' subject knowledge is recognized as an essential component of effective teaching. In the foreign language context, teachers' subject knowledge includes language proficiency. In New Zealand high schools, foreign languages (e.g. Chinese, French, German, Japanese and Spanish) have recently been offered to learners earlier in their schooling,…

  2. Rater Judgment and English Language Speaking Proficiency. Research Report

    Chalhoub-Deville, Micheline; Wigglesworth, Gillian

    2005-01-01

    The paper investigates whether there is a shared perception of speaking proficiency among raters from different English speaking countries. More specifically, this study examines whether there is a significant difference among English language learning (ELL) teachers, residing in Australia, Canada, the UK, and the USA when rating speech samples of…

  3. The Minnesota Articulation Project and Its Proficiency-Based Assessments.

    Chalhoub-Deville, Micheline

    1997-01-01

    Reports on the Minnesota Articulation Project, providing an overview of the projects' three principal working groups: political action, curriculum, and assessment. The article then outlines the theoretical underpinnings of the proficiency-based assessment instruments developed in French, German, and Spanish and describes in detail the content and…

  4. P-2 Years Targeted to Achieve Grade 3 Reading Proficiency

    Gewertz, Catherine

    2011-01-01

    In a bid to help more students read proficiently in 3rd grade--a skill considered critical to their future educational success--new laws and initiatives springing up around the country require educators to step up their efforts to identify and help struggling readers even before they enter kindergarten. It's not unusual for states or school…

  5. Trends in Teacher Certification: Equipping Teachers to Prepare Proficient Readers

    Rowland, Julie

    2015-01-01

    Ensuring that students are reading proficiently by third grade is a key component of keeping students on track to graduate high school and pursue college and careers. Because of the magnitude of this academic milestone, states typically pursue policies that promote early identification and intervention for struggling readers. However, teachers are…

  6. Statistical analysis of nematode counts from interlaboratory proficiency tests

    Berg, van den W.; Hartsema, O.; Nijs, Den J.M.F.

    2014-01-01

    A series of proficiency tests on potato cyst nematode (PCN; n=29) and free-living stages of Meloidogyne and Pratylenchus (n=23) were investigated to determine the accuracy and precision of the nematode counts and to gain insights into possible trends and potential improvements. In each test, each

  7. A retrospective evaluation of proficiency testing, and rapid HIV test ...

    Background: Proficiency testing (PT) has been implemented as a form of External Quality Assurance (EQA) by the National HIV Reference Laboratory in Kenya since 2007 in order to monitor and improve on the quality of HIV testing and counselling HTC services. Objective: To compare concordance between National HIV ...

  8. Predicting Lexical Proficiency in Language Learner Texts Using Computational Indices

    Crossley, Scott A.; Salsbury, Tom; McNamara, Danielle S.; Jarvis, Scott

    2011-01-01

    The authors present a model of lexical proficiency based on lexical indices related to vocabulary size, depth of lexical knowledge, and accessibility to core lexical items. The lexical indices used in this study come from the computational tool Coh-Metrix and include word length scores, lexical diversity values, word frequency counts, hypernymy…

  9. 76 FR 66318 - Announcement of Funding Awards; Limited English Proficiency Initiative Program (LEPI), Fiscal...

    2011-10-26

    ... limited English proficiency (LEP), and develop and implement a system to provide those services so LEP... Awards; Limited English Proficiency Initiative Program (LEPI), Fiscal Year 2010/2011 AGENCY: Office of... (NOFA) for the Limited English Proficiency Initiative (LEPI) Program for Fiscal Year (FY) 2010/2011...

  10. Comparing Examinee Attitudes Toward Computer-Assisted and Other Oral Proficiency Assessments.

    Kenyon, Dorry M.; Malabonga, Valerie

    2001-01-01

    Examined attitudes toward taking different formats of oral proficiency assessments across three languages: Spanish, Arabic, and Chinese. Students were administered both the tape-mediated Simulated Oral Proficiency Interview (SOPI) and a new Computerized Oral Proficiency Instrument (COPI). Questionnaire responses showed examinees, particularly…

  11. Measures for Determining English Language Proficiency and the Resulting Implications for Instructional Provision and Intervention

    Albers, Craig A.; Kenyon, Dorry M.; Boals, Timothy J.

    2009-01-01

    Although numerous English language proficiency (ELP) measures currently exist, many were developed prior to the No Child Left Behind Act of 2001 (NCLB). These pre-NCLB measures typically focused on social language proficiency, whereas post-NCLB measures are linked to ELP standards and focus on academic language proficiency (ALP). ELP measures are…

  12. A Review of Immune Checkpoint Inhibitors for the Management of Locally Advanced or Metastatic Urothelial Carcinoma.

    Hanna, Kirollos S

    2017-11-01

    Urothelial carcinoma (UC) is the second most common malignancy of the genitourinary system and the sixth most common cancer in the United States. The overall incidence of UC appears to be on the decline, but death rates have remained stable. Stage IV metastatic disease is associated with only a 5% survival rate at 5 years. Gemcitabine and cisplatin combinations or dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin are the preferred regimens for individuals with advance, metastatic disease and a good performance status and organ function. Second-line therapies in this setting are limited. During the course of 1 year, five immune checkpoint inhibitors were approved for treatment of cancers in the locally advanced or metastatic setting: atezolizumab, nivolumab, durvalumab, avelumab, and pembrolizumab. Immunotherapies have played a significant role in the treatment of various cancers and have continued to expand. It is of utmost importance that practitioners include checkpoint inhibitors as treatment options for UC. Based on the limited data, pembrolizumab and atezolizumab may be the drugs of choice, as they are supported by the most influential data to date; however, further research is warranted. Ongoing clinical trials will further assess the benefits of inducing cellular immunity in the treatment of UC. These therapies mark a new landscape in the treatment of UC. In this article, the available data on immune checkpoint inhibitors for the treatment of locally advanced or metastatic UC and their place in therapy are reviewed. © 2017 Pharmacotherapy Publications, Inc.

  13. Biological significance of the focus on DNA damage checkpoint factors remained after irradiation of ionizing radiation

    Yamauchi, Motohiro; Suzuki, Keiji

    2005-01-01

    This paper reviews recent reports on the focus formation and participation to checkpoint of (such phosphorylated (P-d) as below) ATM and H2AX, MDC1, 53BP1 and NBS1, and discusses their role in DNA damage checkpoint induction mainly around authors' studies. When the cell is irradiated by ionizing radiation, the subtype histone like H2AX is P-d and the formed focus', seen in the nucleus on immuno-fluorographic observation, represents the P-d H2AX at the damaged site of DNA. The role of P-d ATM (the product of causative gene of ataxia-telangiectasia mutation, a protein kinase) has been first shown by laser beam irradiation. Described are discussions on the roles and functions after irradiation in focus formation and DNA damage checkpoint of P-d H2AX (a specific histone product by the radiation like γ-ray as above), P-d ATM, MDC1 (a mediator of DNA damage check point protein 1), 53BP1, (a p53 binding protein) and NBS1 (the product of the causative gene of Nijmegen Breakage Syndrome). Authors have come to point out the remained focal size increase as implications of the efficient repair of damaged DNA, and the second cycled p53 accumulation, of tumor suppression. Thus evaluation of biological significance of these aspects, scarcely noted hitherto, is concluded important. (S.I.)

  14. Measures to detect and control radioactive contaminated metallurgical scrap at border checkpoints in Poland

    Smagala, G.

    1999-01-01

    The issue of radioactive contaminated metallurgical scrap has never received a high priority in Poland and in the international community. Since the dissolution of the former Soviet Union a higher attention has been given to the problem. Poland which is located between the West and East Europe has the obligation to develop and implement an effective prevention and detection system. The reasons to increase national control and detection system at the border checkpoints in Poland are to avoid the following risks: post Chernobyl contamination transports of commodities; transport of contaminated metal scrap; transfer of radioactive waste for their disposal or utilization; high risk of becoming a transit country of illicit trafficking of nuclear materials and radioactive sources. In order to avoid the above-mentioned risks, Poland initiated in 1990, a deployment of the portable radiation devices at the border checkpoints and, as of 1998, the number of installed instruments exceeded a hundred. This paper presents Poland's activities to detect contaminated scrap at its border checkpoints. (author)

  15. Immune checkpoint blockade therapy: The 2014 Tang prize in biopharmaceutical science

    Ya-Shan Chen

    2015-02-01

    Full Text Available The first Tang Prize for Biopharmaceutical Science has been awarded to Prof. James P. Allison and Prof. Tasuku Honjo for their contributions leading to an entirely new way to treat cancer by blocking the molecules cytotoxic T lymphocyte-associated antigen 4 (CTLA-4 and programmed cell death protein 1 (PD-1 that turn off immune response. The treatment, called "immune checkpoint blockade therapy," has opened a new therapeutic era. Here the discoveries of the immune checkpoints and how they contribute to the maintenance of self-tolerance, as well as how to protect tissues from the excess immune responses causing damage are reviewed. The efforts made by Prof. Allison and Prof. Honjo for developing the most promising approaches to activate therapeutic antitumor immunity are also summarized. Since these certain immune checkpoint pathways appear to be one of the major mechanisms resulting in immune escape of tumors, the presence of anti-CTLA-4 and/or anti-PD-1 should contribute to removal of the inhibition signals for T cell activation. Subsequently, it will enhance specific T cell activation and, therefore, strengthen antitumor immunity.

  16. TAM receptor tyrosine kinases as emerging targets of innate immune checkpoint blockade for cancer therapy.

    Akalu, Yemsratch T; Rothlin, Carla V; Ghosh, Sourav

    2017-03-01

    Cancer immunotherapy utilizing T-cell checkpoint inhibitors has shown tremendous clinical success. Yet, this mode of treatment is effective in only a subset of patients. Unresponsive patients tend to have non-T-cell-inflamed tumors that lack markers associated with the activation of adaptive anti-tumor immune responses. Notably, elimination of cancer cells by T cells is critically dependent on the optimal activity of innate immune cells. Therefore, identifying new targets that regulate innate immune cell function and promote the engagement of adaptive tumoricidal responses is likely to lead to the development of improved therapies against cancer. Here, we review the TAM receptor tyrosine kinases-TYRO3, AXL, and MERTK-as an emerging class of innate immune checkpoints that participate in key steps of anti-tumoral immunity. Namely, TAM-mediated efferocytosis, negative regulation of dendritic cell activity, and dysregulated production of chemokines collectively favor the escape of malignant cells. Hence, disabling TAM signaling may promote engagement of adaptive immunity and complement T-cell checkpoint blockade. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. Unique cytologic features of thyroiditis caused by immune checkpoint inhibitor therapy for malignant melanoma

    Trevor E. Angell

    2018-03-01

    Full Text Available Blockade of immune checkpoint molecules to reverse cancer-induced immune suppression can improve anti-tumor immune responses in cancer patients. Monoclonal antibodies targeting two such molecules, Programmed cell death protein 1 (PD-1 and cytotoxic T-lymphocyte associated protein 4 (CTLA-4 have shown clinical benefit in the treatment of advanced malignancies, including metastatic melanoma. Adverse effects of these immune checkpoint inhibitors include immune-related adverse events (irAE, of which one of the most common is autoimmune thyroiditis. Though thyroiditis is increasingly recognized, there are no reports of the pathological findings that occur in immunotherapy-induced thyroiditis. We present a case of immunotherapy-induced thyroiditis demonstrating its unique cytopathologic features. A 51-year-old woman with metastatic melanoma was found to have a suppressed TSH and elevated free thyroxine concentration 14 days after starting treatment with nivolumab (PD-1 antagonist plus ipilimumab (CTLA-4 antagonist therapy. A thyroid biopsy was performed based on ultrasound findings and cytopathology revealed unique features including abundant clusters of necrotic cells, lymphocytes and CD163-positive histiocytes. This case reports cytopathologic features found in immune checkpoint inhibitor related thyroiditis. These appear to be unique findings and may help inform future research regarding the pathophysiology and mechanisms of this condition.

  18. Cdk2 is required for p53-independent G2/M checkpoint control.

    Jon H Chung

    2010-02-01

    Full Text Available The activation of phase-specific cyclin-dependent kinases (Cdks is associated with ordered cell cycle transitions. Among the mammalian Cdks, only Cdk1 is essential for somatic cell proliferation. Cdk1 can apparently substitute for Cdk2, Cdk4, and Cdk6, which are individually dispensable in mice. It is unclear if all functions of non-essential Cdks are fully redundant with Cdk1. Using a genetic approach, we show that Cdk2, the S-phase Cdk, uniquely controls the G(2/M checkpoint that prevents cells with damaged DNA from initiating mitosis. CDK2-nullizygous human cells exposed to ionizing radiation failed to exclude Cdk1 from the nucleus and exhibited a marked defect in G(2/M arrest that was unmasked by the disruption of P53. The DNA replication licensing protein Cdc6, which is normally stabilized by Cdk2, was physically associated with the checkpoint regulator ATR and was required for efficient ATR-Chk1-Cdc25A signaling. These findings demonstrate that Cdk2 maintains a balance of S-phase regulatory proteins and thereby coordinates subsequent p53-independent G(2/M checkpoint activation.

  19. Loss of p53 induces M-phase retardation following G2 DNA damage checkpoint abrogation.

    Minemoto, Yuzuru; Uchida, Sanae; Ohtsubo, Motoaki; Shimura, Mari; Sasagawa, Toshiyuki; Hirata, Masato; Nakagama, Hitoshi; Ishizaka, Yukihito; Yamashita, Katsumi

    2003-04-01

    Most cell lines that lack functional p53 protein are arrested in the G2 phase of the cell cycle due to DNA damage. When the G2 checkpoint is abrogated, these cells are forced into mitotic catastrophe. A549 lung adenocarcinoma cells, in which p53 was eliminated with the HPV16 E6 gene, exhibited efficient arrest in the G2 phase when treated with adriamycin. Administration of caffeine to G2-arrested cells induced a drastic change in cell phenotype, the nature of which depended on the status of p53. Flow cytometric and microscopic observations revealed that cells that either contained or lacked p53 resumed their cell cycles and entered mitosis upon caffeine treatment. However, transit to the M phase was slower in p53-negative cells than in p53-positive cells. Consistent with these observations, CDK1 activity was maintained at high levels, along with stable cyclin B1, in p53-negative cells. The addition of butyrolactone I, which is an inhibitor of CDK1 and CDK2, to the p53-negative cells reduced the floating round cell population and induced the disappearance of cyclin B1. These results suggest a relationship between the p53 pathway and the ubiquitin-mediated degradation of mitotic cyclins and possible cross-talk between the G2-DNA damage checkpoint and the mitotic checkpoint.

  20. Immune checkpoint inhibitors: the new frontier in non–small cell lung cancer treatment

    El-Osta HE

    2016-08-01

    Full Text Available Hazem El-Osta, Kamran Shahid, Glenn M Mills, Prakash Peddi Department of Medicine, Division of Hematology-Oncology, Louisiana State University Health Sciences Center, Shreveport, LA, USA Abstract: Lung cancer is the major cause for cancer-related death in the US. Although advances in chemotherapy and targeted therapy have improved the outcome of metastatic non-small-cell lung cancer, its prognosis remains dismal. A deeper understanding of the complex interaction between the immune system and tumor microenvironment has identified immune checkpoint inhibitors as new avenue of immunotherapy. Rather than acting directly on the tumor, these therapies work by removing the inhibition exerted by tumor cell or other immune cells on the immune system, promoting antitumoral immune response. To date, two programmed death-1 inhibitors, namely nivolumab and pembrolizumab, have received the US Food and Drug Administration approval for the treatment of advanced non-small-cell lung cancer that failed platinum-based chemotherapy. This manuscript provides a brief overview of the pathophysiology of cancer immune evasion, summarizes pertinent data on completed and ongoing clinical trials involving checkpoint inhibitors, discusses the different strategies to optimize their function, and outlines various challenges that are faced in this promising yet evolving field. Keywords: checkpoint inhibitors, immunotherapy, nivolumab, non-small-cell lung cancer, pembrolizumab, programmed death-1, programmed death ligand-1

  1. Proficiency training on a virtual reality robotic surgical skills curriculum.

    Bric, Justin; Connolly, Michael; Kastenmeier, Andrew; Goldblatt, Matthew; Gould, Jon C

    2014-12-01

    The clinical application of robotic surgery is increasing. The skills necessary to perform robotic surgery are unique from those required in open and laparoscopic surgery. A validated laparoscopic surgical skills curriculum (Fundamentals of Laparoscopic Surgery or FLS™) has transformed the way surgeons acquire laparoscopic skills. There is a need for a similar skills training and assessment tool for robotic surgery. Our research group previously developed and validated a robotic training curriculum in a virtual reality (VR) simulator. We hypothesized that novice robotic surgeons could achieve proficiency levels defined by more experienced robotic surgeons on the VR robotic curriculum, and that this would result in improved performance on the actual daVinci Surgical System™. 25 medical students with no prior robotic surgery experience were recruited. Prior to VR training, subjects performed 2 FLS tasks 3 times each (Peg Transfer, Intracorporeal Knot Tying) using the daVinci Surgical System™ docked to a video trainer box. Task performance for the FLS tasks was scored objectively. Subjects then practiced on the VR simulator (daVinci Skills Simulator) until proficiency levels on all 5 tasks were achieved before completing a post-training assessment of the 2 FLS tasks on the daVinci Surgical System™ in the video trainer box. All subjects to complete the study (1 dropped out) reached proficiency levels on all VR tasks in an average of 71 (± 21.7) attempts, accumulating 164.3 (± 55.7) minutes of console training time. There was a significant improvement in performance on the robotic FLS tasks following completion of the VR training curriculum. Novice robotic surgeons are able to attain proficiency levels on a VR simulator. This leads to improved performance in the daVinci surgical platform on simulated tasks. Training to proficiency on a VR robotic surgery simulator is an efficient and viable method for acquiring robotic surgical skills.

  2. Chronological age and its impact on associative learning proficiency and brain structure in middle adulthood.

    Diwadkar, Vaibhav A; Bellani, Marcella; Ahmed, Rizwan; Dusi, Nicola; Rambaldelli, Gianluca; Perlini, Cinzia; Marinelli, Veronica; Ramaseshan, Karthik; Ruggeri, Mirella; Bambilla, Paolo

    2016-01-15

    The rate of biological change in middle-adulthood is relatively under-studied. Here, we used behavioral testing in conjunction with structural magnetic resonance imaging to examine the effects of chronological age on associative learning proficiency and on brain regions that previous functional MRI studies have closely related to the domain of associative learning. Participants (n=66) completed a previously established associative learning paradigm, and consented to be scanned using structural magnetic resonance imaging. Age-related effects were investigated both across sub-groups in the sample (younger vs. older) and across the entire sample (using regression approaches). Chronological age had substantial effects on learning proficiency (independent of IQ and Education Level), with older adults showing a decrement compared to younger adults. In addition, decreases in estimated gray matter volume were observed in multiple brain regions including the hippocampus and the dorsal prefrontal cortex, both of which are strongly implicated in associative learning. The results suggest that middle adulthood may be a more dynamic period of life-span change than previously believed. The conjunctive application of narrowly focused tasks, with conjointly acquired structural MRI data may allow us to enrich the search for, and the interpretation of, age-related changes in cross-sectional samples. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Radiation-induced genetic instability: no association with changes in radiosensitivity or cell cycle checkpoints in C3H 10T1/2 mouse fibroblasts

    Crompton, N.E.A.; Emery, G.C.; Shi Yuquan; Sigg, M.; Blattmann, H.

    1998-01-01

    We investigated various phenotypic characteristics of radiation-induced morphologically transformed C3H 10T1/2 mouse fibroblasts. The cells were treated with 8 Gy x-rays, and type II/III foci were isolated. Cell lines were developed from these foci, and subsequently clones were established from these focal lines. The clones were examined for DNA content, radiosensitivity and inducible cell cycle arrests. Besides the morphological changes associated with the transformed state, the major difference between the isolated focal lines or derived clones and the parental C3H 10T1/2 line was one of ploidy. The transformed cells often displayed aneuploid and multiple polyploid populations. No change in the radiosensitivity of the transformed cells was observed. Furthermore, the two major radiation- and staurosporine-induced G1 and G2 cell cycle arrests observed in the parental cell line were also observed in the morphological transformants, suggesting that checkpoint function was normal. (orig.)

  4. Multilayer checkpoints for microRNA authenticity during RISC assembly.

    Kawamata, Tomoko; Yoda, Mayuko; Tomari, Yukihide

    2011-09-01

    MicroRNAs (miRNAs) function through the RNA-induced silencing complex (RISC), which contains an Argonaute (Ago) protein at the core. RISC assembly follows a two-step pathway: miRNA/miRNA* duplex loading into Ago, and separation of the two strands within Ago. Here we show that the 5' phosphate of the miRNA strand is essential for duplex loading into Ago, whereas the preferred 5' nucleotide of the miRNA strand and the base-pairing status in the seed region and the middle of the 3' region function as additive anchors to Ago. Consequently, the miRNA authenticity is inspected at multiple steps during RISC assembly.

  5. Summary of microsatellite instability test results from laboratories participating in proficiency surveys: proficiency survey results from 2005 to 2012.

    Boyle, Theresa A; Bridge, Julia A; Sabatini, Linda M; Nowak, Jan A; Vasalos, Patricia; Jennings, Lawrence J; Halling, Kevin C

    2014-03-01

    The College of American Pathologists surveys are the largest laboratory peer comparison programs in the world. These programs allow laboratories to regularly evaluate their performance and improve the accuracy of the patient test results they provide. Proficiency testing is offered twice a year to laboratories performing microsatellite instability testing. These surveys are designed to emulate clinical practice, and some surveys have more challenging cases to encourage the refinement of laboratory practices. This report summarizes the results and trends in microsatellite instability proficiency testing from participating laboratories from the inception of the program in 2005 through 2012. We compiled and analyzed data for 16 surveys of microsatellite instability proficiency testing during 2005 to 2012. The number of laboratories participating in the microsatellite instability survey has more than doubled from 42 to 104 during the 8 years analyzed. An average of 95.4% of the laboratories correctly classified each of the survey test samples from the 2005A through 2012B proficiency challenges. In the 2011B survey, a lower percentage of laboratories (78.4%) correctly classified the specimen, possibly because of overlooking subtle changes of microsatellite instability and/or failing to enrich the tumor content of the specimen to meet the limit of detection of their assay. In general, laboratories performed well in microsatellite instability testing. This testing will continue to be important in screening patients with colorectal and other cancers for Lynch syndrome and guiding the management of patients with sporadic colorectal cancer.

  6. Asymmetric Translation between Multiple Representations in Chemistry

    Lin, Yulan I.; Son, Ji Y.; Rudd, James A., II

    2016-01-01

    Experts are more proficient in manipulating and translating between multiple representations (MRs) of a given concept than novices. Studies have shown that instruction using MR can increase student understanding of MR, and one model for MR instruction in chemistry is the chemistry triplet proposed by Johnstone. Concreteness fading theory suggests…

  7. Case report on the role of radiofrequency-assisted spleen-preserving surgery for splenic metastasis in the era of check-point inhibitors.

    Mudan, Satvinder; Kumar, Jayant; Mafalda, Neves C; Kusano, Tomokazu; Reccia, Isabella; Zanallato, Artur; Dalgleish, Angus; Habib, Nagy

    2017-12-01

    An isolated splenic metastasis is a rare phenomenon noted in advanced stage melanoma. We report the role of radiofrequency (RF) -based splenic-preserving splenectomy in a patient with a solitary splenic metastasis from advanced stage melanoma that was managed with checkpoint inhibitors. We report a case of a 60-year-old man who presented with multiple lung metastases and a solitary splenic metastasis with advanced stage melanoma following excision of primary from his trunk 2.3 years back. Considering the diagnosis of advanced stage melanoma with multiple lung metastases and a solitary splenic metastasis, and its ongoing progressive nature. This case was discussed in the tumour board meeting. A decision was made to commence treatment with immunotherapy in the form of PD-1 inhibitor (programmed cell death 1 receptor) pembrolizumab. Follow-up restaging computer tomography (CT) scan of the abdomen and chest showed a significant reduction in the lung and chest wall lesions, but the splenic lesion remained unchanged. Given the lack of response to treatment in the splenic metastasis and the significant decrease in lung metastases, the multidisciplinary team decided that a partial splenectomy combined with continued immunotherapy treatment would be appropriate as the success of immunotherapy was imminent within the splenic preservation. The postoperative recovery was smooth and the patient was discharged from hospital on the sixth postoperative day with normal platelets and white blood cells. The histopathological analysis of the resected specimen showed a metastatic melanoma with negative margins.At 10-month follow-up after the splenic resection the patient had not experienced further tumour recurrences. Spleen-preserving resection for an isolated, solitary splenic metastasis of melanoma is a feasible approach as it not only preserves the ongoing efficacy of checkpoint inhibitors by preserving the physiological T cell milieu, but the immunomodulation properties of RF can

  8. Immune checkpoint inhibitor PD-1 pathway is down-regulated in synovium at various stages of rheumatoid arthritis disease progression.

    Guo, Yanxia; Walsh, Alice M; Canavan, Mary; Wechalekar, Mihir D; Cole, Suzanne; Yin, Xuefeng; Scott, Brittney; Loza, Mathew; Orr, Carl; McGarry, Trudy; Bombardieri, Michele; Humby, Frances; Proudman, Susanna M; Pitzalis, Costantino; Smith, Malcolm D; Friedman, Joshua R; Anderson, Ian; Madakamutil, Loui; Veale, Douglas J; Fearon, Ursula; Nagpal, Sunil

    2018-01-01

    Immune checkpoint blockade with therapeutic anti-cytotoxic T lymphocyte-associated antigen (CTLA)-4 (Ipilimumab) and anti-programmed death (PD)-1 (Nivolumab and Pembrolizumab) antibodies alone or in combination has shown remarkable efficacy in multiple cancer types, concomitant with immune-related adverse events, including arthralgia and inflammatory arthritis (IA) in some patients. Herein, using Nivolumab (anti-PD-1 antagonist)-responsive genes along with transcriptomics of synovial tissue from multiple stages of rheumatoid arthritis (RA) disease progression, we have interrogated the activity status of PD-1 pathway during RA development. We demonstrate that the expression of PD-1 was increased in early and established RA synovial tissue compared to normal and OA synovium, whereas that of its ligands, programmed death ligand-1 (PD-L1) and PD-L2, was increased at all the stages of RA disease progression, namely arthralgia, IA/undifferentiated arthritis, early RA and established RA. Further, we show that RA patients expressed PD-1 on a majority of synovial tissue infiltrating CD4+ and CD8+ T cells. Moreover, enrichment of Nivolumab gene signature was observed in IA and RA, indicating that the PD-1 pathway was downregulated during RA disease progression. Furthermore, serum soluble (s) PD-1 levels were increased in autoantibody positive early RA patients. Interestingly, most of the early RA synovium tissue sections showed negative PD-L1 staining by immunohistochemistry. Therefore, downregulation in PD-1 inhibitory signaling in RA could be attributed to increased serum sPD-1 and decreased synovial tissue PD-L1 levels. Taken together, these data suggest that agonistic PD1 antibody-based therapeutics may show efficacy in RA treatment and interception.

  9. Immune checkpoint inhibitor PD-1 pathway is down-regulated in synovium at various stages of rheumatoid arthritis disease progression.

    Guo, Yanxia

    2018-01-01

    Immune checkpoint blockade with therapeutic anti-cytotoxic T lymphocyte-associated antigen (CTLA)-4 (Ipilimumab) and anti-programmed death (PD)-1 (Nivolumab and Pembrolizumab) antibodies alone or in combination has shown remarkable efficacy in multiple cancer types, concomitant with immune-related adverse events, including arthralgia and inflammatory arthritis (IA) in some patients. Herein, using Nivolumab (anti-PD-1 antagonist)-responsive genes along with transcriptomics of synovial tissue from multiple stages of rheumatoid arthritis (RA) disease progression, we have interrogated the activity status of PD-1 pathway during RA development. We demonstrate that the expression of PD-1 was increased in early and established RA synovial tissue compared to normal and OA synovium, whereas that of its ligands, programmed death ligand-1 (PD-L1) and PD-L2, was increased at all the stages of RA disease progression, namely arthralgia, IA\\/undifferentiated arthritis, early RA and established RA. Further, we show that RA patients expressed PD-1 on a majority of synovial tissue infiltrating CD4+ and CD8+ T cells. Moreover, enrichment of Nivolumab gene signature was observed in IA and RA, indicating that the PD-1 pathway was downregulated during RA disease progression. Furthermore, serum soluble (s) PD-1 levels were increased in autoantibody positive early RA patients. Interestingly, most of the early RA synovium tissue sections showed negative PD-L1 staining by immunohistochemistry. Therefore, downregulation in PD-1 inhibitory signaling in RA could be attributed to increased serum sPD-1 and decreased synovial tissue PD-L1 levels. Taken together, these data suggest that agonistic PD1 antibody-based therapeutics may show efficacy in RA treatment and interception.

  10. The English Proficiency of the Academics of the Teacher Training and Education Institutions

    Ali Saukah

    2016-02-01

    Full Text Available The study is aimed at describing the general English proficiency level of the academics of Teacher Training and Education Institutions (LPTK's as indicated by their TOEFL scores. Specifically, the study is focused on finding out whether there is any difference among the academics' English proficiencies when they are grouped in terms of the geographic regions of their institutions and their fields of study. This study is also intended to reveal any possible relationship between the academics' English proficiency and their age. The results indicate that the English proficiency of the academics on the average is far below the average of that of the international students. The academics in West Java are the highest in their English proficiency, and the English group, as expected, has the best English proficiency. In addition, there is a negative correlation between English proficiency and age

  11. First Language Proficiency and Successful Foreign Language Learning: The Case of High School Students Learning French as a Foreign Language

    Gnintedem, Antoine

    2014-01-01

    This study investigated whether there was a correlation between first language proficiency as measured by the Mississippi Curriculum Test (MCT II) Reading and Language Arts and foreign language proficiency as measured by the French Language Proficiency Test. Data for the independent variable, first language proficiency, was collected from the…

  12. Deaf college students' mathematical skills relative to morphological knowledge, reading level, and language proficiency.

    Kelly, Ronald R; Gaustad, Martha G

    2007-01-01

    This study of deaf college students examined specific relationships between their mathematics performance and their assessed skills in reading, language, and English morphology. Simple regression analyses showed that deaf college students' language proficiency scores, reading grade level, and morphological knowledge regarding word segmentation and meaning were all significantly correlated with both the ACT Mathematics Subtest and National Technical Institute for the Deaf (NTID) Mathematics Placement Test scores. Multiple regression analyses identified the best combination from among these potential independent predictors of students' performance on both the ACT and NTID mathematics tests. Additionally, the participating deaf students' grades in their college mathematics courses were significantly and positively associated with their reading grade level and their knowledge of morphological components of words.

  13. Nordic proficiency test for whole body counting facilities

    del Risco Norrlid, L. (Swedish Radiation Safety Authority (Sweden)); Halldorsson, O. (Icelandic Radiation Safety Authority, GR (Iceland)); Holm, S. (Copenhagen Univ. Hospital. NM and PET (Denmark)); Huikari, J. (Radiation and Nuclear Safety Authority (Finland)); Isaksson, M. (Goeteborg Univ., Dep. Radiation Physics Sahlgren Academy (Sweden)); Lind, B. (Norwegian Radiation Protection Authority (Norway))

    2012-01-15

    The PIANOLIB activity aims to harmonize the calibrations of the measurement equipment in the region and to evaluate the quality of this kind of measurement by means of a proficiency test exercise. In this report the results of the proficiency test are presented. The exercise consisted in determining the activity of a phantom filled with two sets of certified radioactive materials, K-40 and Cs-137, in radioactive rods, uniformly spaced inside of the phantom. Most of the participants were able to quantify correctly the activities of K-40 and Cs-137 and by comparison with the results of a previous exercise of this kind, the overall performance is equally good. The problems experienced by laboratories which submitted non-acceptable results could generally be attributed to the calibration of their systems. It is important to keep the practice of intercomparison and NKS continues to be the best framework for supporting this kind of activity. (Author)

  14. Language proficiency and health status: are bilingual immigrants healthier?

    Schachter, Ariela; Kimbro, Rachel T; Gorman, Bridget K

    2012-03-01

    Bilingual immigrants appear to have a health advantage, and identifying the mechanisms responsible for this is of increasing interest to scholars and policy makers in the United States. Utilizing the National Latino and Asian American Study (NLAAS; n = 3,264), we investigate the associations between English and native-language proficiency and usage and self-rated health for Asian and Latino U.S. immigrants from China, the Philippines, Vietnam, Mexico, Cuba, and Puerto Rico. The findings demonstrate that across immigrant ethnic groups, being bilingual is associated with better self-rated physical and mental health relative to being proficient in only English or only a native language, and moreover, these associations are partially mediated by socioeconomic status and family support but not by acculturation, stress and discrimination, or health access and behaviors.

  15. Linguistic Proficiency and Strategies on Reading Performance in English

    Seyed Hassan Talebi

    2015-01-01

    Full Text Available General English (L2 proficiency and reading strategies are believed to be highly effective in successful reading performance. However, available studies rarely investigated the combined effects of these two variables on successful reading. To fill this gap, 78 university students were divided into four groups of different degrees of these two variables in L2 and given a reading test in English and an interview for assessing how much of the problems in L2 reading among the four groups were rooted in linguistic competence and/or strategic competence. Findings evinced that the high general proficiency level coupled with high awareness and use of reading strategies would result in best performance and that the pattern of answers to different components of reading question is different in different groups. It is concluded that both of the variables should be emphasized simultaneously for the best performance in reading comprehension.

  16. Fluctuation analysis of proficient and dysgraphic handwriting in children

    Rosenblum, S.; Roman, H. E.

    2009-03-01

    We analyze handwriting records from several school children with the aim of characterizing the fluctuating behavior of the writing speed. It will be concluded that remarkable differences exist between proficient and dysgraphic handwritings which were unknown so far. It is shown that in the case of proficient handwriting, the variations in handwriting speed are strongly autocorrelated within times corresponding to the completion of a single character or letter, while become uncorrelated at longer times. In the case of dysgraphia, such correlations persist on longer time scales and the autocorrelation function seems to display algebraic time decay, indicating the presence of strong anomalies in the handwriting process. Applications of the results in educational/clinical programs are envisaged.

  17. Radon Measurement Proficiency (RMP) Program methods and devices

    Harrison, J.; Hoornbeek, J.; Jalbert, P.; Sensintaffar, E.; Hopper, R.

    1991-01-01

    The US EPA developed the voluntary Radon Measurement Proficiency Program in 1986 in response to a Federal and State need for measurement services firms to demonstrate their proficiency with radon measurement methods and devices. Since that time, the program has set basic standards for the radon measurement industry. The program has grown dramatically since its inception. In 1986, fewer than 50 companies participated in the program. By 1989, more than 5,000 companies were participating. Participants represent firms with an analytical capability as well as firms that rely upon another firm for analysis service. Since the beginning of the RMP Program, the Agency has learned a great deal about radon measurement methods and devices. This paper reviews the measurement devices used in the program and what the EPA has learned about them since the program's inception. Performance data from the RMP Program are used to highlight relevant findings

  18. Proficiency Testing Activities of Frequency Calibration Laboratories in Taiwan, 2009

    2009-11-01

    cht.com.tw Abstract In order to meet the requirements of ISO 17025 and the demand of TAF (Taiwan Accreditation Foundation) for calibration inter... IEC 17025 General requirements for the competence of testing and calibration laboratories. The proficiency testing results are then important...on-site evaluation, an assessment team is organized to examine the technical competence of the labs and their compliance with the requirements of ISO

  19. Does childhood motor skill proficiency predict adolescent fitness?

    Barnett, Lisa M; Van Beurden, Eric; Morgan, Philip J; Brooks, Lyndon O; Beard, John R

    2008-12-01

    To determine whether childhood fundamental motor skill proficiency predicts subsequent adolescent cardiorespiratory fitness. In 2000, children's proficiency in a battery of skills was assessed as part of an elementary school-based intervention. Participants were followed up during 2006/2007 as part of the Physical Activity and Skills Study, and cardiorespiratory fitness was measured using the Multistage Fitness Test. Linear regression was used to examine the relationship between childhood fundamental motor skill proficiency and adolescent cardiorespiratory fitness controlling for gender. Composite object control (kick, catch, throw) and locomotor skill (hop, side gallop, vertical jump) were constructed for analysis. A separate linear regression examined the ability of the sprint run to predict cardiorespiratory fitness. Of the 928 original intervention participants, 481 were in 28 schools, 276 (57%) of whom were assessed. Two hundred and forty-four students (88.4%) completed the fitness test. One hundred and twenty-seven were females (52.1%), 60.1% of whom were in grade 10 and 39.0% were in grade 11. As children, almost all 244 completed each motor assessments, except for the sprint run (n = 154, 55.8%). The mean composite skill score in 2000 was 17.7 (SD 5.1). In 2006/2007, the mean number of laps on the Multistage Fitness Test was 50.5 (SD 24.4). Object control proficiency in childhood, adjusting for gender (P = 0.000), was associated with adolescent cardiorespiratory fitness (P = 0.012), accounting for 26% of fitness variation. Children with good object control skills are more likely to become fit adolescents. Fundamental motor skill development in childhood may be an important component of interventions aiming to promote long-term fitness.

  20. Development of a PROficiency-Based StePwise Endovascular Curricular Training (PROSPECT) Program.

    Maertens, Heidi; Aggarwal, Rajesh; Desender, Liesbeth; Vermassen, Frank; Van Herzeele, Isabelle

    2016-01-01

    Focus on patient safety, work-hour limitations, and cost-effective education is putting pressure to improve curricula to acquire minimally invasive techniques during surgical training. This study aimed to design a structured training program for endovascular skills and validate its assessment methods. A PROficiency-based StePwise Endovascular Curricular Training (PROSPECT) program was developed, consisting of e-learning and hands-on simulation modules, focusing on iliac and superficial femoral artery atherosclerotic disease. Construct validity was investigated. Performances were assessed using multiple-choice questionnaires, valid simulation parameters, global rating scorings, and examiner checklists. Feasibility was assessed by passage of 2 final-year medical students through this PROSPECT program. Ghent University Hospital, a tertiary clinical care and academic center in Belgium with general surgery residency program. Senior-year medical students were recruited at Ghent University Hospital. Vascular surgeons were invited to participate during conferences and meetings if they had performed at least 100 endovascular procedures as the primary operator during the last 2 years. Overall, 29 medical students and 20 vascular surgeons participated. Vascular surgeons obtained higher multiple-choice questionnaire scores (median: 24.5-22.0 vs. 15.0-12.0; p train cognitive, technical, and nontechnical endovascular skills was developed. A structured, stepwise, proficiency-based valid endovascular program to train cognitive, technical, and human factor skills has been developed and proven to be feasible. A randomized controlled trial has been initiated to investigate its effect on performances in real life, patient outcomes, and cost-effectiveness. Copyright © 2015 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.

  1. GE Fanuc推出Proficy Historian 3.0

    2005-01-01

    GE基础设施旗下的GE Fanuc自动化美洲公司推出了全新的ProficyTM Historian版本3.0个全新的厂级数据历史库版本。ProficyTM Historian 3.0能采集、归档并发布所有的实时现场生产数据,使用起来非常方便,可用性很高。凭藉Proficy Historian,制造商可以有效地从多个数据源采集并聚合实时工厂数据。对于诸如因设备故障和产品质量存在问题而造成的非满意事件,它能快速找出根本原因以实现最佳绩效。

  2. Cell Phone Use and Child and Adolescent Reading Proficiency

    Hofferth, Sandra L.; Moon, Ui Jeong

    2016-01-01

    This study examined the association between cell phone use, including minutes spent talking and number of text messages sent, and two measures of children’s reading proficiency — tests of word decoding and reading comprehension — in the United States. Data were drawn from the Child Development Supplement to the Panel Study of Income Dynamics, a nationally representative survey of 1,147 children 10–18 in 2009. Children whose parents were better educated, who had higher family incomes, who had fewer siblings, and who lived in urban areas were more likely to own or share a cell phone. Among those with access to a phone, children who spent more time talking on the phone were less proficient at word decoding, whereas children who spent more time sending text messages had greater reading comprehension. Although girls spent more time texting than did boys, there were no gender differences in the association between time spent talking or number of text messages sent with achievement. In spite of racial/ethnic differences in cell phone use levels, there were no racial/ethnic differences in the association between cell phone use and reading proficiency. PMID:27683624

  3. Drosophila MOF controls Checkpoint protein2 and regulates genomic stability during early embryogenesis.

    Pushpavalli, Sreerangam N C V L; Sarkar, Arpita; Ramaiah, M Janaki; Chowdhury, Debabani Roy; Bhadra, Utpal; Pal-Bhadra, Manika

    2013-01-24

    In Drosophila embryos, checkpoints maintain genome stability by delaying cell cycle progression that allows time for damage repair or to complete DNA synthesis. Drosophila MOF, a member of MYST histone acetyl transferase is an essential component of male X hyperactivation process. Until recently its involvement in G2/M cell cycle arrest and defects in ionizing radiation induced DNA damage pathways was not well established. Drosophila MOF is highly expressed during early embryogenesis. In the present study we show that haplo-insufficiency of maternal MOF leads to spontaneous mitotic defects like mitotic asynchrony, mitotic catastrophe and chromatid bridges in the syncytial embryos. Such abnormal nuclei are eliminated and digested in the yolk tissues by nuclear fall out mechanism. MOF negatively regulates Drosophila checkpoint kinase 2 tumor suppressor homologue. In response to DNA damage the checkpoint gene Chk2 (Drosophila mnk) is activated in the mof mutants, there by causing centrosomal inactivation suggesting its role in response to genotoxic stress. A drastic decrease in the fall out nuclei in the syncytial embryos derived from mof¹/+; mnkp⁶/+ females further confirms the role of DNA damage response gene Chk2 to ensure the removal of abnormal nuclei from the embryonic precursor pool and maintain genome stability. The fact that mof mutants undergo DNA damage has been further elucidated by the increased number of single and double stranded DNA breaks. mof mutants exhibited genomic instability as evidenced by the occurance of frequent mitotic bridges in anaphase, asynchronous nuclear divisions, disruption of cytoskeleton, inactivation of centrosomes finally leading to DNA damage. Our findings are consistent to what has been reported earlier in mammals that; reduced levels of MOF resulted in increased genomic instability while total loss resulted in lethality. The study can be further extended using Drosophila as model system and carry out the interaction of MOF

  4. Drosophila MOF controls Checkpoint protein2 and regulates genomic stability during early embryogenesis

    Pushpavalli Sreerangam NCVL

    2013-01-01

    Full Text Available Abstract Background In Drosophila embryos, checkpoints maintain genome stability by delaying cell cycle progression that allows time for damage repair or to complete DNA synthesis. Drosophila MOF, a member of MYST histone acetyl transferase is an essential component of male X hyperactivation process. Until recently its involvement in G2/M cell cycle arrest and defects in ionizing radiation induced DNA damage pathways was not well established. Results Drosophila MOF is highly expressed during early embryogenesis. In the present study we show that haplo-insufficiency of maternal MOF leads to spontaneous mitotic defects like mitotic asynchrony, mitotic catastrophe and chromatid bridges in the syncytial embryos. Such abnormal nuclei are eliminated and digested in the yolk tissues by nuclear fall out mechanism. MOF negatively regulates Drosophila checkpoint kinase 2 tumor suppressor homologue. In response to DNA damage the checkpoint gene Chk2 (Drosophila mnk is activated in the mof mutants, there by causing centrosomal inactivation suggesting its role in response to genotoxic stress. A drastic decrease in the fall out nuclei in the syncytial embryos derived from mof1/+; mnkp6/+ females further confirms the role of DNA damage response gene Chk2 to ensure the removal of abnormal nuclei from the embryonic precursor pool and maintain genome stability. The fact that mof mutants undergo DNA damage has been further elucidated by the increased number of single and double stranded DNA breaks. Conclusion mof mutants exhibited genomic instability as evidenced by the occurance of frequent mitotic bridges in anaphase, asynchronous nuclear divisions, disruption of cytoskeleton, inactivation of centrosomes finally leading to DNA damage. Our findings are consistent to what has been reported earlier in mammals that; reduced levels of MOF resulted in increased genomic instability while total loss resulted in lethality. The study can be further extended using

  5. T cells in chronic lymphocytic leukemia display dysregulated expression of immune checkpoints and activation markers.

    Palma, Marzia; Gentilcore, Giusy; Heimersson, Kia; Mozaffari, Fariba; Näsman-Glaser, Barbro; Young, Emma; Rosenquist, Richard; Hansson, Lotta; Österborg, Anders; Mellstedt, Håkan

    2017-03-01

    Chronic lymphocytic leukemia is characterized by impaired immune functions largely due to profound T-cell defects. T-cell functions also depend on co-signaling receptors, inhibitory or stimulatory, known as immune checkpoints, including cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed death-1 (PD-1). Here we analyzed the T-cell phenotype focusing on immune checkpoints and activation markers in chronic lymphocytic leukemia patients (n=80) with different clinical characteristics and compared them to healthy controls. In general, patients had higher absolute numbers of CD3 + cells and the CD8 + subset was particularly expanded in previously treated patients. Progressive patients had higher numbers of CD4 + and CD8 + cells expressing PD-1 compared to healthy controls, which was more pronounced in previously treated patients ( P =0.0003 and P =0.001, respectively). A significant increase in antigen-experienced T cells was observed in patients within both the CD4 + and CD8 + subsets, with a significantly higher PD-1 expression. Higher numbers of CD4 + and CD8 + cells with intracellular CTLA-4 were observed in patients, as well as high numbers of proliferating (Ki67 + ) and activated (CD69 + ) CD4 + and CD8 + cells, more pronounced in patients with active disease. The numbers of Th1, Th2, Th17 and regulatory T cells were substantially increased in patients compared to controls ( P leukemia T cells display increased expression of immune checkpoints, abnormal subset distribution, and a higher proportion of proliferating cells compared to healthy T cells. Disease activity and previous treatment shape the T-cell profile of chronic lymphocytic leukemia patients in different ways. Copyright© Ferrata Storti Foundation.

  6. Checkpoint Inhibition: Programmed Cell Death 1 and Programmed Cell Death 1 Ligand Inhibitors in Hodgkin Lymphoma.

    Villasboas, Jose Caetano; Ansell, Stephen

    2016-01-01

    Hodgkin lymphoma (HL) is a lymphoid malignancy characterized by a reactive immune infiltrate surrounding relatively few malignant cells. In this scenario, active immune evasion seems to play a central role in allowing tumor progression. Immune checkpoint inhibitor pathways are normal mechanisms of T-cell regulation that suppress immune effector function following an antigenic challenge. Hodgkin lymphoma cells are able to escape immune surveillance by co-opting these mechanisms. The programmed cell death 1 (PD-1) pathway in particular is exploited in HL as the malignant Hodgkin and Reed-Sternberg cells express on their surface cognate ligands (PD-L1/L2) for the PD-1 receptor and thereby dampen the T-cell-mediated antitumoral response. Monoclonal antibodies that interact with and disrupt the PD-1:PD-L1/L2 axis have now been developed and tested in early-phase clinical trials in patients with advanced HL with encouraging results. The remarkable clinical activity of PD-1 inhibitors in HL highlights the importance of immune checkpoint pathways as therapeutic targets in HL. In this review, we discuss the rationale for targeting PD-1 and PD-L1 in the treatment of HL. We will evaluate the published clinical data on the different agents and highlight the safety profile of this class of agents. We discuss the available evidence on the use of biomarkers as predictors of response to checkpoint blockade and summarize the areas under active investigation in the use of PD-1/PD-L1 inhibitors for the treatment of HL.

  7. Immuno-oncologic Approaches: CAR-T Cells and Checkpoint Inhibitors.

    Gay, Francesca; D'Agostino, Mattia; Giaccone, Luisa; Genuardi, Mariella; Festuccia, Moreno; Boccadoro, Mario; Bruno, Benedetto

    2017-08-01

    Advances in understanding myeloma biology have shown that disease progression is not only the consequence of intrinsic tumor changes but also of interactions between the tumor and the microenvironment in which the cancer grows. The immune system is an important component of the tumor microenvironment in myeloma, and acting on the immune system is an appealing new treatment strategy. There are 2 ways to act toward immune cells and boost antitumor immunity: (1) to increase antitumor activity (acting on T and NK cytotoxic cells), and (2) to reduce immunosuppression (acting on myeloid-derived stem cells and T regulatory cells). Checkpoint inhibitors and adoptive cell therapy (ACT) are 2 of the main actors, together with monoclonal antibodies and immunomodulatory agents, in the immune-oncologic approach. The aim of checkpoint inhibitors is to release the brakes that block the action of the immune system against the tumor. Anti-programmed death-1 (PD-1) and PD-1-Ligand, as well as anti-CTLA4 and KIR are currently under evaluation, as single agents or in combination, with the best results achieved so far with combination of anti-PD-1 and immunomodulatory agents. The aim of ACT is to create an immune effector specific against the tumor. Preliminary results on chimeric antigen receptor (CAR) T cells, first against CD19, and more recently against B-cell maturation antigen, have shown to induce durable responses in heavily pretreated patients. This review focuses on the most recent clinical results available on the use of checkpoint inhibitors and CAR-T cells in myeloma, in the context of the new immune-oncologic approach. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Requirement for PLK1 kinase activity in the maintenance of a robust spindle assembly checkpoint

    Aisling O'Connor

    2016-01-01

    Full Text Available During mitotic arrest induced by microtubule targeting drugs, the weakening of the spindle assembly checkpoint (SAC allows cells to progress through the cell cycle without chromosome segregation occurring. PLK1 kinase plays a major role in mitosis and emerging evidence indicates that PLK1 is also involved in establishing the checkpoint and maintaining SAC signalling. However, mechanistically, the role of PLK1 in the SAC is not fully understood, with several recent reports indicating that it can cooperate with either one of the major checkpoint kinases, Aurora B or MPS1. In this study, we assess the role of PLK1 in SAC maintenance. We find that in nocodazole-arrested U2OS cells, PLK1 activity is continuously required for maintaining Aurora B protein localisation and activity at kinetochores. Consistent with published data we find that upon PLK1 inhibition, phosphoThr3-H3, a marker of Haspin activity, is reduced. Intriguingly, Aurora B inhibition causes PLK1 to relocalise from kinetochores into fewer and much larger foci, possibly due to incomplete recruitment of outer kinetochore proteins. Importantly, PLK1 inhibition, together with partial inhibition of Aurora B, allows efficient SAC override to occur. This phenotype is more pronounced than the phenotype observed by combining the same PLK1 inhibitors with partial MPS1 inhibition. We also find that PLK1 inhibition does not obviously cooperate with Haspin inhibition to promote SAC override. These results indicate that PLK1 is directly involved in maintaining efficient SAC signalling, possibly by cooperating in a positive feedback loop with Aurora B, and that partially redundant mechanisms exist which reinforce the SAC.

  9. Mutant p53 perturbs DNA replication checkpoint control through TopBP1 and Treslin.

    Liu, Kang; Lin, Fang-Tsyr; Graves, Joshua D; Lee, Yu-Ju; Lin, Weei-Chin

    2017-05-09

    Accumulating evidence supports the gain-of-function of mutant forms of p53 (mutp53s). However, whether mutp53 directly perturbs the DNA replication checkpoint remains unclear. Previously, we have demonstrated that TopBP1 forms a complex with mutp53s and mediates their gain-of-function through NF-Y and p63/p73. Akt phosphorylates TopBP1 and induces its oligomerization, which inhibits its ATR-activating function. Here we show that various contact and conformational mutp53s bypass Akt to induce TopBP1 oligomerization and attenuate ATR checkpoint response during replication stress. The effect on ATR response caused by mutp53 can be exploited in a synthetic lethality strategy, as depletion of another ATR activator, DNA2, in mutp53-R273H-expressing cancer cells renders cells hypersensitive to cisplatin. Expression of mutp53-R273H also makes cancer cells more sensitive to DNA2 depletion or DNA2 inhibitors. In addition to ATR-activating function during replication stress, TopBP1 interacts with Treslin in a Cdk-dependent manner to initiate DNA replication during normal growth. We find that mutp53 also interferes with TopBP1 replication function. Several contact, but not conformational, mutp53s enhance the interaction between TopBP1 and Treslin and promote DNA replication despite the presence of a Cdk2 inhibitor. Together, these data uncover two distinct mechanisms by which mutp53 enhances DNA replication: ( i ) Both contact and conformational mutp53s can bind TopBP1 and attenuate the checkpoint response to replication stress, and ( ii ) during normal growth, contact (but not conformational) mutp53s can override the Cdk2 requirement to promote replication by facilitating the TopBP1/Treslin interaction.

  10. Effect of salt-inducible kinase 2 on checkpoint in response to γ-ray irradiation

    Yin Jiaojiao; Zhou Lijun; Wang Yu; Liu Xiaodan; Gu Yongqing; Zhou Pingkun

    2014-01-01

    Objective: To investigate the effect of salt-induced kinase 2 (SIK2) in the G_2/M checkpoint in response to ionizing radiation and the possible mechanism. Methods: HeLa cells were irradiated with "6"0Co γ-rays. The cell model of knockdown SIK2 expression was constrcuted by transfecting HeLa cells with a pSicoR-based lentivirus vector of expressing SIK2 shRNA by lipofectamin 2000. Western blot and flow cytometry were performed to measure the changes of SIK2 protein level and cell cycle distribution. The phosphorylated histone protein H3 on Ser 10 was used as a molecular marker of mitotic cells for detecting the function of G2/M checkpoint. Results: The expression level of SIK2 protein increased in HeLa cells after "6"0Co γ-ray irradiation. A cell model of knockdown SIK2 expression was successfully generated by transfecting the specific shRNA against SIK2. Depression of SIK2 significantly increased the cellular sensitivity at 1, 2, 4, 6 Gy post-irradiation (t = -3.445, -2.581, -3.251, -2.553, P < 0.05), and led cells to release earlier from the G_2/M boundary arrest compared to control cells at 5, 6 h post-irradiation(t = 4.341, 6.500, P < 0.05). Western blot analysis indicated that the irradiation-induced phosphorylated CHK2/T68 in SIK2 knock-down cells was earlier than that in control cells. Conclusions: salt-induced kinase 2 (SIK2) participates in the regulation of G_2/M checkpoint induced by ionizing radiation and affects cellular radiosensitivity. (authors)

  11. Rad9 contribution to radiosensitivity and the G2 checkpoint in a DT40 cell line

    Kumano, Tomoyasu [Kanazawa Univ. (Japan). Graduate School of Medical Science

    2002-12-01

    In fission yeast, the rad9 (radiation sensitive) gene was cloned from a mutant that is sensitive to ionizing radiation, ultraviolet and hydroxyurea. This gene has also been shown to be required for a DNA damage checkpoint. Orthologues of the rad9 gene have recently been identified in higher eukaryote cells including human. Here we generated Rad9 knockout (Rad9-/-) cells from the chicken B lymphocyte line DT40 to examine the role of Rad9 in higher eukaryotes. First we isolated a part of the chicken Rad9 gene which was 54% identical with human Rad9 at the amino acid sequence level. Next we isolated genomic clones, determined exons and introns, and constructed targeting vectors designed to disrupt exon 1-3 of the chicken Rad9 gene by replacement with a drug-resistant gene. Successful targeted integration was verified by Southern blot analysis and the disruption of the Rad9 gene was confirmed by reverse transcription polymerase chain reaction (RT-PCR). To analyze the radiosensitivity of these Rad9-/- cells, we monitored the clonogenic survival after various degrees of X-ray irradiation. Rad9-/- cells were more sensitive to X-rays than wild type cells at all dosages. However, these cells were less sensitive than ATM knockout (ATM-/-) cells that are known to be X-ray sensitive and that showed a defective checkpoint control. In contrast, Rad9-/- cells were markedly more sensitive to ultraviolet and hydroxyruea. In addition, we assessed the G2 checkpoint by measurement of the mitotic index that is the fraction of the accumulating number of cells in mitosis at various times after X-ray irradiation. While the number of mitotic wild type cells did not increase until 2 hrs after X-ray irradiation, the number of mitotic Rad9-/- cells showed an increase similar to that of ATM-/- cells. These results suggest that just as in fission yeast, in higher eukaryotes Rad9 also contributes to X-ray, ultraviolet and hydroxyurea sensitivity, and plays an important role in the G2 checkpoint

  12. Rad9 contribution to radiosensitivity and the G2 checkpoint in a DT40 cell line

    Kumano, Tomoyasu

    2002-01-01

    In fission yeast, the rad9 (radiation sensitive) gene was cloned from a mutant that is sensitive to ionizing radiation, ultraviolet and hydroxyurea. This gene has also been shown to be required for a DNA damage checkpoint. Orthologues of the rad9 gene have recently been identified in higher eukaryote cells including human. Here we generated Rad9 knockout (Rad9-/-) cells from the chicken B lymphocyte line DT40 to examine the role of Rad9 in higher eukaryotes. First we isolated a part of the chicken Rad9 gene which was 54% identical with human Rad9 at the amino acid sequence level. Next we isolated genomic clones, determined exons and introns, and constructed targeting vectors designed to disrupt exon 1-3 of the chicken Rad9 gene by replacement with a drug-resistant gene. Successful targeted integration was verified by Southern blot analysis and the disruption of the Rad9 gene was confirmed by reverse transcription polymerase chain reaction (RT-PCR). To analyze the radiosensitivity of these Rad9-/- cells, we monitored the clonogenic survival after various degrees of X-ray irradiation. Rad9-/- cells were more sensitive to X-rays than wild type cells at all dosages. However, these cells were less sensitive than ATM knockout (ATM-/-) cells that are known to be X-ray sensitive and that showed a defective checkpoint control. In contrast, Rad9-/- cells were markedly more sensitive to ultraviolet and hydroxyruea. In addition, we assessed the G2 checkpoint by measurement of the mitotic index that is the fraction of the accumulating number of cells in mitosis at various times after X-ray irradiation. While the number of mitotic wild type cells did not increase until 2 hrs after X-ray irradiation, the number of mitotic Rad9-/- cells showed an increase similar to that of ATM-/- cells. These results suggest that just as in fission yeast, in higher eukaryotes Rad9 also contributes to X-ray, ultraviolet and hydroxyurea sensitivity, and plays an important role in the G2 checkpoint

  13. Monitoring of scrap loads at Gorzia border checkpoints: A thirty months experience and some suggestions

    Fabretto, M.

    1999-01-01

    The following topics are highlighted: personnel training, assistance from foreign scrap suppliers, and computerized database. It is suggested that when selecting personnel for this job, major attention should be paid to their attitudes; the personnel should be given very good training, teaching them also how to make controls manually; expert physicist' support should be available within a very short time; each monitoring checkpoint should have its local electronic database; periodical exchange and updating of information should be practised on the standardization of methods of detection, of levels of attention and alarm, of statistics among the people in charge of EU and non-EU countries. (P.A.)

  14. Strategies to overcome HBV-specific T cell exhaustion: checkpoint inhibitors and metabolic re-programming.

    Fisicaro, Paola; Boni, Carolina; Barili, Valeria; Laccabue, Diletta; Ferrari, Carlo

    2018-01-29

    HBV-specific T cells play a key role in antiviral protection and failure to control HBV is associated with severely dysfunctional T cell responses. Therefore, functional T cell reconstitution represents a potential way to treat chronically infected patients. The growing understanding of the dysregulated transcriptional/epigenetic and metabolic programs underlying T cell exhaustion allows to envisage functional T cell reconstitution strategies based on the combined/sequential use of compounds able to induce decline of antigen load, checkpoint modulation, metabolic and epigenetic reprogramming with possible boosting of functionally restored responses by specific vaccines. Copyright © 2018 Elsevier B.V. All rights reserved.

  15. Identification of Current Proficiency Level of Extension Competencies and the Competencies Needed for Extension Agents to Be Successful in the 21st Century

    Dona Lakai

    2014-02-01

    Full Text Available In this era of globalization, competency is an issue of concern to any field of professionals and their clients. Competency is an integrated set of skills, knowledge, and attitudes that allow one to effectively carry out the activities of a given work to the standards expected in the employment context. The purpose of this descriptive survey study was to determine the current proficiency level of North Carolina Cooperative Extension agents’ competencies and the other competencies they need to develop to be successful in Cooperative Extension. Findings indicate that the current proficiency level of competency for Extension agents in North Carolina Cooperative Extension varies from moderate to high in all 42 items listed in the survey. Multiple regression analysis confirmed that Extension agents’ years of Extension experience and age were major determinants of their overall proficiency level. Extension agents’ proficiency levels did not vary with gender, level of education, professional association affiliation, job position, or area of job responsibility. The research revealed that emotional intelligence, interpersonal skills, flexibility for adapting to changing environments, and ability to manage resources were the most significant other competencies needed for Extension agents to be successful in current context.

  16. In vitro analysis of the role of replication protein A (RPA) and RPA phosphorylation in ATR-mediated checkpoint signaling.

    Lindsey-Boltz, Laura A; Reardon, Joyce T; Wold, Marc S; Sancar, Aziz

    2012-10-19

    Replication protein A (RPA) plays essential roles in DNA metabolism, including replication, checkpoint, and repair. Recently, we described an in vitro system in which the phosphorylation of human Chk1 kinase by ATR (ataxia telangiectasia mutated and Rad3-related) is dependent on RPA bound to single-stranded DNA. Here, we report that phosphorylation of other ATR targets, p53 and Rad17, has the same requirements and that RPA is also phosphorylated in this system. At high p53 or Rad17 concentrations, RPA phosphorylation is inhibited and, in this system, RPA with phosphomimetic mutations cannot support ATR kinase function, whereas a non-phosphorylatable RPA mutant exhibits full activity. Phosphorylation of these ATR substrates depends on the recruitment of ATR and the substrates by RPA to the RPA-ssDNA complex. Finally, mutant RPAs lacking checkpoint function exhibit essentially normal activity in nucleotide excision repair, revealing RPA separation of function for checkpoint and excision repair.

  17. In Vitro Analysis of the Role of Replication Protein A (RPA) and RPA Phosphorylation in ATR-mediated Checkpoint Signaling*

    Lindsey-Boltz, Laura A.; Reardon, Joyce T.; Wold, Marc S.; Sancar, Aziz

    2012-01-01

    Replication protein A (RPA) plays essential roles in DNA metabolism, including replication, checkpoint, and repair. Recently, we described an in vitro system in which the phosphorylation of human Chk1 kinase by ATR (ataxia telangiectasia mutated and Rad3-related) is dependent on RPA bound to single-stranded DNA. Here, we report that phosphorylation of other ATR targets, p53 and Rad17, has the same requirements and that RPA is also phosphorylated in this system. At high p53 or Rad17 concentrations, RPA phosphorylation is inhibited and, in this system, RPA with phosphomimetic mutations cannot support ATR kinase function, whereas a non-phosphorylatable RPA mutant exhibits full activity. Phosphorylation of these ATR substrates depends on the recruitment of ATR and the substrates by RPA to the RPA-ssDNA complex. Finally, mutant RPAs lacking checkpoint function exhibit essentially normal activity in nucleotide excision repair, revealing RPA separation of function for checkpoint and excision repair. PMID:22948311

  18. Targeting Tumor-Associated Macrophages as a Potential Strategy to Enhance the Response to Immune Checkpoint Inhibitors.

    Cassetta, Luca; Kitamura, Takanori

    2018-01-01

    Inhibition of immune checkpoint pathways in CD8 + T cell is a promising therapeutic strategy for the treatment of solid tumors that has shown significant anti-tumor effects and is now approved by the FDA to treat patients with melanoma and lung cancer. However the response to this therapy is limited to a certain fraction of patients and tumor types, for reasons still unknown. To ensure success of this treatment, CD8 + T cells, the main target of the checkpoint inhibitors, should exert full cytotoxicity against tumor cells. However recent studies show that tumor-associated macrophages (TAM) can impede this process by different mechanisms. In this mini-review we will summarize recent studies showing the effect of TAM targeting on immune checkpoint inhibitors efficacy. We will also discuss on the limitations of the current strategies as well on the future scientific challenges for the progress of the tumor immunology field.

  19. Targeting neddylation induces DNA damage and checkpoint activation and sensitizes chronic lymphocytic leukemia B cells to alkylating agents.

    Paiva, C; Godbersen, J C; Berger, A; Brown, J R; Danilov, A V

    2015-07-09

    Microenvironment-mediated upregulation of the B-cell receptor (BCR) and nuclear factor-κB (NF-κB) signaling in CLL cells resident in the lymph node and bone marrow promotes apoptosis evasion and clonal expansion. We recently reported that MLN4924 (pevonedistat), an investigational agent that inhibits the NEDD8-activating enzyme (NAE), abrogates stromal-mediated NF-κB pathway activity and CLL cell survival. However, the NAE pathway also assists degradation of multiple other substrates. MLN4924 has been shown to induce DNA damage and cell cycle arrest, but the importance of this mechanism in primary neoplastic B cells has not been studied. Here we mimicked the lymph node microenvironment using CD40 ligand (CD40L)-expressing stroma and interleukin-21 (IL-21) to find that inducing proliferation of the primary CLL cells conferred enhanced sensitivity to NAE inhibition. Treatment of the CD40-stimulated CLL cells with MLN4924 resulted in deregulation of Cdt1, a DNA replication licensing factor, and cell cycle inhibitors p21 and p27. This led to DNA damage, checkpoint activation and G2 arrest. Alkylating agents bendamustine and chlorambucil enhanced MLN4924-mediated DNA damage and apoptosis. These events were more prominent in cells stimulated with IL-21 compared with CD40L alone, indicating that, following NAE inhibition, the culture conditions were able to direct CLL cell fate from an NF-κB inhibition to a Cdt1 induction program. Our data provide insight into the biological consequences of targeting NAE in CLL and serves as further rationale for studying the clinical activity of MLN4924 in CLL, particularly in combination with alkylating agents.

  20. KinD is a checkpoint protein linking spore formation to extracellular-matrix production in Bacillus subtilis biofilms.

    Aguilar, Claudio; Vlamakis, Hera; Guzman, Alejandra; Losick, Richard; Kolter, Roberto

    2010-05-18

    Bacillus subtilis cells form multicellular biofilm communities in which spatiotemporal regulation of gene expression occurs, leading to differentiation of multiple coexisting cell types. These cell types include matrix-producing and sporulating cells. Extracellular matrix production and sporulation are linked in that a mutant unable to produce matrix is delayed for sporulation. Here, we show that the delay in sporulation is not due to a growth advantage of the matrix-deficient mutant under these conditions. Instead, we show that the link between matrix production and sporulation is through the Spo0A signaling pathway. Both processes are regulated by the phosphorylated form of the master transcriptional regulator Spo0A. When cells have low levels of phosphorylated Spo0A (Spo0A~P), matrix genes are expressed; however, at higher levels of Spo0A~P, sporulation commences. We have found that Spo0A~P levels are maintained at low levels in the matrix-deficient mutant, thereby delaying expression of sporulation-specific genes. This is due to the activity of one of the components of the Spo0A phosphotransfer network, KinD. A deletion of kinD suppresses the sporulation defect of matrix mutants, while its overproduction delays sporulation. Our data indicate that KinD displays a dual role as a phosphatase or a kinase and that its activity is linked to the presence of extracellular matrix in the biofilms. We propose a novel role for KinD in biofilms as a checkpoint protein that regulates the onset of sporulation by inhibiting the activity of Spo0A until matrix, or a component therein, is sensed.

  1. Grp/DChk1 is required for G(2)-M checkpoint activation in Drosophila S2 cells, whereas Dmnk/DChk2 is dispensable

    de Vries, HI; Uyetake, L; Lemstra, W; Brunsting, JF; Su, TT; Kampinga, HH; Sibon, OCM

    2005-01-01

    Cell-cycle checkpoints are signal-transduction pathways required to maintain genomic stability in dividing cells. Previously, it was reported that two kinases essential for checkpoint signalling, Chk1 and Chk2 are structurally conserved. In contrast to yeast, Xenopus and mammals, the Chk1- and

  2. The Geography of Deterrence: Exploring the Small Area Effects of Sobriety Checkpoints on Alcohol-Impaired Collision Rates within a City

    Nunn, Samuel; Newby, William

    2011-01-01

    This article examines alcohol-impaired collision metrics around nine sobriety checkpoint locations in Indianapolis, Indiana, before and after implementation of 22 checkpoints, using a pre/post examination, a pre/post nonequivalent comparison group analysis, and an interrupted time series approach. Traffic safety officials used geographical…

  3. Nek2A destruction marks APC/C activation at the prophase-to-prometaphase transition by spindle-checkpoint-restricted Cdc20.

    Boekhout, Michiel; Wolthuis, Rob

    2015-04-15

    Nek2 isoform A (Nek2A) is a presumed substrate of the anaphase-promoting complex/cyclosome containing Cdc20 (APC/C(Cdc20)). Nek2A, like cyclin A, is degraded in mitosis while the spindle checkpoint is active. Cyclin A prevents spindle checkpoint proteins from binding to Cdc20 and is recruited to the APC/C in prometaphase. We found that Nek2A and cyclin A avoid being stabilized by the spindle checkpoint in different ways. First, enhancing mitotic checkpoint complex (MCC) formation by nocodazole treatment inhibited the degradation of geminin and cyclin A, whereas Nek2A disappeared at a normal rate. Second, depleting Cdc20 effectively stabilized cyclin A but not Nek2A. Nevertheless, Nek2A destruction crucially depended on Cdc20 binding to the APC/C. Third, in contrast to cyclin A, Nek2A was recruited to the APC/C before the start of mitosis. Interestingly, the spindle checkpoint very effectively stabilized an APC/C-binding mutant of Nek2A, which required the Nek2A KEN box. Apparently, in cells, the spindle checkpoint primarily prevents Cdc20 from binding destruction motifs. Nek2A disappearance marks the prophase-to-prometaphase transition, when Cdc20, regardless of the spindle checkpoint, activates the APC/C. However, Mad2 depletion accelerated Nek2A destruction, showing that spindle checkpoint release further increases APC/C(Cdc20) catalytic activity. © 2015. Published by The Company of Biologists Ltd.

  4. PCP-B class pollen coat proteins are key regulators of the hydration checkpoint in Arabidopsis thaliana pollen-stigma interactions.

    Wang, Ludi; Clarke, Lisa A; Eason, Russell J; Parker, Christopher C; Qi, Baoxiu; Scott, Rod J; Doughty, James

    2017-01-01

    The establishment of pollen-pistil compatibility is strictly regulated by factors derived from both male and female reproductive structures. Highly diverse small cysteine-rich proteins (CRPs) have been found to play multiple roles in plant reproduction, including the earliest stages of the pollen-stigma interaction. Secreted CRPs found in the pollen coat of members of the Brassicaceae, the pollen coat proteins (PCPs), are emerging as important signalling molecules that regulate the pollen-stigma interaction. Using a combination of protein characterization, expression and phylogenetic analyses we identified a novel class of Arabidopsis thaliana pollen-borne CRPs, the PCP-Bs (for pollen coat protein B-class) that are related to embryo surrounding factor (ESF1) developmental regulators. Single and multiple PCP-B mutant lines were utilized in bioassays to assess effects on pollen hydration, adhesion and pollen tube growth. Our results revealed that pollen hydration is severely impaired when multiple PCP-Bs are lost from the pollen coat. The hydration defect also resulted in reduced pollen adhesion and delayed pollen tube growth in all mutants studied. These results demonstrate that AtPCP-Bs are key regulators of the hydration 'checkpoint' in establishment of pollen-stigma compatibility. In addition, we propose that interspecies diversity of PCP-Bs may contribute to reproductive barriers in the Brassicaceae. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

  5. [An experimental proficiency test for ability to screen 104 residual pesticides in agricultural products].

    Tsumura, Yukari; Ishimitsu, Susumu; Otaki, Kayo; Uchimi, Hiroyuki; Matsumoto, Nobuyuki; Daba, Masaki; Tsuchiya, Tetsu; Ukyo, Masaho; Tonogai, Yasuhide

    2003-10-01

    An experimental proficiency test program for ability to screen 104 residual pesticides in agricultural products has been conducted. Eight Japanese laboratories joined the program. Items tested in the present study were limit of detection, internal proficiency test (self spike) and external proficiency test (blind spike). All 104 pesticides were well detected and recovered from agricultural foods in the internal proficiency test. However, the results of the external proficiency test did not completely agree with those of the internal proficiency tests. After 5 rounds of the blind spike test, the ratio of the number of correctly detected pesticides to that of actually contained ones (49 total) ranged from 65% to 100% among laboratories. The numbers of mistakenly detected pesticides by a laboratory were 0 to 15. Thus, there was a great difference among the laboratories in the ability to screen multiresidual pesticides.

  6. Structural basis of a novel PD-L1 nanobody for immune checkpoint blockade.

    Zhang, Fei; Wei, Hudie; Wang, Xiaoxiao; Bai, Yu; Wang, Pilin; Wu, Jiawei; Jiang, Xiaoyong; Wang, Yugang; Cai, Haiyan; Xu, Ting; Zhou, Aiwu

    2017-01-01

    The use of antibodies to target immune checkpoints, particularly PD-1/PD-L1, has made a profound impact in the field of cancer immunotherapy. Here, we identified KN035, an anti-PD-L1 nanobody that can strongly induce T-cell responses and inhibit tumor growth. The crystal structures of KN035 complexed with PD-L1 and free PD-L1, solved here at 1.7 and 2.7 Å resolution, respectively, show that KN035 competes with PD-1 (programmed death protein 1) for the same flat surface on PD-L1, mainly through a single surface loop of 21 amino acids. This loop forms two short helices and develops key hydrophobic and ionic interactions with PD-L1 residues, such as Ile54, Tyr56 and Arg113, which are also involved in PD-1 binding. The detailed mutagenesis study identified the hotspot residues of the PD-L1 surface and provides an explanation for the stronger (~1 000-fold) binding of KN035 to PD-L1 than PD-1 and its lack of binding to PD-L2. Overall, this study reveals how a single immunoglobulin-variable scaffold of KN035 or PD-1 can bind to a flat protein surface through either a single surface loop or beta-sheet strands; and provides a basis for designing new immune checkpoint blockers and generating bi-specific antibodies for combination therapy.

  7. Checkpoint-dependent RNR induction promotes fork restart after replicative stress.

    Morafraile, Esther C; Diffley, John F X; Tercero, José Antonio; Segurado, Mónica

    2015-01-20

    The checkpoint kinase Rad53 is crucial to regulate DNA replication in the presence of replicative stress. Under conditions that interfere with the progression of replication forks, Rad53 prevents Exo1-dependent fork degradation. However, although EXO1 deletion avoids fork degradation in rad53 mutants, it does not suppress their sensitivity to the ribonucleotide reductase (RNR) inhibitor hydroxyurea (HU). In this case, the inability to restart stalled forks is likely to account for the lethality of rad53 mutant cells after replication blocks. Here we show that Rad53 regulates replication restart through the checkpoint-dependent transcriptional response, and more specifically, through RNR induction. Thus, in addition to preventing fork degradation, Rad53 prevents cell death in the presence of HU by regulating RNR-expression and localization. When RNR is induced in the absence of Exo1 and RNR negative regulators, cell viability of rad53 mutants treated with HU is increased and the ability of replication forks to restart after replicative stress is restored.

  8. Immune checkpoint inhibitors for non-small-cell lung cancer: does that represent a 'new frontier'?

    Pilotto, Sara; Kinspergher, Stefania; Peretti, Umberto; Calio, Anna; Carbognin, Luisa; Ferrara, Roberto; Brunelli, Matteo; Chilosi, Marco; Tortora, Giampaolo; Bria, Emilio

    2015-01-01

    Advances in the interpretation and understanding of cancer behaviour, particularly of its ability to evade the host immunosurveillance, deregulating the balance between inhibitory and stimulatory factors, led to the development of an innovative category of immunotherapeutic agents, currently under investigation. Although the disappointing data deriving from the employment of vaccines in non-small cell lung cancer (NSCLC), more promising results have been obtained in the early phase trials with immune checkpoint inhibitors, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors. This review delineates the main features of the available immunotherapeutic agents, focusing the discussion on immune checkpoint inhibitors, those that have already demonstrated a relevant clinical activity (such as Ipilimumab and Nivolumab) and those molecules still in early development phase. Moreover, we underline the possible emerging issues deriving from the progressive diffusion of Immuno-Oncology into the standard clinical practice. The careful and accurate identification and management of immune-related toxicities, the validation of more reliable immune response criteria and the increasing research of potential predictive biomarkers are key points of discussion. The perspective is that immunotherapy might represent an effective 'magic bullet', able to change the treatment paradigm of NSCLC, particularly of those subgroups featured by a heavily mutant cancer (squamous histology and smokers), where the immunologic agents contribute in cancer development and progression seems to be strong and, concurrently, the efficacy of standard therapies particularly limited.

  9. Preferential radiosensitization of G1 checkpoint--deficient cells by methylxanthines

    Russell, Kenneth J.; Wiens, Linda W.; Demers, G. William; Galloway, Denise A.; Le, Tiep; Rice, Glenn C.; Bianco, James A.; Singer, Jack W.; Groudine, Mark

    1996-01-01

    Purpose: To develop a checkpoint-based strategy for preferential radiosensitization of human tumors with deficient and/or mutant p53. Methods and Materials: A549 human lung adenocarcinoma cell lines differing in their expression of the p53 tumor suppressor gene were produced by transduction with the E6 oncogene from human papilloma virus type 16. The cells expressing E6 (E6+) lack a G1 arrest in response to ionizing radiation, are deficient in p53 and p21 expression, and exhibit a fivefold greater clonogenic survival following 10 Gy radiation. Results: Postirradiation incubation with millimolar concentrations of the methylxanthine pentoxifylline (PTX) results in preferential radiosensitization of the E6+ cells compared to the LXSN+ vector transduced controls. There is a threefold sensitization of the LXSN+ cells and a 15-fold sensitization of the E6+ cells, which results in equal clonogenic survival of the two lines. Flow cytometry reveals PTX abrogation of the radiation induced G2 arrest for both cell lines. PTX also prolongs G1 transit for both cell lines. Preliminary results are presented using a novel methylxanthine, lisofylline (LSF), which has similar cell cycle effects on G1 and G2 and achieves differential radiosensitization at micromolar concentrations that are sustainable in humans. Conclusions: This checkpoint-based strategy is a promising approach for achieving preferential radiosensitization of p53- tumors relative to p53+ normal tissues

  10. Hepatic neuregulin 4 signaling defines an endocrine checkpoint for steatosis-to-NASH progression

    Guo, Liang; Chen, Zhimin; Xia, Houjun; Li, Siming; Zhang, Yanqiao; Kobberup, Sune; Zou, Weiping; Lin, Jiandie D.

    2017-01-01

    Nonalcoholic steatohepatitis (NASH) is characterized by progressive liver injury, inflammation, and fibrosis; however, the mechanisms that govern the transition from hepatic steatosis, which is relatively benign, to NASH remain poorly defined. Neuregulin 4 (Nrg4) is an adipose tissue–enriched endocrine factor that elicits beneficial metabolic effects in obesity. Here, we show that Nrg4 is a key component of an endocrine checkpoint that preserves hepatocyte health and counters diet-induced NASH in mice. Nrg4 deficiency accelerated liver injury, fibrosis, inflammation, and cell death in a mouse model of NASH. In contrast, transgenic expression of Nrg4 in adipose tissue alleviated diet-induced NASH. Nrg4 attenuated hepatocyte death in a cell-autonomous manner by blocking ubiquitination and proteasomal degradation of c-FLIPL, a negative regulator of cell death. Adeno-associated virus–mediated (AAV-mediated) rescue of hepatic c-FLIPL expression in Nrg4-deficent mice functionally restored the brake for steatosis to NASH transition. Thus, hepatic Nrg4 signaling serves as an endocrine checkpoint for steatosis-to-NASH progression by activating a cytoprotective pathway to counter stress-induced liver injury. PMID:29106384

  11. Molecular basis of APC/C regulation by the spindle assembly checkpoint

    Zhang, Ziguo; Yang, Jing; Maslen, Sarah; Skehel, Mark; Barford, David

    2016-01-01

    In the dividing eukaryotic cell the spindle assembly checkpoint (SAC) ensures each daughter cell inherits an identical set of chromosomes. The SAC coordinates the correct attachment of sister chromatid kinetochores to the mitotic spindle with activation of the anaphase-promoting complex/cyclosome (APC/C), the E3 ubiquitin ligase that initiates chromosome separation. In response to unattached kinetochores, the SAC generates the mitotic checkpoint complex (MCC), a multimeric assembly that inhibits the APC/C, delaying chromosome segregation. Here, using cryo-electron microscopy we determined the near-atomic resolution structure of an APC/C-MCC complex (APC/CMCC). We reveal how degron-like sequences of the MCC subunit BubR1 block degron recognition sites on Cdc20, the APC/C coactivator subunit (Cdc20APC/C) responsible for substrate interactions. BubR1 also obstructs binding of UbcH10 (APC/C’s initiating E2) to repress APC/C ubiquitination activity. Conformational variability of the complex allows for UbcH10 association, and we show from a structure of APC/CMCC in complex with UbcH10 how the Cdc20 subunit intrinsic to the MCC (Cdc20MCC) is ubiquitinated, a process that results in APC/C reactivation when the SAC is silenced. PMID:27509861

  12. Proficiency Test SYKE 8/2012. Volatile organic compounds in water and soil

    Korhonen-Ylönen, Kaija; Nuutinen, Jari; Leivuori, Mirja; Ilmakunnas, Markku

    2013-01-01

    Proftest SYKE carried out the proficiency test for analysis of volatile organic compounds from water and soil in October 2012. One artificial sample and one river water sample and one soil sample were distributed. In total, 15 laboratories participated in the proficiency test. Either the calculated concentration or the robust mean value was chosen to be the assigned value for the measurement. The performance of the participants was evaluated by using z scores. In this proficiency test 72 % of...

  13. Students' proficiency scores within multitrait item response theory

    Scott, Terry F.; Schumayer, Daniel

    2015-12-01

    In this paper we present a series of item response models of data collected using the Force Concept Inventory. The Force Concept Inventory (FCI) was designed to poll the Newtonian conception of force viewed as a multidimensional concept, that is, as a complex of distinguishable conceptual dimensions. Several previous studies have developed single-trait item response models of FCI data; however, we feel that multidimensional models are also appropriate given the explicitly multidimensional design of the inventory. The models employed in the research reported here vary in both the number of fitting parameters and the number of underlying latent traits assumed. We calculate several model information statistics to ensure adequate model fit and to determine which of the models provides the optimal balance of information and parsimony. Our analysis indicates that all item response models tested, from the single-trait Rasch model through to a model with ten latent traits, satisfy the standard requirements of fit. However, analysis of model information criteria indicates that the five-trait model is optimal. We note that an earlier factor analysis of the same FCI data also led to a five-factor model. Furthermore the factors in our previous study and the traits identified in the current work match each other well. The optimal five-trait model assigns proficiency scores to all respondents for each of the five traits. We construct a correlation matrix between the proficiencies in each of these traits. This correlation matrix shows strong correlations between some proficiencies, and strong anticorrelations between others. We present an interpretation of this correlation matrix.

  14. Scientific issues related to the cytology proficiency testing regulations

    Prey Marianne

    2006-01-01

    Full Text Available Abstract The member organizations of the Cytology Education and Technology Consortium believe there are significant flaws in current cytology proficiency testing regulations. The most immediate needed modifications include lengthening the required testing interval, utilizing stringently validated and continuously monitored slides, changing the grading scheme, and changing the focus of the test from the individual to laboratory level testing. Integration of new computer-assisted and located-guided screening technologies into the testing protocols is necessary for the testing protocol to be compliant with the law.

  15. Inter-laboratory proficiency tests to detect viral fish diseases

    Kahns, Søren; Nicolajsen, Nicole; Skall, Helle Frank

    An inter-laboratory proficiency test has ben provided by the European Community Laboratory (CRL) for Fish Diseases every year since 1996. The test is provided to all European National Reference Laboratories (NRLs) that are obliged to participate and to a limited number of non-European NRLs, making......) but also to assess their ability to differentiate other fish viruses as spring viraemia of carp virus, infectious pancreatic necrosis virus, perch rhabdovirus etc. Five coded ampoules are provided to participants containing lyophilised supernatant from infected cell cultures. The CRL collect the data...

  16. Culture, identity and difference relationship and the proficiency exam EPPLE

    Priscila Petian Anchieta

    2017-11-01

    Full Text Available The present work discusses how aspects such as identity, culture and difference are important aspects in for language teaching and learning environments. Using Woodward's (2011 definition that identity is marked by difference, we considered these aspects in foreign language teaching and learning contexts when we learn the laguage of others. In addition, we present a proficiency exam called EPPLE, aimed at language teachers, and we suggest the implementation of a task that addresses cultural issues, because we need to prepare language teachers that search not only for their linguistic and pedagogical knowledge construction, but also for their understanding about culture, identity and difference.

  17. The Relationship between Actual Fundamental Motor Skill Proficiency, Perceived Motor Skill Confidence and Competence, and Physical Activity in 8–12-Year-Old Irish Female Youth

    Orlagh Farmer

    2017-09-01

    Full Text Available This study examines the relationship between actual fundamental motor skill (FMS proficiency, perceived motor confidence and competence, and physical activity (PA among female children (n= 160; mean age = 10.69 ± 1.40 years. The Test of Gross Motor Development-2nd Edition (TGMD-2 was used to assess seven FMSs (locomotor, object-control, and stability. Motor confidence and competence were assessed using a valid skill-specific scale, and a modified version of the Self-Perception Profile for Children. PA levels were assessed using self-report (PA Questionnaire for Older Children (PAQ-C and classified as low, moderate, and high active. One-way and two-way ANOVAs (post-hoc honest significant difference (HSD and correlation coefficients were used to analyse the data. Findings indicate that the majority of youth (71.8% were not meeting the minimum 60 min of daily PA recommended for health, and that 98.1% did not achieve the FMS proficiency expected for their age. While there were high levels of perceived physical self-confidence (PSC reported within FMS skill-specific tasks, there was no significant correlation observed between actual FMS proficiency and perceived PSC among the cohort. Results show that low, moderately, and highly active female participants differ significantly in terms of their overall FMS (p = 0.03 and locomotor (LOC control scores (p = 0.03. Results from a two-way between-groups analysis of variance also revealed no statistically significant interaction effect between PA grouping and physical performance self-concept (PPSC on overall FMS proficiency levels. Results of a multiple linear regression indicate that perceived PSC is a significant predictor (beta = 0.183 of participants’ overall PA levels. Data show a need for targeting low levels of PA, and low FMS proficiency in female youth, and for developing interventions aiming to enhance perceived PSC levels.

  18. Centromere replication timing determines different forms of genomic instability in Saccharomyces cerevisiae checkpoint mutants during replication stress.

    Feng, Wenyi; Bachant, Jeff; Collingwood, David; Raghuraman, M K; Brewer, Bonita J

    2009-12-01

    Yeast replication checkpoint mutants lose viability following transient exposure to hydroxyurea, a replication-impeding drug. In an effort to understand the basis for this lethality, we discovered that different events are responsible for inviability in checkpoint-deficient cells harboring mutations in the mec1 and rad53 genes. By monitoring genomewide replication dynamics of cells exposed to hydroxyurea, we show that cells with a checkpoint deficient allele of RAD53, rad53K227A, fail to duplicate centromeres. Following removal of the drug, however, rad53K227A cells recover substantial DNA replication, including replication through centromeres. Despite this recovery, the rad53K227A mutant fails to achieve biorientation of sister centromeres during recovery from hydroxyurea, leading to secondary activation of the spindle assembly checkpoint (SAC), aneuploidy, and lethal chromosome segregation errors. We demonstrate that cell lethality from this segregation defect could be partially remedied by reinforcing bipolar attachment. In contrast, cells with the mec1-1 sml1-1 mutations suffer from severely impaired replication resumption upon removal of hydroxyurea. mec1-1 sml1-1 cells can, however, duplicate at least some of their centromeres and achieve bipolar attachment, leading to abortive segregation and fragmentation of incompletely replicated chromosomes. Our results highlight the importance of replicating yeast centromeres early and reveal different mechanisms of cell death due to differences in replication fork progression.

  19. Mad2 binding to Mad1 and Cdc20, rather than oligomerization, is required for the spindle checkpoint

    Sironi, L; Melixetian, M; Faretta, M

    2001-01-01

    Mad2 is a key component of the spindle checkpoint, a device that controls the fidelity of chromosome segregation in mitosis. The ability of Mad2 to form oligomers in vitro has been correlated with its ability to block the cell cycle upon injection into Xenopus embryos. Here we show that Mad2 forms...

  20. Structural Biology of the Immune Checkpoint Receptor PD-1 and Its Ligands PD-L1/PD-L2

    Zak, Krzysztof M.; Grudnik, Przemyslaw; Magiera, Katarzyna; Dömling, Alexander; Dubin, Grzegorz; Holak, Tad A.

    2017-01-01

    Cancer cells can avoid and suppress immune responses through activation of inhibitory immune checkpoint proteins, such as PD-1, PD-L1, and CTLA-4. Blocking the activities of these proteins with monoclonal antibodies, and thus restoring T cell function, has delivered breakthrough therapies against

  1. ATM/Wip1 activities at chromatin control Plk1 re-activation to determine G2 checkpoint duration

    Jaiswal, H.; Benada, Jan; Müllers, E.; Akopyan, K.; Burdová, Kamila; Koolmeister, T.; Helleday, T.; Medema, R.H.; Macůrek, Libor; Lindqvist, A.

    2017-01-01

    Roč. 36, č. 14 (2017), s. 2161-2176 ISSN 0261-4189 R&D Projects: GA ČR GA13-18392S Institutional support: RVO:68378050 Keywords : ATM * ATR * checkpoint recovery * G2 * Pik1 Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Cell biology Impact factor: 9.792, year: 2016

  2. Wip1 phosphatase is associated with chromatin and dephosphorylates gammaH2AX to promote checkpoint inhibition

    Macůrek, Libor; Lindqvist, A.; Voets, O.; Kool, J.; Vos, H.R.; Medema, R.H.

    2010-01-01

    Roč. 29, č. 15 (2010), s. 2281-2291 ISSN 0950-9232 R&D Projects: GA ČR GPP305/10/P420 Institutional research plan: CEZ:AV0Z50520514 Keywords : DNA damage * checkpoint * phosphatase Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 7.414, year: 2010

  3. Design Optimization of Time- and Cost-Constrained Fault-Tolerant Embedded Systems with Checkpointing and Replication

    Pop, Paul; Izosimov, Viacheslav; Eles, Petru

    2009-01-01

    We present an approach to the synthesis of fault-tolerant hard real-time systems for safety-critical applications. We use checkpointing with rollback recovery and active replication for tolerating transient faults. Processes and communications are statically scheduled. Our synthesis approach deci...

  4. ProAtlantic - The Atlantic Checkpoint - Data Availability and Adequacy in the Atlantic Basin

    McGrath, F.

    2017-12-01

    DG MAREs Atlantic Checkpoint is a basin scale wide monitoring system assessment activity based upon targeted end-user applications. It is designed to be a benchmark for the assessment of hydrographic, geological, habitat, climate and fisheries data existence and availability in the Atlantic basin. DG MAREs Atlantic Checkpoint service will be delivered by the ProAtlantic project. The objective of this project is to investigate, through appropriate methodologies in the framework of 11 key marine challenges, how current international and national data providers - e.g. EMODNet, Copernicus - meet the requirements of the stakeholders and deliver fit for purpose data. By so doing, the main thematic and geographic gaps will be readily identified in the Atlantic basin for future consideration by DG MARE. For each challenge, specific web products in the form of maps, metadata, spreadsheets and reports will be delivered. These products are not an end by themselves but rather a means of showing whether data were available, let alone accessible. For example, the Fisheries Impact Challenge outputs include data grids (VMS/Seabed) and data adequacy reports. Production of gridded data layers in order to show the extent of fisheries impact on the seafloor involved the identification, acquisition and collation of data sources for the required data types (VMS/Seabed/Habitats Data) in the Atlantic basin. The resulting spatial coverage of these grids indicates the relatively low level of data availability and adequacy across the Atlantic basin. Aside from the data delivered by programmes such as EMODNet and Copernicus, there are a lot of initiatives by regional bodies such as OSPAR and ICES that consist of assembling and disseminating data to address specific issues. Several international projects have delivered research, data collection, and networking around several of the Atlantic Checkpoint challenge topics, namely MPAs, renewable energy assessment, seabed mapping, oil spill

  5. Radiation-induced apoptosis and cell cycle checkpoints in human colorectal tumour cell lines

    Playle, L.C.

    2001-03-01

    The p53 tumour suppressor gene is mutated in 75% of colorectal carcinomas and is critical for DNA damage-induced G1 cell cycle arrest. Data presented in this thesis demonstrate that after treatment with Ionizing Radiation (IR), colorectal tumour cell lines with mutant p53 are unable to arrest at G1 and undergo cell cycle arrest at G2. The staurosporine derivative, UCN-01, was shown to abrogate the IR-induced G2 checkpoint in colorectal tumour cell lines. Furthermore, in some cell lines, abrogation of the G2 checkpoint was associated with radiosensitisation. Data presented in this study demonstrate that 2 out of 5 cell lines with mutant p53 were sensitised to IR by UCN-01. In order to determine whether radiosensitisation correlated with lack of functional p53, transfected derivatives of an adenoma-derived cell line were studied, in which endogenous wild type p53 was disrupted by expression of a dominant negative p53 mutant protein (and with a vector control). In both these cell lines UCN-01 abrogated the G2 arrest however this was not associated with radiosensitisation, indicating that radiosensitisation is a cell type-specific phenomenon. Although 2 colorectal carcinoma cell lines, with mutant p53, were sensitised to IR by UCN-01, the mechanisms of p53-independent IR-induced apoptosis in the colon are essentially unknown. The mitogen-activated protein kinase (MAPK) pathways (that is the JNK, p38 and ERK pathways) have been implicated in apoptosis in a range of cell systems and in IR-induced apoptosis in some cell types. Data presented in this study show that, although the MAPKs can be activated by the known activator anisomycin, there is no evidence of a role for MAPKs in IR-induced apoptosis in colorectal tumour cell lines, regardless of p53 status. In summary, some colorectal tumour cell lines with mutant p53 can be sensitised to IR-induced cell death by G2 checkpoint abrogation and this may be an important treatment strategy, however mechanisms of IR-induced p53

  6. Uncertainty evaluation in 2008 IAEA proficiency test using phosphogypsum

    Dias, Fabiana F.; Taddei, Maria Helena T.; Geraldo, Bianca; Jacomino, Vanusa M.F.; Pontedeiro, Elizabeth M.B.

    2009-01-01

    LAPOC participated in the 2008 IAEA ALMERA (Analytical Laboratories for the Measurement of Environmental Radioactivity) Proficiency Test (PT) for phosphogypsum, which is a NORM (Naturally Occurring Radioactive Material) derived from phosphate industry, an abundant solid waste of low cost. Its reutilization would avoid environmental impact in large areas where the product is stored. Research involving possible uses for phosphogypsum is ever more important, from economic, technological, and environmental points of view. This paper describes results from this Proficiency Test (measured radionuclides: 234 U, 238 U, 226 Ra, 230 Th, and 210 Pb), as well as a short description of the nuclear analytical techniques emphasizing sources of uncertainty, such as Alpha Spectrometry (Alpha Analyst, Canberra, surface barrier detectors) and Gamma Spectrometry (Canberra, Hyper Pure Germanium Detector with 45 % efficiency). Corrections for decay, reference date, and recovery were applied. As an example, results obtained for 210 Pb through the use of a specific uncertainty calculation software are presented below. Each parameter whose uncertainty is quantified was carefully described, with appropriate numerical value and unit, to determine its partial contribution to the combined total uncertainty. Results from PTs provide independent information on performance of a Laboratory and have an important role in method validation; especially because it allows the assessment of the method performance over an entire range of concentrations and matrices. PTs are an important tool to demonstrate equivalence of measurements, if not their metrological comparability, and to promote education and improvement of Laboratory practice. (author)

  7. SYNCHRONOUS CMC, WORKING MEMORY, AND L2 ORAL PROFICIENCY DEVELOPMENT

    J. Scott Payne

    2005-09-01

    Full Text Available Recently a number of quasi-experimental studies have investigated the potential of a cross-modality transfer of second language competency between real-time, conversational exchange via text and speech (Abrams, 2003; Beauvious, 1998; Kost, 2004; Payne & Whitney, 2002. Payne and Whitney employed Levelt's (1989 model of language production and concepts from working memory as a rationale for a hypothesized connection between synchronous computer-mediated communication (SCMC and second language (L2 speech and as a basis for predicting the differential contributions of SCMC to the L2 oral proficiency development.This study extends the psycholinguistic framework reported in Payne and Whitney (2002 with discourse and corpus analytic techniques to explore how individual differences in working memory capacity may affect the frequency of repetition and other patterns of language use in chatroom discourse. Working memory capacity was measured by a reading span and nonword repetition test. Oral proficiency was measured with a speaking task that solicited a 5-minute speech sample and was scored based on a holistic scale. The data collected from 20 chat sessions were analyzed for occurrences of repetition and relexicalization, as well as language output measures. Findings suggest a connection between working memory and language output as measured in this study.

  8. Proficiency evaluation of maintenance personnel: Training equivalency determination

    Price, W.J.

    1991-01-01

    The nuclear industry has recognized the importance of safe, quality, productive maintenance practices and has taken a number of initiatives that have generally improved maintenance programs. Because proficient maintenance practices are critical to plant safety and reliability, most plants have also recognized the need for reliable, valid testing techniques that demonstrate and assure the competence of their maintenance personnel. Until now, resource demands were too great to develop in-plant testing programs. In the past, maintenance supervisors have exempted personnel from training, using informal judgment of the employees' previous training and experience and informal observation of the employee on the job. While this procedure may have some degree of validity, it fails to provide the documentation for training equivalency that is required to satisfy the US Nuclear Regulatory Commission (NRC) regulations and Institute of Nuclear Power Operations (INPO) guidelines. To assess and demonstrate the proficiency levels of personnel, Calvert Cliffs needed to establish an objective, reliable, time-saving, and valid system to evaluate the competency levels of personnel. This was done in a joint effort with the Electric Power Research Institute

  9. Targeting cytokine signaling checkpoint CIS activates NK cells to protect from tumor initiation and metastasis

    Putz, Eva M.; Guillerey, Camille; Kos, Kevin; Stannard, Kimberley; Miles, Kim; Delconte, Rebecca B.; Nicholson, Sandra E.; Huntington, Nicholas D.; Smyth, Mark J.

    2017-01-01

    ABSTRACT The cytokine-induced SH2-containing protein CIS belongs to the suppressor of cytokine signaling (SOCS) protein family. Here, we show the critical role of CIS in suppressing natural killer (NK) cell control of tumor initiation and metastasis. Cish-deficient mice were highly resistant to methylcholanthrene-induced sarcoma formation and protected from lung metastasis of B16F10 melanoma and RM-1 prostate carcinoma cells. In contrast, the growth of primary subcutaneous tumors, including those expressing the foreign antigen OVA, was unchanged in Cish-deficient mice. The combination of Cish deficiency and relevant targeted and immuno-therapies such as combined BRAF and MEK inhibitors, immune checkpoint blockade antibodies, IL-2 and type I interferon revealed further improved control of metastasis. The data clearly indicate that targeting CIS promotes NK cell antitumor functions and CIS holds great promise as a novel target in NK cell immunotherapy. PMID:28344878

  10. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade

    McGranahan, Nicholas; Furness, Andrew J. S.; Rosenthal, Rachel; Ramskov, Sofie; Lyngaa, Rikke; Saini, Sunil Kumar; Jamal-Hanjani, Mariam; Wilson, Gareth A.; Birkbak, Nicolai J.; Hiley, Crispin T.; Watkins, Thomas B. K.; Shafi, Seema; Murugaesu, Nirupa; Mitter, Richard; Akarca, Ayse U.; Linares, Joseph; Marafioti, Teresa; Henry, Jake Y.; Van Allen, Eliezer M.; Miao, Diana; Schilling, Bastian; Schadendorf, Dirk; Garraway, Levi A.; Makarov, Vladimir; Rizvi, Naiyer A.; Snyder, Alexandra; Hellmann, Matthew D.; Merghoub, Taha; Wolchok, Jedd D.; Shukla, Sachet A.; Wu, Catherine J.; Peggs, Karl S.; Chan, Timothy A.; Hadrup, Sine R.; Quezada, Sergio A.; Swanton, Charles

    2016-01-01

    As tumors grow, they acquire mutations, some of which create neoantigens that influence the response of patients to immune checkpoint inhibitors. We explored the impact of neoantigen intratumor heterogeneity (ITH) on antitumor immunity. Through integrated analysis of ITH and neoantigen burden, we demonstrate a relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas. CD8+ tumor-infiltrating lymphocytes reactive to clonal neoantigens were identified in early-stage non–small cell lung cancer and expressed high levels of PD-1. Sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. T cells recognizing clonal neoantigens were detectable in patients with durable clinical benefit. Cytotoxic chemotherapy–induced subclonal neoantigens, contributing to an increased mutational load, were enriched in certain poor responders. These data suggest that neoantigen heterogeneity may influence immune surveillance and support therapeutic developments targeting clonal neoantigens. PMID:26940869

  11. Mitosis-specific phosphorylation of PML at T409 regulates spindle checkpoint.

    Jin, J; Liu, J

    2016-08-31

    During mitosis, Promyelocytic leukemia nuclear bodies (PML NBs) change dramatically in morphology and composition, but little is known about function of PML in mitosis. Here, we show that PML is phosphorylated at T409 (PML p409) in a mitosis-specific manner. More importantly, PML p409 contributes to maintain the duration of pro-metaphase and regulates spindle checkpoint. Deficient PML p409 caused a shortening of pro-metaphase and challenged the nocodazole-triggered mitotic arrest. T409A mutation led to a higher frequency of misaligned chromosomes on metaphase plate, and subsequently death in late mitosis. In addition, inhibition of PML p409 repressed growth of tumor cells, suggesting that PML p409 is a potential target for cancer therapy. Collectively, our study demonstrated an important phosphorylated site of PML, which contributed to explore the role of PML in mitosis.

  12. A direct role of Mad1 in the spindle assembly checkpoint beyond Mad2 kinetochore recruitment

    Kruse, Thomas; Larsen, Marie Sofie Yoo; Sedgwick, Garry G

    2014-01-01

    in the SAC beyond recruitment of C-Mad2 to kinetochores has not yet been addressed. Here, we show that Mad1 is required for mitotic arrest even when C-Mad2 is artificially recruited to kinetochores, indicating that it has indeed an additional function in promoting the checkpoint. The C-terminal globular...... domain of Mad1 and conserved residues in this region are required for this unexpected function of Mad1........ The conversion of O-Mad2 into C-Mad2 at unattached kinetochores is thought to be a key step in activating the SAC. The "template model" proposes that this is achieved by the recruitment of soluble O-Mad2 to C-Mad2 bound at kinetochores through its interaction with Mad1. Whether Mad1 has additional roles...

  13. The modulatory role of second language proficiency on performance monitoring: evidence from a saccadic countermanding task in high and low proficient bilinguals.

    Singh, Niharika; Mishra, Ramesh K

    2014-01-01

    We compared Hindi-English bilinguals differing in their L2 proficiency on a saccadic countermanding task which taps inhibitory control as well as monitoring. We particularly explored whether response inhibition and performance monitoring within the oculomotor domain are affected by language proficiency in bilinguals. There were two different oculomotor redirect tasks: Visually Guided Redirect (VGR) task (Experiment1) and Memory Guided Redirect (MGR) task (Experiment 2). In the redirect task, typically a target is presented and the subject is required to make a saccade (no-step trials), unless a new target appears on a different location after some delay from the first target onset (step trials). On such trials participants are required to inhibit and cancel the saccade to the first target and programme a saccade to the new target. Using trial switch reaction time (TSRT), the time taken to inhibit the initiated saccade to the first target as a measure of response inhibition and post-step slowing as a measure of performance monitoring. The results showed the high proficient bilinguals displayed more post-step slowing on the no-step trials as compared to the low proficient bilinguals for both VGR and MGR versions of the task. Secondly, both the high and low proficient bilinguals exhibited comparable TSRT in both VGR and MGR task, showing no modulatory effects of language proficiency on the response inhibition. These results suggest that language proficiency may have an effect on performance monitoring, but not the inhibitory control per se. Thus, we infer that higher proficiency may lead to superior cognitive flexibility and an ability to adjust behavior that facilitates the attainment of the cognitive goal. These findings are in consonance with other current studies that suggest a top-down effect of bilingualism on action control systems.

  14. Incorporation of proficiency criteria for basic laparoscopic skills training: How does it work?

    E. Verdaasdonk (Egg); J. Dankelman (Jenny); J.F. Lange (Johan); L.P. Stassen (Laurents)

    2008-01-01

    textabstractBackground: It is desirable that surgical trainees are proficient in basic laparoscopic motor skills (eye-hand coordination). The present study evaluated the use of predefined proficiency criteria on a basic virtual reality (VR) simulator in preparation for a laparoscopic course on

  15. The Relationship between Reading Proficiency and Reading Strategy Use: A Study of Adult ESL Learners

    Huang, Jiuhan; Nisbet, Deanna

    2014-01-01

    This article explores the relationship between reading strategy use and reading proficiency among 121 adult ESL learners. Reading strategy use was measured by the SORS, and reading proficiency was determined by the CASAS Reading Test and BEST Literacy Test. Findings of the study reveal that (a) adult ESL learners are active strategies users; (b)…

  16. English Proficiency and Acculturation among Chinese Immigrant Youth in Canada: A Reciprocal Relationship

    Jia, Fanli; Gottardo, Alexandra; Chen, Xi; Koh, Pohwee; Pasquarella, Adrian

    2016-01-01

    The main focus of this study was to refine our understanding of the link between English proficiency and mainstream acculturation in adolescent Chinese immigrants. The sample consisted of 112 adolescents in grades 7-12 living in urban areas in southern Ontario, Canada. English proficiency was assessed individually using standardised tests of…

  17. L2-proficiency-dependent laterality shift in structural connectivity of brain language pathways

    Xiang, H.; Leeuwen, T.M. van; Dediu, D.; Roberts, L.; Norris, D.; Hagoort, P.

    2015-01-01

    Diffusion tensor imaging (DTI) and a longitudinal language learning approach were applied to investigate the relationship between the achieved second language (L2) proficiency during L2 learning and the reorganization of structural connectivity between core language areas. Language proficiency tests

  18. Understanding the Relationship between Language Proficiency, Language Impairment and Rehabilitation: Evidence from a Case Study

    Kiran, Swathi; Iakupova, Regina

    2011-01-01

    The goal of this study was to address the relationship between language proficiency, language impairment and rehabilitation in bilingual Russian-English individuals with aphasia. As a first step, we examined two Russian-English patients' pre-stroke language proficiency using a detailed and comprehensive language use and history questionnaire and…

  19. ELL High School Students' Metacognitive Awareness of Reading Strategy Use and Reading Proficiency

    Hong-Nam, Kay

    2014-01-01

    This study investigated the metacognitive awareness and reading strategies use of high school-­aged English language learners (ELLs) and the relationship between ELL reading strategy use and reading proficiency as measured by a standardized reading test and self-­rated reading proficiency. Results reveal that participants reported moderate use of…

  20. Development and Validation of the Spanish-English Language Proficiency Scale (SELPS)

    Smyk, Ekaterina; Restrepo, M. Adelaida; Gorin, Joanna S.; Gray, Shelley

    2013-01-01

    Purpose: This study examined the development and validation of a criterion-referenced Spanish-English Language Proficiency Scale (SELPS) that was designed to assess the oral language skills of sequential bilingual children ages 4-8. This article reports results for the English proficiency portion of the scale. Method: The SELPS assesses syntactic…

  1. Digital Games and the US National Research Council's Science Proficiency Goals

    Martinez-Garza, Mario; Clark, Douglas B.; Nelson, Brian C.

    2013-01-01

    This review synthesises research on digital games and science learning as it supports the goals for science proficiency outlined in the report by the US National Research Council on science education reform. The review is organised in terms of these research-based goals for science proficiency in light of their alignment with current science…

  2. Volunteer Administration Leadership Proficiency and Leadership Styles: Perceptions of Southern Region 4-H County Faculty

    Stedman, Nicole L. P.; Rudd, Rick D.

    2005-01-01

    Volunteers play an integral role in supporting the mission of 4-H programs in the southern region. For this reason their proficiency in volunteer administration competence and perceived leadership style is important. The researchers sought to examine both the perceived proficiency of 4-H faculty in the southern region in seven competencies…

  3. Motor Proficiency and Body Mass Index of Preschool Children: In Relation to Socioeconomic Status

    Mülazimoglu-Balli, Özgür

    2016-01-01

    The aim of the study was to investigate the correlation between motor proficiency and body mass index and to assess the socioeconomic status differences in motor proficiency and body mass index of preschool children. Sixty preschool children in the different socioeconomic status areas of central Denizli in Turkey participated in the study. The…

  4. Language Learning Strategies and English Proficiency: Interpretations from Information-Processing Theory

    Rao, Zhenhui

    2016-01-01

    The research reported here investigated the relationship between students' use of language learning strategies and their English proficiency, and then interpreted the data from two models in information-processing theory. Results showed that the students' English proficiency significantly affected their use of learning strategies, with high-level…

  5. Hi-LAB: A New Measure of Aptitude for High-Level Language Proficiency

    Linck, Jared A.; Hughes, Meredith M.; Campbell, Susan G.; Silbert, Noah H.; Tare, Medha; Jackson, Scott R.; Smith, Benjamin K.; Bunting, Michael F.; Doughty, Catherine J.

    2013-01-01

    Few adult second language (L2) learners successfully attain high-level proficiency. Although decades of research on beginning to intermediate stages of L2 learning have identified a number of predictors of the rate of acquisition, little research has examined factors relevant to predicting very high levels of L2 proficiency. The current study,…

  6. L2-Proficiency-Dependent Laterality Shift in Structural Connectivity of Brain Language Pathways

    Xiang, Huadong; van Leeuwen, Tessa Marije; Dediu, Dan; Roberts, Leah; Norris, David G.; Hagoort, Peter

    2015-01-01

    Diffusion tensor imaging (DTI) and a longitudinal language learning approach were applied to investigate the relationship between the achieved second language (L2) proficiency during L2 learning and the reorganization of structural connectivity between core language areas. Language proficiency tests

  7. The application of data from proficiency testing to laboratory accreditation according to ISO 17025

    Heydorn, Kaj

    2008-01-01

    Current methods of testing laboratories for their proficiency in reporting correct measurement results are liable to substantial errors of the 2nd kind. This means that laboratories with deflated uncertainties are accepted as proficient, even though their reported measurement results pave the way...

  8. A Blueprint for Developing Culturally Proficient/Responsive School Administrators in Special Education

    Bakken, Jeffrey P.; Smith, Beverly A.

    2011-01-01

    This article addresses the important topic of culturally proficient/responsive school administrators for culturally and linguistically diverse (CLD) students with learning disabilities (LD). Culturally proficient/responsive school administrators with knowledge and strong leadership skills in multicultural education are essential to impact school…

  9. Self-Efficacy Ratings of Technology Proficiency among Teachers in Mexico and Texas

    Morales, Cesareo; Knezek, Gerald; Christensen, Rhonda

    2008-01-01

    The Technology Proficiency Self-Assessment (TPSA) questionnaire was administered to 978 elementary and middle school teachers from Mexico City, and 932 elementary and middle school teachers from the Dallas, Texas, metroplex in the USA, in order to examine self-efficacy similarities and differences for technology proficiency self-appraisals in a…

  10. The Reading Habits of Developmental College Students at Different Levels of Reading Proficiency.

    Sheorey, Ravi; Mokhtari, Kouider

    1994-01-01

    Examines differences in reading habits of developmental college students with varying levels of reading proficiency. Finds that subjects spent an unusually low amount of time on academic reading and even less time on nonacademic reading. Finds no significant differences between high- and low-proficient readers with regard to amount of time spent…

  11. Reading Habits of University ESL Students at Different Levels of English Proficiency and Education.

    Mokhtari, Kouider; Sheorey, Ravi

    1994-01-01

    Examines the degree to which the levels of English proficiency (high vs. low) and education (graduate vs. undergraduate) of English-as-a-Second-Language (ESL) students were associated with differences in their reading behaviors. Finds that the subjects' level of education and English proficiency were associated with their reading behavior…

  12. Non-Discriminatory Assessment: Formal and Informal Assessment of Limited English Proficient Children.

    Mares, Sharon

    PEOPLE (Pruebas de Expresion Oral y Percepcion de la Lengua Espanol) was developed as a test to help distinguish between a language difference and a language deficit in non English proficient (NEP) and limited English proficient (LEP) elementary Hispanic students. PEOPLE was developed, pilot tested in 14 school districts in Los Angeles County with…

  13. Issues in Vertical Scaling of a K-12 English Language Proficiency Test

    Kenyon, Dorry M.; MacGregor, David; Li, Dongyang; Cook, H. Gary

    2011-01-01

    One of the mandates of the No Child Left Behind Act is that states show adequate yearly progress in their English language learners' (ELLs) acquisition of English language proficiency. States are required to assess ELLs' English language proficiency annually in four language domains (listening, reading, writing, and speaking) to measure their…

  14. Self-Assessment, Preparation and Response Time on a Computerized Oral Proficiency Test

    Malabonga, Valerie; Kenyon, Dorry M.; Carpenter, Helen

    2005-01-01

    Two studies investigated technical aspects of a computer-mediated test, the Computerized Oral Proficiency Instrument (COPI), particularly in contrast to a similar tape-mediated test, the Simulated Oral Proficiency Interview (SOPI). The first study investigated how examinees used self-assessment to choose an appropriate starting level on the COPI.…

  15. Technological Proficiency as a Key to Job Security. Trends and Issues Alert No. 6.

    Imel, Susan

    Although not all current jobs require basic computer skills, technological advances in society have created new jobs and changed the ways many existing jobs are performed. Clearly, workers who are proficient in technology have a greater advantage in the current workplace and the need for technologically proficient workers will only continue to…

  16. Immune checkpoint inhibitors and targeted therapies for metastatic melanoma: A network meta-analysis.

    Pasquali, Sandro; Chiarion-Sileni, Vanna; Rossi, Carlo Riccardo; Mocellin, Simone

    2017-03-01

    Immune checkpoint inhibitors and targeted therapies, two new class of drugs for treatment of metastatic melanoma, have not been compared in randomized controlled trials (RCT). We quantitatively summarized the evidence and compared immune and targeted therapies in terms of both efficacy and toxicity. A comprehensive search for RCTs of immune checkpoint inhibitors and targeted therapies was conducted to August 2016. Using a network meta-analysis approach, treatments were compared with each other and ranked based on their effectiveness (as measured by the impact on progression-free survival [PFS]) and acceptability (the inverse of high grade toxicity). Twelve RCTs enrolling 6207 patients were included. Network meta-analysis generated 15 comparisons. Combined BRAF and MEK inhibitors were associated with longer PFS as compared to anti-CTLA4 (HR: 0.22; 95% confidence interval [CI]: 0.12-0.41) and anti-PD1 antibodies alone (HR: 0.38; CI: 0.20-0.72). However, anti-PD1 monoclonal antibodies were less toxic than anti-CTLA4 monoclonal antibodies (RR: 0.65; CI: 0.40-0.78) and their combination significantly increased toxicity compared to either single agent anti-CTLA4 (RR: 2.06; CI: 1.45-2.93) or anti-PD1 monoclonal antibodies (RR: 3.67; CI: 2.27-5.96). Consistently, ranking analysis suggested that the combination of targeted therapies is the most effective strategy, whereas single agent anti-PD1 antibodies have the best acceptability. The GRADE level of evidence quality for these findings was moderate to low. The simultaneous inhibition of BRAF and MEK appears the most effective treatment for melanomas harboring BRAF V600 mutation, although anti-PD1 antibodies appear to be less toxic. Further research is needed to increase the quality of evidence. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. An Archaeosome-Adjuvanted Vaccine and Checkpoint Inhibitor Therapy Combination Significantly Enhances Protection from Murine Melanoma

    Felicity C. Stark

    2017-10-01

    Full Text Available Archaeosomes constitute archaeal lipid vesicle vaccine adjuvants that evoke a strong CD8+ T cell response to antigenic cargo. Therapeutic treatment of murine B16-ovalbumin (B16-OVA melanoma with archaeosome-OVA eliminates small subcutaneous solid tumors; however, they eventually resurge despite an increased frequency of circulating and tumor infiltrating OVA-CD8+ T cells. Herein, a number of different approaches were evaluated to improve responses, including dose number, interval, and the combination of vaccine with checkpoint inhibitors. Firstly, we found that tumor protection could not be enhanced by repetitive and/or delayed boosting to maximize the CD8+ T cell number and/or phenotype. The in vivo cytotoxicity of vaccine-induced OVA-CD8+ T cells was impaired in tumor-bearing mice. Additionally, tumor-infiltrating OVA-CD8+ T cells had an increased expression of programmed cell death protein-1 (PD-1 compared to other organ compartments, suggesting impaired function. Combination therapy of tumor-bearing mice with the vaccine archaeosome-OVA, and α-CTLA-4 administered concurrently as well as α-PD-1 and an α-PD-L1 antibody administered starting 9 days after tumor challenge given on a Q3Dx4 schedule (days 9, 12, 15 and 18, significantly enhanced survival. Following multi-combination therapy ~70% of mice had rapid tumor recession, with no detectable tumor mass after >80 days in comparison to a median survival of 17–22 days for untreated or experimental groups receiving single therapies. Overall, archaeosomes offer a powerful platform for delivering cancer antigens when used in combination with checkpoint inhibitor immunotherapies.

  18. The relationship between constructivist supervisory practices, school climate, and student proficiency in reading, mathematics, and science: Evidence from NELS:88

    Molnar, John Alexander

    In an effort to improve instruction and student learning, school reform efforts have become prevalent. School reformers have examined many aspects of the school experience, including learning theories such as behaviorism and constructivism, the changing roles of teachers and supervisors, and even the concept of the school itself. The theoretical framework for this study centered around constructivist learning theory. The study itself focused on the application of constructivist learning theory to the supervisory process. The study examined five areas of interest: (a) teachers' perceptions of constructivist supervisory behavior; (b) teachers' perceptions of efficacy and control in the classroom; (c) teachers' perceptions of school climate; (d) teachers' perceptions of job satisfaction, and (e) the influences of each of the aforementioned on student proficiency in mathematics, reading, and science. Data for the study was drawn from the first follow-up survey of the National Educational Longitudinal Study of 1988 (NELS: 88). NELS: 88 investigated a wide variety of factors that influence the educational process. The first follow-up focuses on environmental factors that affect teachers and students. Variables were selected from the NELS:88 data set that represented the areas to be examined. Factor analysis and correlational analysis were applied to ensure that the variables were measuring distinct constructs and to determine ways they could be grouped for analysis. Multiple linear regression analysis was applied to determine relationships among the individual and composite variables, controlling for student and teacher demographic factors. The results of the study suggest that varying relationships do exist between constructivist supervisory practices and the constructs measuring school climate and job satisfaction. The results also suggest that varying relationships exist between each of these factors and student proficiency in mathematics, reading, and science

  19. The relationship between automatic assessment of oral proficiency and other indicators of first year students' linguistic abilities

    De Wet, Febe

    2012-11-01

    Full Text Available Academic literacy proficiency is key to the success of a student at university. Currently, the large-scale assessment of language proficiency, particularly at higher education levels, is dominated by reading and writing tests because listening...

  20. Research on the proficient machine system. Theoretical part; Jukutatsu machine system no chosa kenkyu. Rironhen

    NONE

    1996-03-01

    The basic theory of the proficient machine system to be developed was studied. Important proficient techniques in manufacturing industries are becoming extinct because of insufficient succession to next generation. The proficient machine system was proposed to cope with such situation. This machine system includes the mechanism for progress and evolution of techniques and sensibilities to be adaptable to environmental changes by learning and recognizing various motions such as work and process. Consequently, the basic research fields are composed of thought, learning, perception and action. This machine requires not only deigned fixed functions but also introduction of the same proficient concept as human being to be adaptable to changes in situation, purpose, time and machine`s complexity. This report explains in detail the basic concept, system principle, approaching procedure and practical elemental technologies of the proficient machine system, and also describes the future prospect. 133 refs., 110 figs., 7 tabs.

  1. Gaining Proficiency through Task-Based Activities in the Portuguese Classroom (Beginning and Intermediate Year Case Studies)

    Jones-Kellogg, Rebecca

    2015-01-01

    This paper describes a task-based activity used at the United States Military Academy, in their first- through third-semester Portuguese language sequence "Proficiencies" (Proficiências). The stand-alone task-based activity can be an effective tool in gaining foreign-language proficiency at even the lowest levels of classroom instruction…

  2. 40 CFR 798.5500 - Differential growth inhibition of repair proficient and repair deficient bacteria: “Bacterial DNA...

    2010-07-01

    ... repair proficient and repair deficient bacteria: âBacterial DNA damage or repair tests.â 798.5500 Section... inhibition of repair proficient and repair deficient bacteria: “Bacterial DNA damage or repair tests.” (a... killing or growth inhibition of repair deficient bacteria in a set of repair proficient and deficient...

  3. The subunits of the S-phase checkpoint complex Mrc1/Tof1/Csm3: dynamics and interdependence.

    Uzunova, Sonya Dimitrova; Zarkov, Alexander Stefanov; Ivanova, Anna Marianova; Stoynov, Stoyno Stefanov; Nedelcheva-Veleva, Marina Nedelcheva

    2014-01-01

    The S-phase checkpoint aims to prevent cells from generation of extensive single-stranded DNA that predisposes to genome instability. The S. cerevisiae complex Tof1/Csm3/Mrc1 acts to restrain the replicative MCM helicase when DNA synthesis is prohibited. Keeping the replication machinery intact allows restart of the replication fork when the block is relieved. Although the subunits of the Tof1/Csm3/Mrc1 complex are well studied, the impact of every single subunit on the triple complex formation and function needs to be established. This work studies the cellular localization and the chromatin binding of GFP-tagged subunits when the complex is intact and when a subunit is missing. We demonstrate that the complex is formed in cell nucleus, not the cytoplasm, as Tof1, Csm3 and Mrc1 enter the nucleus independently from one another. Via in situ chromatin binding assay we show that a Tof1-Csm3 dimer formation and chromatin binding is required to ensure the attachment of Mrc1 to chromatin. Our study indicates that the translocation into the nucleus is not the process to regulate the timing of chromatin association of Mrc1. We also studied the nuclear behavior of Mrc1 subunit in the process of adaptation to the presence hydroxyurea. Our results indicate that after prolonged HU incubation, cells bypass the S-phase checkpoint and proceed throughout the cell cycle. This process is accompanied by Mrc1 chromatin detachment and Rad53 dephosphorylation. In S. cerevisiae the subunits of the S-phase checkpoint complex Mrc1/Tof1/Csm3 independently enter the cell nucleus, where a Tof1-Csm3 dimer is formed to ensure the chromatin binding of Mrc1 and favor DNA replication and S-phase checkpoint fork arrest. In the process of adaptation to the presence of hydroxyurea Mrc1 is detached from chromatin and Rad53 checkpoint activity is diminished in order to allow S-phase checkpoint escape and completion of the cell cycle.

  4. Comparative Analysis of Immune Checkpoint Molecules and Their Potential Role in the Transmissible Tasmanian Devil Facial Tumor Disease

    Andrew S. Flies

    2017-05-01

    Full Text Available Immune checkpoint molecules function as a system of checks and balances that enhance or inhibit immune responses to infectious agents, foreign tissues, and cancerous cells. Immunotherapies that target immune checkpoint molecules, particularly the inhibitory molecules programmed cell death 1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4, have revolutionized human oncology in recent years, yet little is known about these key immune signaling molecules in species other than primates and rodents. The Tasmanian devil facial tumor disease is caused by transmissible cancers that have resulted in a massive decline in the wild Tasmanian devil population. We have recently demonstrated that the inhibitory checkpoint molecule PD-L1 is upregulated on Tasmanian devil (Sarcophilus harrisii facial tumor cells in response to the interferon-gamma cytokine. As this could play a role in immune evasion by tumor cells, we performed a thorough comparative analysis of checkpoint molecule protein sequences among Tasmanian devils and eight other species. We report that many of the key signaling motifs and ligand-binding sites in the checkpoint molecules are highly conserved across the estimated 162 million years of evolution since the last common ancestor of placental and non-placental mammals. Specifically, we discovered that the CTLA-4 (MYPPPY ligand-binding motif and the CTLA-4 (GVYVKM inhibitory domain are completely conserved across all nine species used in our comparative analysis, suggesting that the function of CTLA-4 is likely conserved in these species. We also found that cysteine residues for intra- and intermolecular disulfide bonds were also highly conserved. For instance, all 20 cysteine residues involved in disulfide bonds in the human 4-1BB molecule were also present in devil 4-1BB. Although many key sequences were conserved, we have also identified immunoreceptor tyrosine-based inhibitory motifs (ITIMs and immunoreceptor tyrosine-based switch

  5. Language proficiency and metacognition as predictors of spontaneous rehearsal in children.

    Bebko, James M; McMorris, Carly A; Metcalfe, Alisa; Ricciuti, Christina; Goldstein, Gayle

    2014-03-01

    Despite decades of research on fundamental memory strategies such as verbal rehearsal, the potential underlying skills associated with the emergence of rehearsal are still not fully understood. Two studies examined the relative roles of language proficiency and metamemory in predicting rehearsal use, as well as the prediction of metamemory performance by language proficiency. In Study 1, 59 children, 5 to 8 years old, were administered a serial recall task, 2 language measures, a nonverbal cognitive measure, and a rapid automatized naming (RAN) task. Language proficiency, RAN, and age were significant individual predictors of rehearsal use. In hierarchical regression analyses, language proficiency mediated almost completely the age → rehearsal use relation. In addition, automatized naming was a strong but partial mediator of the contribution of language proficiency to rehearsal use. In Study 2, 54 children were administered a metamemory test, a language measure, and a serial recall task. Metamemory skills and, again, language proficiency significantly predicted rehearsal use in the task. The predictive strength of metamemory skills was mediated by the children's language proficiency. The mutually supportive roles of automatized naming, language, and metamemory in the emergence of spontaneous cumulative verbal rehearsal are discussed in the context of the resulting model, along with the minimal roles of age and aspects of intelligence.

  6. Childhood motor skill proficiency as a predictor of adolescent physical activity.

    Barnett, Lisa M; van Beurden, Eric; Morgan, Philip J; Brooks, Lyndon O; Beard, John R

    2009-03-01

    Cross-sectional evidence has demonstrated the importance of motor skill proficiency to physical activity participation, but it is unknown whether skill proficiency predicts subsequent physical activity. In 2000, children's proficiency in object control (kick, catch, throw) and locomotor (hop, side gallop, vertical jump) skills were assessed in a school intervention. In 2006/07, the physical activity of former participants was assessed using the Australian Physical Activity Recall Questionnaire. Linear regressions examined relationships between the reported time adolescents spent participating in moderate-to-vigorous or organized physical activity and their childhood skill proficiency, controlling for gender and school grade. A logistic regression examined the probability of participating in vigorous activity. Of 481 original participants located, 297 (62%) consented and 276 (57%) were surveyed. All were in secondary school with females comprising 52% (144). Adolescent time in moderate-to-vigorous and organized activity was positively associated with childhood object control proficiency. Respective models accounted for 12.7% (p = .001), and 18.2% of the variation (p = .003). Object control proficient children became adolescents with a 10% to 20% higher chance of vigorous activity participation. Object control proficient children were more likely to become active adolescents. Motor skill development should be a key strategy in childhood interventions aiming to promote long-term physical activity.

  7. Clinical features, predictive correlates, and pathophysiology of immune-related adverse events in immune checkpoint inhibitor treatments in cancer: a short review

    Yoest, Jennifer M

    2017-01-01

    Jennifer M Yoest Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA Abstract: Identification and characterization of T-cell regulatory mechanisms, or checkpoints, have led to a wave of drug development aimed at inhibiting these targets to “remove the brakes” of the immune system. This class of anticancer therapeutics, termed immune checkpoint inhibitors (ICIs), has harnessed the potential of the body’s own immune system to reco...

  8. Using ergonomics checkpoints to support a participatory ergonomics intervention in an industrially developing country (IDC)--a case study.

    Helali, Faramarz

    2009-01-01

    To achieve ergonomics awareness in 3 subsidiary companies, an intervention team was formed. The aims of this study were to implement basic ergonomics through a participatory ergonomics intervention process that can support a continuous learning process and lead to an improvement in health and safety as well as in the work systems in the organization. The findings of this study (i.e., method, continuous learning and integration) were key to making the participatory ergonomics intervention successful. Furthermore, 4 issues of the ergonomics checkpoints (i.e., work schedules, work tasks, healthy work organization and learning) for assessing the work system were found suitable for both changing work schedules and for improving the work system. This paper describes the result of this project and also the experiences gained and the conclusions reached from using the International Labour Office's ergonomics checkpoints in the industries of industrially developing country.

  9. Broken English, broken bones? Mechanisms linking language proficiency and occupational health in a Montreal garment factory.

    Premji, Stéphanie; Messing, Karen; Lippel, Katherine

    2008-01-01

    Language barriers are often cited as a factor contributing to ethnic inequalities in occupational health; however, little information is available about the mechanisms at play. The authors describe the multiple ways in which language influences occupational health in a large garment factory employing many immigrants in Montreal. Between 2004 and 2006, individual, semi-structured interviews were conducted with 15 women and 10 men from 14 countries of birth. Interviews were conducted in French and English, Canada's official languages, as well as in non-official languages with the help of colleague-interpreters. Observation within the workplace was also carried out at various times during the project. The authors describe how proficiency in the official languages influences occupational health by affecting workers' ability to understand and communicate information, and supporting relationships that can affect work-related health. They also describe workers' strategies to address communication barriers and discuss the implications of these strategies from an occupational health standpoint. Along with the longer-term objectives of integrating immigrants into the linguistic majority and addressing structural conditions that can affect health, policies and practices need to be put in place to protect the health and well-being of those who face language barriers in the short term.

  10. Virtual reality laparoscopy: which potential trainee starts with a higher proficiency level?

    Paschold, M; Schröder, M; Kauff, D W; Gorbauch, T; Herzer, M; Lang, H; Kneist, W

    2011-09-01

    Minimally invasive surgery requires technical skills distinct from those used in conventional surgery. The aim of this prospective study was to identify personal characteristics that may predict the attainable proficiency level of first-time virtual reality laparoscopy (VRL) trainees. Two hundred and seventy-nine consecutive undergraduate medical students without experience attended a standardized VRL training. Performance data of an abstract and a procedural task were correlated with possible predictive factors providing potential competence in VRL. Median global score requirement status was 86.7% (interquartile range (IQR) 75-93) for the abstract task and 74.4% (IQR 67-88) for the procedural task. Unadjusted analysis showed significant increase in the global score in both tasks for trainees who had a gaming console at home and frequently used it as well as for trainees who felt self-confident to assist in a laparoscopic operation. Multiple logistic regression analysis identified frequency of video gaming (often/frequently vs. rarely/not at all, odds ratio: abstract model 2.1 (95% confidence interval 1.2; 3.6), P = 0.009; virtual reality operation procedure 2.4 (95% confidence interval 1.3; 4.2), P = 0.003) as a predictive factor for VRL performance. Frequency of video gaming is associated with quality of first-time VRL performance. Video game experience may be used as trainee selection criteria for tailored concepts of VRL training programs.

  11. Pharmacometrics and systems pharmacology of immune checkpoint inhibitor nivolumab in cancer translational medicine

    Sujit Nair

    2016-02-01

    Full Text Available Nivolumab, a fully human immunoglobulin G4 (IgG4 monoclonal antibody (mAb that targets the programmed cell death-1 (PD-1 inhibitory receptor expressed on lymphocytes and dendritic cells, has been approved for metastatic melanoma, advanced squamous non-small cell lung cancer (NSCLC and metastatic renal cell carcinoma. In this review, pharmacology and pharmacometrics systems of this immunopharmaceutical are discussed. Mechanistic actions of T-cell biology with respect to both “priming phase” (anti-cytotoxic T-lymphocyte associated antigen 4 (anti-CTLA-4 mAb; ipilimumab and “effector phase” (anti-PD-1 mAb; nivolumab was discussed, respectively. Key pharmacometric variables in anticancer efficacy of nivolumab such as target engagement, metabolism, pharmacology systems and clearance are elucidated with an emphasis on current knowledge from pre-clinical as well as phase 1, 2 and 3 clinical trials information, including the data presented at the American Society of Clinical Oncology (ASCO 2015 and European Cancer Congress 2015. Nivolumab biomarkers, safety, and synergistic combination immunotherapies are delineated. Nivolumab, administered via intravenous infusion, has an acceptable safety profile and good efficacy. Indeed, the way forward to leverage maximum benefits for the cancer patient may be to synergize anti-PD-1 blockade with complementary targets in immune checkpoint pathways or other oncogenic signal transduction pathways. The encouraging results with nivolumab lend credence to the promise of immune checkpoint blockade as a therapeutic strategy that has been come-of-age in clinical oncology. Of necessity, the burden of “financial toxicity” on cancer patients and families must be factored in considering nivolumab therapy. The problem of ligand PD-L1 being a weak biomarker in clinical practice was discussed. Appropriate patient selection methods including immunopharmacogenomics may be used to identify those patients who are most

  12. EFL Speech Production: Exploring the relationship between working memory capacity and proficiency level

    Gicele Vergine Vieira PREBIANCA

    2013-12-01

    Full Text Available The present study explores the relationship between working memory capacity (WMC and proficiency level in EFL1 speech production. Forty-one participants performed two WMC tests – the Speaking Span Test in L1 and in L2. The statistical analysis indicated both a variation on WMC scores in L2 as a function of proficiency as well as a difference between WMC scores in L1 and in L2. Findings are explained mainly in respect to the interplay between automatic and controlled processes on memory retrieval and on the development of L2 proficiency.

  13. Results of the Proficiency Test, PT1 and PT2, 2012

    Vendramin, Niccolò; Nicolajsen, Nicole; Christophersen, Maj-Britt

    A comparative test of diagnostic procedures was provided by the European Union Reference Laboratory (EURL) for Fish Diseases. The test was divided into proficiency test 1 (PT1) and proficiency test 2 (PT2). The number of National Reference Laboratories (NRLs) participating in PT1 and PT2 was 43. ....... The tests were sent from the EURL in the beginning of September 2012. Both PT1 and PT2 are accredited by DANAK under registration number 515 for proficiency testing according to the quality assurance standard DS/EN ISO/IEC 17043....

  14. The Interplay among Emotional Intelligence, Classroom Management, and Language Proficiency of Iranian EFL Teachers

    Hadi Hamidi

    2016-06-01

    Full Text Available The present study was an attempt to investigate the interplay among Iranian EFL teachers’ emotional intelligence, classroom management, and their general English language proficiency. The result of the data analysis showed that: 1 there was a statistically significant relationship between the emotional intelligence and the classroom management of Iranian EFL teachers, 2 there was a statistically significant relationship between the emotional intelligence and the language proficiency of Iranian EFL teachers, and 3 there was a statistically significant relationship between the classroom management and the language proficiency of Iranian EFL teachers. Teacher trainers, researchers in teacher education, and language teachers may benefit from the findings of the present research.

  15. EXPLORING THE RELATION OF STUDENTS’ LANGUAGE PROFICIENCY, ONLINE INSTRUCTOR GUIDANCE, AND ONLINE COLLABORATION WITH THEIR LEARNING IN HONG KONG BILINGUAL CYBER EDUCATION

    Simon Wong

    2015-12-01

    Full Text Available This research study adopted a quantitative approach to explore how the variables, namely student’s English proficiency, online instructor guidance, and online collaboration, influence the learning effectiveness of the students taking an online introductory information technology course in cyber education in a bilingual higher education institution in Hong Kong. This study is important for cyber education administrators, as it investigated the important pedagogical quality of cyber education. Correlation analysis was conducted to identify whether any of these variables collected from the survey could be associated with students’ online learning while multiple regression analysis was used to explore the combined effect of these variables on students’ online learning. Validity and reliability of this study are highlighted in this paper. The major findings in this study revealed that (1 the students’ English proficiency, online instructor guidance, and online collaboration are potential factors contributing to the students’ online learning, and (2 the students’ English proficiency has the largest effect while online instructor guidance and online collaboration have a moderate effect on the students’ online learning.

  16. Immune Checkpoint Inhibitor-Associated Type 1 Diabetes Mellitus: Case Series, Review of the Literature, and Optimal Management

    Kapke, Jonathan; Shaheen, Zachary; Kilari, Deepak; Knudson, Paul; Wong, Stuart

    2017-01-01

    With the introduction of immune checkpoint inhibitors into clinical practice, various autoimmune toxicities have been described. Antibodies targeting the receptor:ligand pairing of programmed death receptor-1 (PD-1) and its cognate ligand programmed death-ligand 1 (PD-L1) in rare reports have been associated with autoimmune diabetes mellitus. We report 2 cases of rapid-onset, insulin-dependent, type 1 diabetes mellitus in the setting of administration of nivolumab, a fully human monoclonal an...

  17. Direct and indirect control of the initiation of meiotic recombination by DNA damage checkpoint mechanisms in budding yeast.

    Bilge Argunhan

    Full Text Available Meiotic recombination plays an essential role in the proper segregation of chromosomes at meiosis I in many sexually reproducing organisms. Meiotic recombination is initiated by the scheduled formation of genome-wide DNA double-strand breaks (DSBs. The timing of DSB formation is strictly controlled because unscheduled DSB formation is detrimental to genome integrity. Here, we investigated the role of DNA damage checkpoint mechanisms in the control of meiotic DSB formation using budding yeast. By using recombination defective mutants in which meiotic DSBs are not repaired, the effect of DNA damage checkpoint mutations on DSB formation was evaluated. The Tel1 (ATM pathway mainly responds to unresected DSB ends, thus the sae2 mutant background in which DSB ends remain intact was employed. On the other hand, the Mec1 (ATR pathway is primarily used when DSB ends are resected, thus the rad51 dmc1 double mutant background was employed in which highly resected DSBs accumulate. In order to separate the effect caused by unscheduled cell cycle progression, which is often associated with DNA damage checkpoint defects, we also employed the ndt80 mutation which permanently arrests the meiotic cell cycle at prophase I. In the absence of Tel1, DSB formation was reduced in larger chromosomes (IV, VII, II and XI whereas no significant reduction was found in smaller chromosomes (III and VI. On the other hand, the absence of Rad17 (a critical component of the ATR pathway lead to an increase in DSB formation (chromosomes VII and II were tested. We propose that, within prophase I, the Tel1 pathway facilitates DSB formation, especially in bigger chromosomes, while the Mec1 pathway negatively regulates DSB formation. We also identified prophase I exit, which is under the control of the DNA damage checkpoint machinery, to be a critical event associated with down-regulating meiotic DSB formation.

  18. The Robust Running Ape: Unraveling the Deep Underpinnings of Coordinated Human Running Proficiency

    John Kiely

    2017-06-01

    Full Text Available In comparison to other mammals, humans are not especially strong, swift or supple. Nevertheless, despite these apparent physical limitations, we are among Natures most superbly well-adapted endurance runners. Paradoxically, however, notwithstanding this evolutionary-bestowed proficiency, running-related injuries, and Overuse syndromes in particular, are widely pervasive. The term ‘coordination’ is similarly ubiquitous within contemporary coaching, conditioning, and rehabilitation cultures. Various theoretical models of coordination exist within the academic literature. However, the specific neural and biological underpinnings of ‘running coordination,’ and the nature of their integration, remain poorly elaborated. Conventionally running is considered a mundane, readily mastered coordination skill. This illusion of coordinative simplicity, however, is founded upon a platform of immense neural and biological complexities. This extensive complexity presents extreme organizational difficulties yet, simultaneously, provides a multiplicity of viable pathways through which the computational and mechanical burden of running can be proficiently dispersed amongst expanded networks of conditioned neural and peripheral tissue collaborators. Learning to adequately harness this available complexity, however, is a painstakingly slowly emerging, practice-driven process, greatly facilitated by innate evolutionary organizing principles serving to constrain otherwise overwhelming complexity to manageable proportions. As we accumulate running experiences persistent plastic remodeling customizes networked neural connectivity and biological tissue properties to best fit our unique neural and architectural idiosyncrasies, and personal histories: thus neural and peripheral tissue plasticity embeds coordination habits. When, however, coordinative processes are compromised—under the integrated influence of fatigue and/or accumulative cycles of injury, overuse

  19. The effect of tributyltin chloride on Caenorhabditis elegans germline is mediated by a conserved DNA damage checkpoint pathway.

    Cheng, Zhe; Tian, Huimin; Chu, Hongran; Wu, Jianjian; Li, Yingying; Wang, Yanhai

    2014-03-21

    Tributyltin (TBT), one of the environmental pollutants, has been shown to impact the reproduction of animals. However, due to the lack of appropriate animal model, analysis of the affected molecular pathways in germ cells is lagging and has been particularly challenging. In the present study, we investigated the effects of tributyltin chloride (TBTCL) on the nematode Caenorhabditis elegans germline. We show that exposure of C. elegans to TBTCL causes significantly elevated level of sterility and embryonic lethality. TBTCL exposure results in an increased number of meiotic DNA double-strand breaks in germ cells, subsequently leading to activated DNA damage checkpoint. Exposing C. elegans to TBTCL causes dose- and time-dependent germline apoptosis. This apoptotic response was blocked in loss-of-function mutants of hus-1 (op241), mrt-2 (e2663) and p53/cep-1 (gk138), indicating that checkpoints and p53 are essential for mediating TBTCL-induced germ cell apoptosis. Moreover, TBTCL exposure can inhibit germ cell proliferation, which is also mediated by the conserved checkpoint pathway. We thereby propose that TBT exhibits its effects on the germline by inducing DNA damage and impaired maintenance of genomic integrity. Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  20. The tumor suppressor homolog in fission yeast, myh1+, displays a strong interaction with the checkpoint gene rad1+

    Jansson, Kristina; Warringer, Jonas; Farewell, Anne; Park, Han-Oh; Hoe, Kwang-Lae; Kim, Dong-Uk; Hayles, Jacqueline; Sunnerhagen, Per

    2008-01-01

    The DNA glycosylase MutY is strongly conserved in evolution, and homologs are found in most eukaryotes and prokaryotes examined. This protein is implicated in repair of oxidative DNA damage, in particular adenine mispaired opposite 7,8-dihydro-8-oxoguanine. Previous investigations in Escherichia coli, fission yeast, and mammalian cells show an association of mutations in MutY homologs with a mutator phenotype and carcinogenesis. Eukaryotic MutY homologs physically associate with several proteins with a role in replication, DNA repair, and checkpoint signaling, specifically the trimeric 9-1-1 complex. In a genetic investigation of the fission yeast MutY homolog, myh1 + , we show that the myh1 mutation confers a moderately increased UV sensitivity alone and in combination with mutations in several DNA repair genes. The myh1 rad1, and to a lesser degree myh1 rad9, double mutants display a synthetic interaction resulting in enhanced sensitivity to DNA damaging agents and hydroxyurea. UV irradiation of myh1 rad1 double mutants results in severe chromosome segregation defects and visible DNA fragmentation, and a failure to activate the checkpoint. Additionally, myh1 rad1 double mutants exhibit morphological defects in the absence of DNA damaging agents. We also found a moderate suppression of the slow growth and UV sensitivity of rhp51 mutants by the myh1 mutation. Our results implicate fission yeast Myh1 in repair of a wider range of DNA damage than previously thought, and functionally link it to the checkpoint pathway

  1. The internal Cdc20 binding site in BubR1 facilitates both spindle assembly checkpoint signalling and silencing

    Lischetti, Tiziana; Zhang, Gang; Sedgwick, Garry G

    2014-01-01

    Improperly attached kinetochores activate the spindle assembly checkpoint (SAC) and by an unknown mechanism catalyse the binding of two checkpoint proteins, Mad2 and BubR1, to Cdc20 forming the mitotic checkpoint complex (MCC). Here, to address the functional role of Cdc20 kinetochore localization...... in the SAC, we delineate the molecular details of its interaction with kinetochores. We find that BubR1 recruits the bulk of Cdc20 to kinetochores through its internal Cdc20 binding domain (IC20BD). We show that preventing Cdc20 kinetochore localization by removal of the IC20BD has a limited effect...... on the SAC because the IC20BD is also required for efficient SAC silencing. Indeed, the IC20BD can disrupt the MCC providing a mechanism for its role in SAC silencing. We thus uncover an unexpected dual function of the second Cdc20 binding site in BubR1 in promoting both efficient SAC signalling and SAC...

  2. Why do some countries publish more than others? An international comparison of research funding, English proficiency and publication output in highly ranked general medical journals.

    Man, Jonathan P; Weinkauf, Justin G; Tsang, Monica; Sin, Don D

    2004-01-01

    National factor(s) influencing publication output in the highest ranked medical journals are largely unknown. We sought to examine the relationship between national research funding and English proficiency on publication output. We identified all original research articles appearing in the five highest ranked general medical journals between 1997 and 2001. Using the country of the corresponding author as the source nation for each article, we determined a standardized publication rate across developed nations. We used multiple regression techniques to determine the influence of national expenditures on research and scores from the Test of English as a Foreign Language (TOEFL), a surrogate for English proficiency, on publication output. There was a significant relationship of national spending on research and TOEFL scores to publication output of developed countries (p = 0.04; p < 0.01, respectively). These two variables explained approximately 71.5% of the variation in publication rate across developed nations around the world (R = 0.85; p < 0.01). Normalized for population size, English-speaking nations and certain northern European countries such as Denmark, The Netherlands, Switzerland, and Sweden had the highest rate of publication in the five highest ranked general medical journals, while Asian countries had generally low rates of publication. Research spending and English proficiency were strongly associated with publication output in the highest ranked general medical journals. While these data cannot be considered definitive due to their observational nature, they do suggest that for English-language medical journals, research funding and English proficiency may be important determinants of publication.

  3. The Spindle Assembly Checkpoint in Arabidopsis Is Rapidly Shut Off during Severe Stress.

    Komaki, Shinichiro; Schnittger, Arp

    2017-10-23

    The spindle assembly checkpoint (SAC) in animals and yeast assures equal segregation of chromosomes during cell division. The prevalent occurrence of polyploidy in flowering plants together with the observation that many plants can be readily forced to double their genomes by application of microtubule drugs raises the question of whether plants have a proper SAC. Here, we provide a functional framework of the core SAC proteins in Arabidopsis. We reveal that Arabidopsis will delay mitosis in a SAC-dependent manner if the spindle is perturbed. However, we also show that the molecular architecture of the SAC is unique in plants. Moreover, the SAC is short-lived and cannot stay active for more than 2 hr, after which the cell cycle is reset. This resetting opens the possibility for genome duplications and raises the hypothesis that a rapid termination of a SAC-induced mitotic arrest provides an adaptive advantage for plants impacting plant genome evolution. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Morphogenesis checkpoint kinase Swe1 is the executor of lipolysis-dependent cell-cycle progression.

    Chauhan, Neha; Visram, Myriam; Cristobal-Sarramian, Alvaro; Sarkleti, Florian; Kohlwein, Sepp D

    2015-03-10

    Cell growth and division requires the precise duplication of cellular DNA content but also of membranes and organelles. Knowledge about the cell-cycle-dependent regulation of membrane and storage lipid homeostasis is only rudimentary. Previous work from our laboratory has shown that the breakdown of triacylglycerols (TGs) is regulated in a cell-cycle-dependent manner, by activation of the Tgl4 lipase by the major cyclin-dependent kinase Cdc28. The lipases Tgl3 and Tgl4 are required for efficient cell-cycle progression during the G1/S (Gap1/replication phase) transition, at the onset of bud formation, and their absence leads to a cell-cycle delay. We now show that defective lipolysis activates the Swe1 morphogenesis checkpoint kinase that halts cell-cycle progression by phosphorylation of Cdc28 at tyrosine residue 19. Saturated long-chain fatty acids and phytosphingosine supplementation rescue the cell-cycle delay in the Tgl3/Tgl4 lipase-deficient strain, suggesting that Swe1 activity responds to imbalanced sphingolipid metabolism, in the absence of TG degradation. We propose a model by which TG-derived sphingolipids are required to activate the protein phosphatase 2A (PP2A(Cdc55)) to attenuate Swe1 phosphorylation and its inhibitory effect on Cdc28 at the G1/S transition of the cell cycle.

  5. Evaluation of response to immune checkpoint inhibitors: Is there a role for positron emission tomography?

    Matteo Bauckneht; Roberta Piva; Gianmario Sambuceti; Francesco Grossi; Silvia Morbelli

    2017-01-01

    Strategies targeting intracellular negative regulators such as immune checkpoint inhibitors(ICPIs) have demonstrated significant antitumor activity across a wide range of solid tumors. In the clinical practice, the radiological effect of immunotherapeutic agents has raised several more relevant and complex challenges for the determination of their imaging-based response at single patient level. Accordingly, it has been suggested that the conventional Response Evaluation Criteria in Solid Tumors assessment alone, based on dimensional evaluation provided by computed tomography(CT), tends to underestimate the benefit of ICPIs at least in a subset of patients, supporting the need of immunerelated response criteria. Different from CT, very few data are available for the evaluation of immunotherapy by means of 18F-fluoro-2-deoxy-D-glucose positron emission tomography(FDG-PET). Moreover, since the antineoplastic activity of ICPIs is highly related to the activation of T cells against cancer cells, FDG accumulation might cause false-positive findings. Yet, discrimination between benign and malignant processes represents a huge challenge for FDG-PET in this clinical setting. Consequently, it might be of high interest to test the complex and variegated response to ICPIs by means of PET and thus it is worthwhile to ask if a similar introduction of immune-related PET-based criteria could be proposed in the future. Finally, PET might offer a new insight into the biology and pathophysiology of ICPIs thanks to a growing number of non-invasive immunediagnostic approaches based on non-FDG tracers.

  6. Checkpoint Kinase 1 Expression Predicts Poor Prognosis in Nigerian Breast Cancer Patients.

    Ebili, Henry Okuchukwu; Iyawe, Victoria O; Adeleke, Kikelomo Rachel; Salami, Babatunde Abayomi; Banjo, Adekunbiola Aina; Nolan, Chris; Rakha, Emad; Ellis, Ian; Green, Andrew; Agboola, Ayodeji Olayinka Johnson

    2018-02-01

    Checkpoint kinase 1 (CHEK1), a DNA damage sensor and cell death pathway stimulator, is regarded as an oncogene in tumours, where its activities are considered essential for tumourigenesis and the survival of cancer cells treated with chemotherapy and radiotherapy. In breast cancer, CHEK1 expression has been associated with an aggressive tumour phenotype, the triple-negative breast cancer subtype, an aberrant response to tamoxifen, and poor prognosis. However, the relevance of CHEK1 expression has, hitherto, not been investigated in an indigenous African population. We therefore aimed to investigate the clinicopathological, biological, and prognostic significance of CHEK1 expression in a cohort of Nigerian breast cancer cases. Tissue microarrays of 207 Nigerian breast cancer cases were tested for CHEK1 expression using immunohistochemistry. The clinicopathological, molecular, and prognostic characteristics of CHEK1-positive tumours were determined using the Chi-squared test and Kaplan-Meier and Cox regression analyses in SPSS Version 16. Nuclear expression of CHEK1 was present in 61% of breast tumours and was associated with tumour size, triple-negative cancer, basal-like phenotype, the epithelial-mesenchymal transition, p53 over-expression, DNA homologous repair pathway dysfunction, and poor prognosis. The rate expression of CHEK1 is high in Nigerian breast cancer cases and is associated with an aggressive phenotype and poor prognosis.

  7. Inhibition of CDK7 bypasses spindle assembly checkpoint via premature cyclin B degradation during oocyte meiosis.

    Wang, HaiYang; Jo, Yu-Jin; Sun, Tian-Yi; Namgoong, Suk; Cui, Xiang-Shun; Oh, Jeong Su; Kim, Nam-Hyung

    2016-12-01

    To ensure accurate chromosome segregation, the spindle assembly checkpoint (SAC) delays anaphase onset by preventing the premature activation of anaphase-promoting complex/cyclosome (APC/C) until all kinetochores are attached to the spindle. Although an escape from mitosis in the presence of unsatisfied SAC has been shown in several cancer cells, it has not been reported in oocyte meiosis. Here, we show that CDK7 activity is required to prevent a bypass of SAC during meiosis I in mouse oocytes. Inhibition of CDK7 using THZ1 accelerated the first meiosis, leading to chromosome misalignment, lag of chromosomes during chromosome segregation, and a high incidence of aneuploidy. Notably, this acceleration occurred in the presence of SAC proteins including Mad2 and Bub3 at the kinetochores. However, inhibition of APC/C-mediated cyclin B degradation blocked the THZ1-induced premature polar body extrusion. Moreover, chromosomal defects mediated by THZ1 were rescued when anaphase onset was delayed. Collectively, our results show that CDK7 activity is required to prevent premature anaphase onset by suppressing the bypass of SAC, thus ensuring chromosome alignment and proper segregation. These findings reveal new roles of CDK7 in the regulation of meiosis in mammalian oocytes. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Arabidopsis pdr2 reveals a phosphate-sensitive checkpoint in root development.

    Ticconi, Carla A; Delatorre, Carla A; Lahner, Brett; Salt, David E; Abel, Steffen

    2004-03-01

    Plants have evolved complex strategies to maintain phosphate (Pi) homeostasis and to maximize Pi acquisition when the macronutrient is limiting. Adjustment of root system architecture via changes in meristem initiation and activity is integral to the acclimation process. However, the mechanisms that monitor external Pi status and interpret the nutritional signal remain to be elucidated. Here, we present evidence that the Pi deficiency response, pdr2, mutation disrupts local Pi sensing. The sensitivity and amplitude of metabolic Pi-starvation responses, such as Pi-responsive gene expression or accumulation of anthocyanins and starch, are enhanced in pdr2 seedlings. However, the most conspicuous alteration of pdr2 is a conditional short-root phenotype that is specific for Pi deficiency and caused by selective inhibition of root cell division followed by cell death below a threshold concentration of about 0.1 mm external Pi. Measurements of general Pi uptake and of total phosphorus (P) in root tips exclude a defect in high-affinity Pi acquisition. Rescue of root meristem activity in Pi-starved pdr2 by phosphite (Phi), a non-metabolizable Pi analog, and divided-root experiments suggest that pdr2 disrupts sensing of low external Pi availability. Thus, PDR2 is proposed to function at a Pi-sensitive checkpoint in root development, which monitors environmental Pi status, maintains and fine-tunes meristematic activity, and finally adjusts root system architecture to maximize Pi acquisition.

  9. Centromeric DNA replication reconstitution reveals DNA loops and ATR checkpoint suppression.

    Aze, Antoine; Sannino, Vincenzo; Soffientini, Paolo; Bachi, Angela; Costanzo, Vincenzo

    2016-06-01

    Half of the human genome is made up of repetitive DNA. However, mechanisms underlying replication of chromosome regions containing repetitive DNA are poorly understood. We reconstituted replication of defined human chromosome segments using bacterial artificial chromosomes in Xenopus laevis egg extract. Using this approach we characterized the chromatin assembly and replication dynamics of centromeric alpha-satellite DNA. Proteomic analysis of centromeric chromatin revealed replication-dependent enrichment of a network of DNA repair factors including the MSH2-6 complex, which was required for efficient centromeric DNA replication. However, contrary to expectations, the ATR-dependent checkpoint monitoring DNA replication fork arrest could not be activated on highly repetitive DNA due to the inability of the single-stranded DNA binding protein RPA to accumulate on chromatin. Electron microscopy of centromeric DNA and supercoil mapping revealed the presence of topoisomerase I-dependent DNA loops embedded in a protein matrix enriched for SMC2-4 proteins. This arrangement suppressed ATR signalling by preventing RPA hyper-loading, facilitating replication of centromeric DNA. These findings have important implications for our understanding of repetitive DNA metabolism and centromere organization under normal and stressful conditions.

  10. Akt Kinase-Mediated Checkpoint of cGAS DNA Sensing Pathway

    Gil Ju Seo

    2015-10-01

    Full Text Available Upon DNA stimulation, cyclic GMP-AMP synthase (cGAS synthesizes the second messenger cyclic GMP-AMP (cGAMP that binds to the STING, triggering antiviral interferon-β (IFN-β production. However, it has remained undetermined how hosts regulate cGAS enzymatic activity after the resolution of DNA immunogen. Here, we show that Akt kinase plays a negative role in cGAS-mediated anti-viral immune response. Akt phosphorylated the S291 or S305 residue of the enzymatic domain of mouse or human cGAS, respectively, and this phosphorylation robustly suppressed its enzymatic activity. Consequently, expression of activated Akt led to the reduction of cGAMP and IFN-β production and the increase of herpes simplex virus 1 replication, whereas treatment with Akt inhibitor augmented cGAS-mediated IFN-β production. Furthermore, expression of the phosphorylation-resistant cGAS S291A mutant enhanced IFN-β production upon DNA stimulation, HSV-1 infection, and vaccinia virus infection. Our study identifies an Akt kinase-mediated checkpoint to fine-tune hosts’ immune responses to DNA stimulation.

  11. Akt Kinase-Mediated Checkpoint of cGAS DNA Sensing Pathway.

    Seo, Gil Ju; Yang, Aerin; Tan, Brandon; Kim, Sungyoon; Liang, Qiming; Choi, Younho; Yuan, Weiming; Feng, Pinghui; Park, Hee-Sung; Jung, Jae U

    2015-10-13

    Upon DNA stimulation, cyclic GMP-AMP synthase (cGAS) synthesizes the second messenger cyclic GMP-AMP (cGAMP) that binds to the STING, triggering antiviral interferon-β (IFN-β) production. However, it has remained undetermined how hosts regulate cGAS enzymatic activity after the resolution of DNA immunogen. Here, we show that Akt kinase plays a negative role in cGAS-mediated anti-viral immune response. Akt phosphorylated the S291 or S305 residue of the enzymatic domain of mouse or human cGAS, respectively, and this phosphorylation robustly suppressed its enzymatic activity. Consequently, expression of activated Akt led to the reduction of cGAMP and IFN-β production and the increase of herpes simplex virus 1 replication, whereas treatment with Akt inhibitor augmented cGAS-mediated IFN-β production. Furthermore, expression of the phosphorylation-resistant cGAS S291A mutant enhanced IFN-β production upon DNA stimulation, HSV-1 infection, and vaccinia virus infection. Our study identifies an Akt kinase-mediated checkpoint to fine-tune hosts' immune responses to DNA stimulation. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  12. Inhibition of checkpoint kinase 1 sensitizes lung cancer brain metastases to radiotherapy

    Yang, Heekyoung; Yoon, Su Jin; Jin, Juyoun; Choi, Seung Ho; Seol, Ho Jun; Lee, Jung-Il

    2011-01-01

    Research highlights: → The most important therapeutic tool in brain metastasis is radiation therapy. → Radiosensitivity of cancer cells was enhanced with treatment of Chk1 inhibitor. → Depletion of Chk1 in cancer cells showed an enhancement of sensitivity to radiation. → Chk1 can be a good target for enhancement of radiosensitivity. -- Abstract: The most important therapeutic tool in brain metastasis is radiation therapy. However, resistance to radiation is a possible cause of recurrence or treatment failure. Recently, signal pathways about DNA damage checkpoints after irradiation have been noticed. We investigated the radiosensitivity can be enhanced with treatment of Chk1 inhibitor, AZD7762 in lung cancer cell lines and xenograft models of lung cancer brain metastasis. Clonogenic survival assays showed enhancement of radiosensitivity with AZD7762 after irradiation of various doses. AZD7762 increased ATR/ATM-mediated Chk1 phosphorylation and stabilized Cdc25A, suppressed cyclin A expression in lung cancer cell lines. In xenograft models of lung cancer (PC14PE6) brain metastasis, AZD7762 significantly prolonged the median survival time in response to radiation. Depletion of Chk1 using shRNA also showed an enhancement of sensitivity to radiation in PC14PE6 cells. The results of this study support that Chk1 can be a good target for enhancement of radiosensitivity.

  13. Dietary flavonoid fisetin induces a forced exit from mitosis by targeting the mitotic spindle checkpoint

    Salmela, Anna-Leena; Pouwels, Jeroen; Varis, Asta; Kukkonen, Anu M.; Toivonen, Pauliina; Halonen, Pasi K.; Perälä, Merja; Kallioniemi, Olli; Gorbsky, Gary J.; Kallio, Marko J.

    2009-01-01

    Fisetin is a natural flavonol present in edible vegetables, fruits and wine at 2–160 μg/g concentrations and an ingredient in nutritional supplements with much higher concentrations. The compound has been reported to exert anticarcinogenic effects as well as antioxidant and anti-inflammatory activity via its ability to act as an inhibitor of cell proliferation and free radical scavenger, respectively. Our cell-based high-throughput screen for small molecules that override chemically induced mitotic arrest identified fisetin as an antimitotic compound. Fisetin rapidly compromised microtubule drug-induced mitotic block in a proteasome-dependent manner in several human cell lines. Moreover, in unperturbed human cancer cells fisetin caused premature initiation of chromosome segregation and exit from mitosis without normal cytokinesis. To understand the molecular mechanism behind these mitotic errors, we analyzed the consequences of fisetin treatment on the localization and phoshorylation of several mitotic proteins. Aurora B, Bub1, BubR1 and Cenp-F rapidly lost their kinetochore/centromere localization and others became dephosphorylated upon addition of fisetin to the culture medium. Finally, we identified Aurora B kinase as a novel direct target of fisetin. The activity of Aurora B was significantly reduced by fisetin in vitro and in cells, an effect that can explain the observed forced mitotic exit, failure of cytokinesis and decreased cell viability. In conclusion, our data propose that fisetin perturbs spindle checkpoint signaling, which may contribute to the antiproliferative effects of the compound. PMID:19395653

  14. Dual personality of Mad1: regulation of nuclear import by a spindle assembly checkpoint protein.

    Cairo, Lucas V; Ptak, Christopher; Wozniak, Richard W

    2013-01-01

    Nuclear transport is a dynamic process that can be modulated in response to changes in cellular physiology. We recently reported that the transport activity of yeast nuclear pore complexes (NPCs) is altered in response to kinetochore-microtubule (KT-MT) interaction defects. Specifically, KT detachment from MTs activates a signaling pathway that prevents the nuclear import of cargos by the nuclear transport factor Kap121p. This loss of Kap121p-mediated import is thought to influence the nuclear environment, including the phosphorylation state of nuclear proteins. A key regulator of this process is the spindle assembly checkpoint protein Mad1p. In response to unattached KTs, Mad1p dynamically cycles between NPCs and KTs. This cycling appears to induce NPC molecular rearrangements that prevent the nuclear import of Kap121p-cargo complexes. Here, we discuss the underlying mechanisms and the physiological relevance of Mad1p cycling and the inhibition of Kap121p-mediated nuclear import, focusing on outstanding questions within the pathway.

  15. The bacterial cell cycle checkpoint protein Obg and its role in programmed cell death

    Liselot Dewachter

    2016-03-01

    Full Text Available The phenomenon of programmed cell death (PCD, in which cells initiate their own demise, is not restricted to multicellular organisms. Unicellular organisms, both eukaryotes and prokaryotes, also possess pathways that mediate PCD. We recently identified a PCD mechanism in Escherichia coli that is triggered by a mutant isoform of the essential GTPase ObgE (Obg of E. coli. Importantly, the PCD pathway mediated by mutant Obg (Obg* differs fundamentally from other previously described bacterial PCD pathways and thus constitutes a new mode of PCD. ObgE was previously proposed to act as a cell cycle checkpoint protein able to halt cell division. The implication of ObgE in the regulation of PCD further increases the similarity between this protein and eukaryotic cell cycle regulators that are capable of doing both. Moreover, since Obg is conserved in eukaryotes, the elucidation of this cell death mechanism might contribute to the understanding of PCD in higher organisms. Additionally, if Obg*-mediated PCD is conserved among different bacterial species, it will be a prime target for the development of innovative antibacterials that artificially induce this pathway.

  16. Optimising measles virus-guided radiovirotherapy with external beam radiotherapy and specific checkpoint kinase 1 inhibition

    Touchefeu, Yann; Khan, Aadil A.; Borst, Gerben; Zaidi, Shane H.; McLaughlin, Martin; Roulstone, Victoria; Mansfield, David; Kyula, Joan; Pencavel, Tim; Karapanagiotou, Eleni M.; Clayton, Jamie; Federspiel, Mark J.; Russell, Steve J.; Garrett, Michelle; Collins, Ian; Harrington, Kevin J.

    2013-01-01

    Background and purpose: We previously reported a therapeutic strategy comprising replication-defective NIS-expressing adenovirus combined with radioiodide, external beam radiotherapy (EBRT) and DNA repair inhibition. We have now evaluated NIS-expressing oncolytic measles virus (MV-NIS) combined with NIS-guided radioiodide, EBRT and specific checkpoint kinase 1 (Chk1) inhibition in head and neck and colorectal models. Materials and methods: Anti-proliferative/cytotoxic effects of individual agents and their combinations were measured by MTS, clonogenic and Western analysis. Viral gene expression was measured by radioisotope uptake and replication by one-step growth curves. Potential synergistic interactions were tested in vitro by Bliss independence analysis and in in vivo therapeutic studies. Results: EBRT and MV-NIS were synergistic in vitro. Furthermore, EBRT increased NIS expression in infected cells. SAR-020106 was synergistic with EBRT, but also with MV-NIS in HN5 cells. MV-NIS mediated 131 I-induced cytotoxicity in HN5 and HCT116 cells and, in the latter, this was enhanced by SAR-020106. In vivo studies confirmed that MV-NIS, EBRT and Chk1 inhibition were effective in HCT116 xenografts. The quadruplet regimen of MV-NIS, virally-directed 131 I, EBRT and SAR-020106 had significant anti-tumour activity in HCT116 xenografts. Conclusion: This study strongly supports translational and clinical research on MV-NIS combined with radiation therapy and radiosensitising agents

  17. Drosophila Polo regulates the spindle assembly checkpoint through Mps1-dependent BubR1 phosphorylation.

    Conde, Carlos; Osswald, Mariana; Barbosa, João; Moutinho-Santos, Tatiana; Pinheiro, Diana; Guimarães, Sofia; Matos, Irina; Maiato, Helder; Sunkel, Claudio E

    2013-06-12

    Maintenance of genomic stability during eukaryotic cell division relies on the spindle assembly checkpoint (SAC) that prevents mitotic exit until all chromosomes are properly attached to the spindle. Polo is a mitotic kinase proposed to be involved in SAC function, but its role has remained elusive. We demonstrate that Polo and Aurora B functional interdependency comprises a positive feedback loop that promotes Mps1 kinetochore localization and activity. Expression of constitutively active Polo restores normal Mps1 kinetochore levels even after Aurora B inhibition, highlighting a role for Polo in Mps1 recruitment to unattached kinetochores downstream of Aurora B. We also show that Mps1 kinetochore localization is required for BubR1 hyperphosphorylation and formation of the 3F3/2 phosphoepitope. This is essential to allow recruitment of Cdc20 to unattached kinetochores and the assembly of anaphase-promoting complex/cyclosome-inhibitory complexes to levels that ensure long-term SAC activity. We propose a model in which Polo controls Mps1-dependent BubR1 phosphorylation to promote Cdc20 kinetochore recruitment and sustained SAC function.

  18. Early programming and late-acting checkpoints governing the development of CD4 T cell memory.

    Dhume, Kunal; McKinstry, K Kai

    2018-04-27

    CD4 T cells contribute to protection against pathogens through numerous mechanisms. Incorporating the goal of memory CD4 T cell generation into vaccine strategies thus offers a powerful approach to improve their efficacy, especially in situations where humoral responses alone cannot confer long-term immunity. These threats include viruses such as influenza that mutate coat proteins to avoid neutralizing antibodies, but that are targeted by T cells that recognize more conserved protein epitopes shared by different strains. A major barrier in the design of such vaccines is that the mechanisms controlling the efficiency with which memory cells form remain incompletely understood. Here, we discuss recent insights into fate decisions controlling memory generation. We focus on the importance of three general cues: interleukin-2, antigen, and costimulatory interactions. It is increasingly clear that these signals have a powerful influence on the capacity of CD4 T cells to form memory during two distinct phases of the immune response. First, through 'programming' that occurs during initial priming, and second, through 'checkpoints' that operate later during the effector stage. These findings indicate that novel vaccine strategies must seek to optimize cognate interactions, during which interleukin-2-, antigen, and costimulation-dependent signals are tightly linked, well beyond initial antigen encounter to induce robust memory CD4 T cells. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  19. Checkpoint Kinase Rad53 Couples Leading- and Lagging-Strand DNA Synthesis under Replication Stress.

    Gan, Haiyun; Yu, Chuanhe; Devbhandari, Sujan; Sharma, Sushma; Han, Junhong; Chabes, Andrei; Remus, Dirk; Zhang, Zhiguo

    2017-10-19

    The checkpoint kinase Rad53 is activated during replication stress to prevent fork collapse, an essential but poorly understood process. Here we show that Rad53 couples leading- and lagging-strand synthesis under replication stress. In rad53-1 cells stressed by dNTP depletion, the replicative DNA helicase, MCM, and the leading-strand DNA polymerase, Pol ε, move beyond the site of DNA synthesis, likely unwinding template DNA. Remarkably, DNA synthesis progresses further along the lagging strand than the leading strand, resulting in the exposure of long stretches of single-stranded leading-strand template. The asymmetric DNA synthesis in rad53-1 cells is suppressed by elevated levels of dNTPs in vivo, and the activity of Pol ε is compromised more than lagging-strand polymerase Pol δ at low dNTP concentrations in vitro. Therefore, we propose that Rad53 prevents the generation of excessive ssDNA under replication stress by coordinating DNA unwinding with synthesis of both strands. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. G2 checkpoint abrogator abates the antagonistic interaction between antimicrotubule drugs and radiation therapy

    Sui Meihua; Zhang Hongfang; Di Xiaoyun; Chang Jinjia; Shen Youqing; Fan Weimin

    2012-01-01

    Background and purpose: We previously demonstrated that radiation may arrest tumor cells at G2 phase, which in turn prevents the cytotoxicity of antimicrotubule drugs and results in antagonistic interaction between these two modalities. Herein we tested whether G2 abrogators would attenuate the above antagonistic interaction and improve the therapeutic efficacy of combination therapy between radiation and antimicrotubule drugs. Materials and methods: Breast cancer BCap37 and epidermoid carcinoma KB cell lines were administered with radiation, UCN-01 (a model drug of G2 abrogator), paclitaxel or vincristine, alone or in combinations. The antitumor activities of single and combined treatments were analyzed by a series of cytotoxic, apoptotic, cell cycle, morphological and biochemical assays. Results: UCN-01 significantly enhanced the cytotoxicity of radiation, antimitotic drugs, and their combined treatments in vitro. Further investigations demonstrated that UCN-01 attenuated radiation-induced G2 arrest, and subsequently repressed the inhibitory effect of radiation on drug-induced mitotic arrest and apoptosis. Conclusions: This is the first report demonstrating that G2 checkpoint abrogation represses the inhibitory effect of radiation on antimicrotubule drugs, which may be implicated in cancer combination therapy. Considering that G2 abrogators are under extensive evaluation for cancer treatment, our findings provide valuable information for this class of promising compounds.

  1. Online Assessment of Oral Proficiency for Intercultural Professional Communication: An introduction

    Rusman, Ellen; Stoyanov, Slavi

    2012-01-01

    Rusman, E., & Stoyanov, S. (2011). Online Assessment of Oral Proficiency for Intercultural Professional Communication: An introduction. Presentation about the CEFcult project (www.cefcult.eu) as an introduction to various personal interviews held with stakeholders, Heerlen, The Netherlands: Open

  2. Chinese ESL Students' Learning Strategies: A Look at Frequency, Proficiency, and Gender.

    Foong, Kwah Poh; Goh, Christine C. M.

    1997-01-01

    Examines the learning strategies of English-as-Second-Language students in the People's Republic of China. Surveyed the frequency of strategy use to determine how it is influenced by learners' proficiency level and gender. (Author/VWL)

  3. Five year results of an international proficiency testing programme for measurement of antifungal drug concentrations

    Lempers, V.J.C.; Alffenaar, J.W.C.; Touw, D.J.; Burger, D.M.; Uges, D.R.A.; Aarnoutse, R.E.; Brüggemann, R.J.M.

    2014-01-01

    OBJECTIVES: Since 2007 the Dutch Association for Quality Assessment in Therapeutic Drug Monitoring (KKGT) has organized an international interlaboratory proficiency testing (PT) programme for measurement of antifungal drugs in plasma. We describe the 5 year results of the laboratories' performance.

  4. Paris Chamber of Commerce Examinations and ACTFL/ETS Proficiency Levels.

    Cummins, Patricia W.

    1987-01-01

    Compares the Paris Chamber of Commerce Exams (both certificate and diploma levels) and the ACTFL Guidelines for language proficiency for the benefit of language teachers. Teaching strategies are suggested for preparing students for the Chamber of Commerce exams. (LMO)

  5. TEST OF ENGLISH FOR AVIATION PERSONNEL TO MEET ICAO LANGUAGE PROFICIENCY REQUIREMENTS

    Olena Petrashchuk

    2012-10-01

    Full Text Available  The article is devoted to the actual problem of the assessment of English language proficiency of aviation personnel. The paper presents an English language test, which is used for professional pilots and air traffic controllers.

  6. PROFICIENCY IN ENGLISH AND CAREER OPPORTUNITIES IN THE LABOUR MARKET

    SIMION MINODORA OTILIA

    2013-08-01

    Full Text Available The technological development, the growing economic globalization and the majordemographic shifts have brought about the need for a global language. In international business, travel, scienceand technology, education, immigration, academia, diplomacy and entertainment, English is the dominantlanguage, being spoken by over one billion people. English is used inside and outside the professionalenvironment, both for communication in global business and for communication in social networks, butproficiency in English can definitely enhance people’s career opportunities both if they look for a job in thecountry or plan to go abroad to find employment. It may determine a division among those who have access toinformation and prosperity and those who don’t. In the future not just wealth but also the way it is created willhave a great impact on people’s increasing communicative needs of international languages. It is obvious thenthat more and more people will need proficiency in English ,both as a language for international communicationand as the basis for constructing cultural identities .

  7. Tone Attrition in Mandarin Speakers of Varying English Proficiency

    Creel, Sarah C.

    2017-01-01

    Purpose The purpose of this study was to determine whether the degree of dominance of Mandarin–English bilinguals' languages affects phonetic processing of tone content in their native language, Mandarin. Method We tested 72 Mandarin–English bilingual college students with a range of language-dominance profiles in the 2 languages and ages of acquisition of English. Participants viewed 2 photographs at a time while hearing a familiar Mandarin word referring to 1 photograph. The names of the 2 photographs diverged in tone, vowels, or both. Word recognition was evaluated using clicking accuracy, reaction times, and an online recognition measure (gaze) and was compared in the 3 conditions. Results Relative proficiency in English was correlated with reduced word recognition success in tone-disambiguated trials, but not in vowel-disambiguated trials, across all 3 dependent measures. This selective attrition for tone content emerged even though all bilinguals had learned Mandarin from birth. Lengthy experience with English thus weakened tone use. Conclusions This finding has implications for the question of the extent to which bilinguals' 2 phonetic systems interact. It suggests that bilinguals may not process pitch information language-specifically and that processing strategies from the dominant language may affect phonetic processing in the nondominant language—even when the latter was learned natively. PMID:28124064

  8. Adolescent drivers: a developmental perspective on risk, proficiency, and safety.

    Keating, Daniel P; Halpern-Felsher, Bonnie L

    2008-09-01

    Despite considerable improvement in the rates of crashes, injuries, and fatalities among adolescent drivers, attributable in part to effective interventions such as graduated driver licensing, these rates and their associated health risks remain unacceptably high. To understand the sources of risky driving among teens, as well as to identify potential avenues for further advances in prevention, this article presents a review of the relevant features of contemporary research on adolescent development. Current research offers significant advances in the understanding of the sources of safe driving, proficient driving, and risky driving among adolescents. This multifaceted perspective--as opposed to simple categorization of good versus bad driving--provides new opportunities for using insights on adolescent development to enhance prevention. Drawing on recent work on adolescent physical, neural, and cognitive development, we argue for approaches to prevention that recognize both the strengths and the limitations of adolescent drivers, with particular attention to the acquisition of expertise, regulatory competence, and self-regulation in the context of perceived risk. This understanding of adolescent development spotlights the provision of appropriate and effective scaffolding, utilizing the contexts of importance to adolescents--parents, peers, and the broader culture of driving--to support safe driving and to manage the inherent risks in learning to do so.

  9. Recombinant methods for screening human DNA excision repair proficiency

    Athas, W.F.

    1988-01-01

    A method for measuring DNA excision repair in response to ultraviolet radiation (UV)-induced DNA damage has been developed, validated, and field-tested in cultured human lymphocytes. The methodology is amenable to population-based screening and should facilitate future epidemiologic studies seeking to investigate associations between excision repair proficiency and cancer susceptibility. The impetus for such endeavors derives from the belief that the high incidence of skin cancer in the genetic disorder xeroderma pigmentosum (XP) primarily is a result of the reduced capacity of patients cells to repair UV-induced DNA damage. For assay, UV-irradiated non-replicating recombinant plasmid DNA harboring a chloramphenicol acetyltransferase (CAT) indicator gene is introduced into lymphocytes using DEAE-dextran short-term transfection conditions. Exposure to UV induces transcriptionally-inactivating DNA photoproducts in the plasmid DNA which inactivate CAT gene expression. Excision repair of the damaged CAT gene is monitored indirectly as a function of reactivated CAT enzyme activity following a 40 hour repair/expression incubation period

  10. Developing interviewer proficiency: A self-perception survey

    Riin Kont-Kontson

    2013-04-01

    Full Text Available The article reports the findings of a survey among 440 teachers of English in Estonia who participate in the oral proficiency interview of the national examination in the English language as interviewers. Examining the results of the questionnaire statement by statement, the study reveals that interviewer behavioural patterns emerge during the interview, some of them threatening its validity.The understanding of interviewer competence is very diverse among the interviewers and the degree to which they adhere to the standards defined for the interviewers of national examination in the English langage in Estonia is sometimes quite low. The interviewers are often unable to separate their role as an interviewer from being a teacher; they transfer their teaching behaviour to the interviewing situation. The teachers have difficulties with identification of appropriate accommodation strategies as well as controlling the extent of interaction between the interviewer and the assessor. The authors suggest a number of interviewer training strategies to combat the problems. DOI: http://dx.doi.org/10.5128/ERYa9.08

  11. Race cars and the hellbox:Understanding the development of proficiency among digital art students

    Paquette, Andrew; Reedy, Gabriel; Hatzipanagos, Stylianos

    2016-01-01

    Educating students in the discipline of digital art to a professional standard has generally proven difficult. In an effort to understand the problem, a first-year undergraduate modelling course cohort was observed. Some students in this course progressed from being novices to acquiring proficiency during the nine-week term of the course. Computer Graphics (CG) modelling professionals evaluated student work to confirm their progress. Traditional models of proficiency development expect that p...

  12. Predictors and Outcomes of Early vs. Later English Language Proficiency Among English Language Learners

    Halle, Tamara; Hair, Elizabeth; Wandner, Laura; McNamara, Michelle; Chien, Nina

    2011-01-01

    The development of English language learners (ELLs) was explored from kindergarten through eighth grade within a nationally representative sample of first-time kindergartners (N = 19,890). Growth curve analyses indicated that, compared to native English speakers, ELLs were rated by teachers more favorably on approaches to learning, self control, and externalizing behaviors in kindergarten and generally continued to grow in a positive direction on these social/behavioral outcomes at a steeper rate compared to their native English-speaking peers, holding other factors constant. Differences in reading and math achievement between ELLs and native English speakers varied based on the grade at which English proficiency is attained. Specifically, ELLs who were proficient in English by kindergarten entry kept pace with native English speakers in both reading and math initially and over time; ELLs who were proficient by first grade had modest gaps in reading and math achievement compared to native English speakers that closed narrowly or persisted over time; and ELLs who were not proficient by first grade had the largest initial gaps in reading and math achievement compared to native speakers but the gap narrowed over time in reading and grew over time in math. Among those whose home language is not English, acquiring English proficiency by kindergarten entry was associated with better cognitive and behavioral outcomes through eighth grade compared to taking longer to achieve proficiency. Multinomial regression analyses indicated that child, family, and school characteristics predict achieving English proficiency by kindergarten entry compared to achieving proficiency later. Results are discussed in terms of policies and practices that can support ELL children’s growth and development. PMID:22389551

  13. Proficiency testing of skin prick testers as part of a quality assurance system

    Malling, Hans-Jørgen; Allesen-Holm, Pernille; Karved, Lisbeth Sys

    2016-01-01

    BACKGROUND: Skin prick test is an important diagnostic procedure in clinical allergy but documentation of the quality is often missing. METHODS: We describe a proficiency system to evaluate staff members in relation to the international recommended reproducibility in terms of coefficient...... of variation (CV 0.85) based on blinded octuplicate histamine testing using histamine 3, 10, 30 and 100 mg/ml. RESULTS: Fourteen trained allergy nurses participated in the proficiency testing. More than 95 % of the nurses, generated coefficient of variation...

  14. THE OBSERVATION OF TEACHER CANDIDATE RELATED SCIENCE AND TECHNOLOGY TEACHER'S PROFICIENCY

    BAHŞİ, Muammer; TURAN, Mehmet; YILAYAZ, Ömer

    2009-01-01

    In this study it is evaluated science and tecnology teacher's proficiency based on students insights of science and tecnology education students in education faculty. It was used Standarts for Teacher Proficiency which is prepared from Ministry of National Education. The research was conducted on 85 Science and Tecnology students (4th classes) studying at the education faculty of Firat University. Data from results of study was analysed by using SPSS.

  15. LOGICAL CONDITIONS ANALYSIS METHOD FOR DIAGNOSTIC TEST RESULTS DECODING APPLIED TO COMPETENCE ELEMENTS PROFICIENCY

    V. I. Freyman

    2015-11-01

    Full Text Available Subject of Research.Representation features of education results for competence-based educational programs are analyzed. Solution importance of decoding and proficiency estimation for elements and components of discipline parts of competences is shown. The purpose and objectives of research are formulated. Methods. The paper deals with methods of mathematical logic, Boolean algebra, and parametrical analysis of complex diagnostic test results, that controls proficiency of some discipline competence elements. Results. The method of logical conditions analysis is created. It will give the possibility to formulate logical conditions for proficiency determination of each discipline competence element, controlled by complex diagnostic test. Normalized test result is divided into noncrossing zones; a logical condition about controlled elements proficiency is formulated for each of them. Summarized characteristics for test result zones are imposed. An example of logical conditions forming for diagnostic test with preset features is provided. Practical Relevance. The proposed method of logical conditions analysis is applied in the decoding algorithm of proficiency test diagnosis for discipline competence elements. It will give the possibility to automate the search procedure for elements with insufficient proficiency, and is also usable for estimation of education results of a discipline or a component of competence-based educational program.

  16. Fine motor skill proficiency in typically developing children: On or off the maturation track?

    Gaul, David; Issartel, Johann

    2016-04-01

    Fine motor skill proficiency is an essential component of numerous daily living activities such as dressing, feeding or playing. Poor fine motor skills can lead to difficulties in academic achievement, increased anxiety and poor self-esteem. Recent findings have shown that children's gross motor skill proficiency tends to fall below established developmental norms. A question remains: do fine motor skill proficiency levels also fall below developmental norms? The aim of this study was to examine the current level of fine motor skill in Irish children. Children (N=253) from 2nd, 4th and 6th grades (mean age=7.12, 9.11 and 11.02 respectively) completed the Fine Motor Composite of the Bruininks Oseretsky Test of Motor Proficiency 2nd Edition (BOT-2). Analysis revealed that only 2nd grade children met the expected level of fine motor skill proficiency. It was also found that despite children's raw scores improving with age, children's fine motor skill proficiency was not progressing at the expected rate given by normative data. This leads us to question the role and impact of modern society on fine motor skills development over the past number of decades. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. Complimentary mechanisms of dual checkpoint blockade expand unique T-cell repertoires and activate adaptive anti-tumor immunity in triple-negative breast tumors

    Wei, Junping; Yang, Xiao Yi; Lei, Gangjun; Wang, Tao; Liu, Cong-Xiao; Morse, Michael A.; Gouin, Kenneth; Knott, Simon R. V.; Hartman, Zachary C.

    2018-01-01

    ABSTRACT Triple-negative breast cancer (TNBC) is an aggressive and molecularly diverse breast cancer subtype typified by the presence of p53 mutations (∼80%), elevated immune gene signatures and neoantigen expression, as well as the presence of tumor infiltrating lymphocytes (TILs). As these factors are hypothesized to be strong immunologic prerequisites for the use of immune checkpoint blockade (ICB) antibodies, multiple clinical trials testing single ICBs have advanced to Phase III, with early indications of heterogeneous response rates of <20% to anti-PD1 and anti-PDL1 ICB. While promising, these modest response rates highlight the need for mechanistic studies to understand how different ICBs function, how their combination impacts functionality and efficacy, as well as what immunologic parameters predict efficacy to different ICBs regimens in TNBC. To address these issues, we tested anti-PD1 and anti-CTLA4 in multiple models of TNBC and found that their combination profoundly enhanced the efficacy of either treatment alone. We demonstrate that this efficacy is due to anti-CTLA4-driven expansion of an individually unique T-cell receptor (TCR) repertoire whose functionality is enhanced by both intratumoral Treg suppression and anti-PD1 blockade of tumor expressed PDL1. Notably, the individuality of the TCR repertoire was observed regardless of whether the tumor cells expressed a nonself antigen (ovalbumin) or if tumor-specific transgenic T-cells were transferred prior to sequencing. However, responsiveness was strongly correlated with systemic measures of tumor-specific T-cell and B-cell responses, which along with systemic assessment of TCR expansion, may serve as the most useful predictors for clinical responsiveness in future clinical trials of TNBC utilizing anti-PD1/anti-CTLA4 ICB. PMID:29721371

  18. Complimentary mechanisms of dual checkpoint blockade expand unique T-cell repertoires and activate adaptive anti-tumor immunity in triple-negative breast tumors.

    Crosby, Erika J; Wei, Junping; Yang, Xiao Yi; Lei, Gangjun; Wang, Tao; Liu, Cong-Xiao; Agarwal, Pankaj; Korman, Alan J; Morse, Michael A; Gouin, Kenneth; Knott, Simon R V; Lyerly, H Kim; Hartman, Zachary C

    2018-01-01

    Triple-negative breast cancer (TNBC) is an aggressive and molecularly diverse breast cancer subtype typified by the presence of p53 mutations (∼80%), elevated immune gene signatures and neoantigen expression, as well as the presence of tumor infiltrating lymphocytes (TILs). As these factors are hypothesized to be strong immunologic prerequisites for the use of immune checkpoint blockade (ICB) antibodies, multiple clinical trials testing single ICBs have advanced to Phase III, with early indications of heterogeneous response rates of <20% to anti-PD1 and anti-PDL1 ICB. While promising, these modest response rates highlight the need for mechanistic studies to understand how different ICBs function, how their combination impacts functionality and efficacy, as well as what immunologic parameters predict efficacy to different ICBs regimens in TNBC. To address these issues, we tested anti-PD1 and anti-CTLA4 in multiple models of TNBC and found that their combination profoundly enhanced the efficacy of either treatment alone. We demonstrate that this efficacy is due to anti-CTLA4-driven expansion of an individually unique T-cell receptor (TCR) repertoire whose functionality is enhanced by both intratumoral Treg suppression and anti-PD1 blockade of tumor expressed PDL1. Notably, the individuality of the TCR repertoire was observed regardless of whether the tumor cells expressed a nonself antigen (ovalbumin) or if tumor-specific transgenic T-cells were transferred prior to sequencing. However, responsiveness was strongly correlated with systemic measures of tumor-specific T-cell and B-cell responses, which along with systemic assessment of TCR expansion, may serve as the most useful predictors for clinical responsiveness in future clinical trials of TNBC utilizing anti-PD1/anti-CTLA4 ICB.

  19. Requirement for the Phospho-H2AX Binding Module of Crb2 in Double-Strand Break Targeting and Checkpoint Activation▿

    Sanders, Steven L.; Arida, Ahmad R.; Phan, Funita P.

    2010-01-01

    Activation of DNA damage checkpoints requires the rapid accumulation of numerous factors to sites of genomic lesions, and deciphering the mechanisms of this targeting is central to our understanding of DNA damage response. Histone modification has recently emerged as a critical element for the correct localization of damage response proteins, and one key player in this context is the fission yeast checkpoint mediator Crb2. Accumulation of Crb2 at ionizing irradiation-induced double-strand breaks (DSBs) requires two distinct histone marks, dimethylated H4 lysine 20 (H4K20me2) and phosphorylated H2AX (pH2AX). A tandem tudor motif in Crb2 directly binds H4K20me2, and this interaction is required for DSB targeting and checkpoint activation. Similarly, pH2AX is required for Crb2 localization to DSBs and checkpoint control. Crb2 can directly bind pH2AX through a pair of C-terminal BRCT repeats, but the functional significance of this binding has been unclear. Here we demonstrate that loss of its pH2AX-binding activity severely impairs the ability of Crb2 to accumulate at ionizing irradiation-induced DSBs, compromises checkpoint signaling, and disrupts checkpoint-mediated cell cycle arrest. These impairments are similar to that reported for abolition of pH2AX or mutation of the H4K20me2-binding tudor motif of Crb2. Intriguingly, a combined ablation of its two histone modification binding modules yields a strikingly additive reduction in Crb2 activity. These observations argue that binding of the Crb2 BRCT repeats to pH2AX is critical for checkpoint activity and provide new insight into the mechanisms of chromatin-mediated genome stability. PMID:20679488

  20. Requirement for the phospho-H2AX binding module of Crb2 in double-strand break targeting and checkpoint activation.

    Sanders, Steven L; Arida, Ahmad R; Phan, Funita P

    2010-10-01

    Activation of DNA damage checkpoints requires the rapid accumulation of numerous factors to sites of genomic lesions, and deciphering the mechanisms of this targeting is central to our understanding of DNA damage response. Histone modification has recently emerged as a critical element for the correct localization of damage response proteins, and one key player in this context is the fission yeast checkpoint mediator Crb2. Accumulation of Crb2 at ionizing irradiation-induced double-strand breaks (DSBs) requires two distinct histone marks, dimethylated H4 lysine 20 (H4K20me2) and phosphorylated H2AX (pH2AX). A tandem tudor motif in Crb2 directly binds H4K20me2, and this interaction is required for DSB targeting and checkpoint activation. Similarly, pH2AX is required for Crb2 localization to DSBs and checkpoint control. Crb2 can directly bind pH2AX through a pair of C-terminal BRCT repeats, but the functional significance of this binding has been unclear. Here we demonstrate that loss of its pH2AX-binding activity severely impairs the ability of Crb2 to accumulate at ionizing irradiation-induced DSBs, compromises checkpoint signaling, and disrupts checkpoint-mediated cell cycle arrest. These impairments are similar to that reported for abolition of pH2AX or mutation of the H4K20me2-binding tudor motif of Crb2. Intriguingly, a combined ablation of its two histone modification binding modules yields a strikingly additive reduction in Crb2 activity. These observations argue that binding of the Crb2 BRCT repeats to pH2AX is critical for checkpoint activity and provide new insight into the mechanisms of chromatin-mediated genome stability.

  1. Comparison of checkpoint responses triggered by DNA polymerase inhibition versus DNA damaging agents

    Liu, J.-S.; Kuo, S.-R.; Melendy, Thomas

    2003-01-01

    To better understand the different cellular responses to replication fork pausing versus blockage, early DNA damage response markers were compared after treatment of cultured mammalian cells with agents that either inhibit DNA polymerase activity (hydroxyurea (HU) or aphidicolin) or selectively induce S-phase DNA damage responses (the DNA alkylating agents, methyl methanesulfonate (MMS) and adozelesin). These agents were compared for their relative abilities to induce phosphorylation of Chk1, H2AX, and replication protein A (RPA), and intra-nuclear focalization of γ-H2AX and RPA. Treatment by aphidicolin and HU resulted in phosphorylation of Chk1, while HU, but not aphidicolin, induced focalization of γ-H2AX and RPA. Surprisingly, pre-treatment with aphidicolin to stop replication fork progression, did not abrogate HU-induced γ-H2AX and RPA focalization. This suggests that HU may act on the replication fork machinery directly, such that fork progression is not required to trigger these responses. The DNA-damaging fork-blocking agents, adozelesin and MMS, both induced phosphorylation and focalization of H2AX and RPA. Unlike adozelesin and HU, the pattern of MMS-induced RPA focalization did not match the BUdR incorporation pattern and was not blocked by aphidicolin, suggesting that MMS-induced damage is not replication fork-dependent. In support of this, MMS was the only reagent used that did not induce phosphorylation of Chk1. These results indicate that induction of DNA damage checkpoint responses due to adozelesin is both replication fork and fork progression dependent, induction by HU is replication fork dependent but progression independent, while induction by MMS is independent of both replication forks and fork progression

  2. Adrenergic Signaling: A Targetable Checkpoint Limiting Development of the Antitumor Immune Response

    Qiao, Guanxi; Chen, Minhui; Bucsek, Mark J.; Repasky, Elizabeth A.; Hylander, Bonnie L.

    2018-01-01

    An immune response must be tightly controlled so that it will be commensurate with the level of response needed to protect the organism without damaging normal tissue. The roles of cytokines and chemokines in orchestrating these processes are well known, but although stress has long been thought to also affect immune responses, the underlying mechanisms were not as well understood. Recently, the role of nerves and, specifically, the sympathetic nervous system, in regulating immune responses is being revealed. Generally, an acute stress response is beneficial but chronic stress is detrimental because it suppresses the activities of effector immune cells while increasing the activities of immunosuppressive cells. In this review, we first discuss the underlying biology of adrenergic signaling in cells of both the innate and adaptive immune system. We then focus on the effects of chronic adrenergic stress in promoting tumor growth, giving examples of effects on tumor cells and immune cells, explaining the methods commonly used to induce stress in preclinical mouse models. We highlight how this relates to our observations that mandated housing conditions impose baseline chronic stress on mouse models, which is sufficient to cause chronic immunosuppression. This problem is not commonly recognized, but it has been shown to impact conclusions of several studies of mouse physiology and mouse models of disease. Moreover, the fact that preclinical mouse models are chronically immunosuppressed has critical ramifications for analysis of any experiments with an immune component. Our group has found that reducing adrenergic stress by housing mice at thermoneutrality or treating mice housed at cooler temperatures with β-blockers reverses immunosuppression and significantly improves responses to checkpoint inhibitor immunotherapy. These observations are clinically relevant because there are numerous retrospective epidemiological studies concluding that cancer patients who were

  3. Comparison of checkpoint responses triggered by DNA polymerase inhibition versus DNA damaging agents

    Liu, J.-S.; Kuo, S.-R.; Melendy, Thomas

    2003-11-27

    To better understand the different cellular responses to replication fork pausing versus blockage, early DNA damage response markers were compared after treatment of cultured mammalian cells with agents that either inhibit DNA polymerase activity (hydroxyurea (HU) or aphidicolin) or selectively induce S-phase DNA damage responses (the DNA alkylating agents, methyl methanesulfonate (MMS) and adozelesin). These agents were compared for their relative abilities to induce phosphorylation of Chk1, H2AX, and replication protein A (RPA), and intra-nuclear focalization of {gamma}-H2AX and RPA. Treatment by aphidicolin and HU resulted in phosphorylation of Chk1, while HU, but not aphidicolin, induced focalization of {gamma}-H2AX and RPA. Surprisingly, pre-treatment with aphidicolin to stop replication fork progression, did not abrogate HU-induced {gamma}-H2AX and RPA focalization. This suggests that HU may act on the replication fork machinery directly, such that fork progression is not required to trigger these responses. The DNA-damaging fork-blocking agents, adozelesin and MMS, both induced phosphorylation and focalization of H2AX and RPA. Unlike adozelesin and HU, the pattern of MMS-induced RPA focalization did not match the BUdR incorporation pattern and was not blocked by aphidicolin, suggesting that MMS-induced damage is not replication fork-dependent. In support of this, MMS was the only reagent used that did not induce phosphorylation of Chk1. These results indicate that induction of DNA damage checkpoint responses due to adozelesin is both replication fork and fork progression dependent, induction by HU is replication fork dependent but progression independent, while induction by MMS is independent of both replication forks and fork progression.

  4. Regulation of cell cycle checkpoint kinase WEE1 by miR-195 in malignant melanoma.

    Bhattacharya, A; Schmitz, U; Wolkenhauer, O; Schönherr, M; Raatz, Y; Kunz, M

    2013-06-27

    WEE1 kinase has been described as a major gate keeper at the G2 cell cycle checkpoint and to be involved in tumour progression in different malignant tumours. Here we analysed the expression levels of WEE1 in a series of melanoma patient samples and melanoma cell lines using immunoblotting, quantitative real-time PCR and immunohistochemistry. WEE1 expression was significantly downregulated in patient samples of metastatic origin as compared with primary melanomas and in melanoma cell lines of high aggressiveness as compared with cell lines of low aggressiveness. Moreover, there was an inverse correlation between the expression of WEE1 and WEE1-targeting microRNA miR-195. Further analyses showed that transfection of melanoma cell lines with miR-195 indeed reduced WEE1 mRNA and protein expression in these cells. Reporter gene analysis confirmed direct targeting of the WEE1 3' untranslated region (3'UTR) by miR-195. Overexpression of miR-195 in SK-Mel-28 melanoma cells was accompanied by WEE1 reduction and significantly reduced stress-induced G2-M cell cycle arrest, which could be restored by stable overexpression of WEE1. Moreover, miR-195 overexpression and WEE1 knockdown, respectively, increased melanoma cell proliferation. miR-195 overexpression also enhanced migration and invasiveness of melanoma cells. Taken together, the present study shows that WEE1 expression in malignant melanoma is directly regulated by miR-195. miR-195-mediated downregulation of WEE1 in metastatic lesions may help to overcome cell cycle arrest under stress conditions in the local tissue microenvironment to allow unrestricted growth of tumour cells.

  5. How oocytes try to get it right: spindle checkpoint control in meiosis.

    Touati, Sandra A; Wassmann, Katja

    2016-06-01

    The generation of a viable, diploid organism depends on the formation of haploid gametes, oocytes, and spermatocytes, with the correct number of chromosomes. Halving the genome requires the execution of two consecutive specialized cell divisions named meiosis I and II. Unfortunately, and in contrast to male meiosis, chromosome segregation in oocytes is error prone, with human oocytes being extraordinarily "meiotically challenged". Aneuploid oocytes, that are with the wrong number of chromosomes, give rise to aneuploid embryos when fertilized. In humans, most aneuploidies are lethal and result in spontaneous abortions. However, some trisomies survive to birth or even adulthood, such as the well-known trisomy 21, which gives rise to Down syndrome (Nagaoka et al. in Nat Rev Genet 13:493-504, 2012). A staggering 20-25 % of oocytes ready to be fertilized are aneuploid in humans. If this were not bad enough, there is an additional increase in meiotic missegregations as women get closer to menopause. A woman above 40 has a risk of more than 30 % of getting pregnant with a trisomic child. Worse still, in industrialized western societies, child birth is delayed, with women getting their first child later in life than ever. This trend has led to an increase of trisomic pregnancies by 70 % in the last 30 years (Nagaoka et al. in Nat Rev Genet 13:493-504, 2012; Schmidt et al. in Hum Reprod Update 18:29-43, 2012). To understand why errors occur so frequently during the meiotic divisions in oocytes, we review here the molecular mechanisms at works to control chromosome segregation during meiosis. An important mitotic control mechanism, namely the spindle assembly checkpoint or SAC, has been adapted to the special requirements of the meiotic divisions, and this review will focus on our current knowledge of SAC control in mammalian oocytes. Knowledge on how chromosome segregation is controlled in mammalian oocytes may help to identify risk factors important for questions

  6. Differential immune microenvironments and response to immune checkpoint blockade amongst molecular subtypes of murine medulloblastoma

    Pham, Christina D.; Flores, Catherine; Yang, Changlin; Pinheiro, Elaine M.; Yearley, Jennifer H.; Sayour, Elias J.; Pei, Yanxin; Moore, Colin; McLendon, Roger E.; Huang, Jianping; Sampson, John H.; Wechsler-Reya, Robert; Mitchell, Duane A.

    2016-01-01

    PURPOSE Despite significant strides in the identification and characterization of potential therapeutic targets for medulloblastoma (MB), the role of the immune system and its interplay with the tumor microenvironment within these tumors are poorly understood. To address this, we adapted two syngeneic animal models of human Sonic Hedgehog (SHH)-driven and Group 3 MB for preclinical evaluation in immunocompetent C57BL/6 mice. METHODS AND RESULTS Multicolor flow cytometric analyses were used to phenotype and characterize immune infiltrating cells within established cerebellar tumors. We observed significantly higher percentages of dendritic cells, infiltrating lymphocytes, myeloid derived suppressor cells and tumor-associated macrophages in murine SHH model tumors compared with Group 3 tumors. However, murine Group 3 tumors had higher percentages of CD8+ PD-1+ T cells within the CD3 population. PD-1 blockade conferred superior antitumor efficacy in animals bearing intracranial Group 3 tumors compared to SHH group tumors, indicating that immunologic differences within the tumor microenvironment can be leveraged as potential targets to mediate antitumor efficacy. Further analysis of anti-PD-1 monoclonal antibody localization revealed binding to PD-1+ peripheral T cells, but not tumor infiltrating lymphocytes within the brain tumor microenvironment. Peripheral PD-1 blockade additionally resulted in a marked increase in CD3+ T cells within the tumor microenvironment. CONCLUSIONS This is the first immunologic characterization of preclinical models of molecular subtypes of MB and demonstration that response to immune checkpoint blockade differs across subtype classification. Our findings also suggest that effective anti-PD-1 blockade does not require that systemically administered antibodies penetrate the brain tumor microenvironment. PMID:26405194

  7. DNA damage checkpoint kinase ATM regulates germination and maintains genome stability in seeds.

    Waterworth, Wanda M; Footitt, Steven; Bray, Clifford M; Finch-Savage, William E; West, Christopher E

    2016-08-23

    Genome integrity is crucial for cellular survival and the faithful transmission of genetic information. The eukaryotic cellular response to DNA damage is orchestrated by the DNA damage checkpoint kinases ATAXIA TELANGIECTASIA MUTATED (ATM) and ATM AND RAD3-RELATED (ATR). Here we identify important physiological roles for these sensor kinases in control of seed germination. We demonstrate that double-strand breaks (DSBs) are rate-limiting for germination. We identify that desiccation tolerant seeds exhibit a striking transcriptional DSB damage response during germination, indicative of high levels of genotoxic stress, which is induced following maturation drying and quiescence. Mutant atr and atm seeds are highly resistant to aging, establishing ATM and ATR as determinants of seed viability. In response to aging, ATM delays germination, whereas atm mutant seeds germinate with extensive chromosomal abnormalities. This identifies ATM as a major factor that controls germination in aged seeds, integrating progression through germination with surveillance of genome integrity. Mechanistically, ATM functions through control of DNA replication in imbibing seeds. ATM signaling is mediated by transcriptional control of the cell cycle inhibitor SIAMESE-RELATED 5, an essential factor required for the aging-induced delay to germination. In the soil seed bank, seeds exhibit increased transcript levels of ATM and ATR, with changes in dormancy and germination potential modulated by environmental signals, including temperature and soil moisture. Collectively, our findings reveal physiological functions for these sensor kinases in linking genome integrity to germination, thereby influencing seed quality, crucial for plant survival in the natural environment and sustainable crop production.

  8. Immune checkpoint inhibitor-induced gastrointestinal and hepatic injury: pathologists' perspective.

    Karamchandani, Dipti M; Chetty, Runjan

    2018-04-27

    Immune checkpoint inhibitors (CPIs) are a relatively new class of 'miracle' dugs that have revolutionised the treatment and prognosis of some advanced-stage malignancies, and have increased the survival rates significantly. This class of drugs includes cytotoxic T lymphocyte antigen-4 inhibitors such as ipilimumab; programmed cell death protein-1 inhibitors such as nivolumab, pembrolizumab and avelumab; and programmed cell death protein ligand-1 inhibitors such as atezolizumab. These drugs stimulate the immune system by blocking the coinhibitory receptors on the T cells and lead to antitumoural response. However, a flip side of these novel drugs is immune-related adverse events (irAEs), secondary to immune-mediated process due to disrupted self-tolerance. The irAEs in the gastrointestinal (GI) tract/liver may result in diarrhoea, colitis or hepatitis. An accurate diagnosis of CPI-induced colitis and/or hepatitis is essential for optimal patient management. As we anticipate greater use of these drugs in the future given the significant clinical response, pathologists need to be aware of the spectrum of histological findings that may be encountered in GI and/or liver biopsies received from these patients, as well as differentiate them from its histopathological mimics. This present review discusses the clinical features, detailed histopathological features, management and the differential diagnosis of the luminal GI and hepatic irAEs that may be encountered secondary to CPI therapy. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  9. Differential Immune Microenvironments and Response to Immune Checkpoint Blockade among Molecular Subtypes of Murine Medulloblastoma.

    Pham, Christina D; Flores, Catherine; Yang, Changlin; Pinheiro, Elaine M; Yearley, Jennifer H; Sayour, Elias J; Pei, Yanxin; Moore, Colin; McLendon, Roger E; Huang, Jianping; Sampson, John H; Wechsler-Reya, Robert; Mitchell, Duane A

    2016-02-01

    Despite significant strides in the identification and characterization of potential therapeutic targets for medulloblastoma, the role of the immune system and its interplay with the tumor microenvironment within these tumors are poorly understood. To address this, we adapted two syngeneic animal models of human Sonic Hedgehog (SHH)-driven and group 3 medulloblastoma for preclinical evaluation in immunocompetent C57BL/6 mice. Multicolor flow cytometric analyses were used to phenotype and characterize immune infiltrating cells within established cerebellar tumors. We observed significantly higher percentages of dendritic cells, infiltrating lymphocytes, myeloid-derived suppressor cells, and tumor-associated macrophages in murine SHH model tumors compared with group 3 tumors. However, murine group 3 tumors had higher percentages of CD8(+) PD-1(+) T cells within the CD3 population. PD-1 blockade conferred superior antitumor efficacy in animals bearing intracranial group 3 tumors compared with SHH group tumors, indicating that immunologic differences within the tumor microenvironment can be leveraged as potential targets to mediate antitumor efficacy. Further analysis of anti-PD-1 monoclonal antibody localization revealed binding to PD-1(+) peripheral T cells, but not tumor infiltrating lymphocytes within the brain tumor microenvironment. Peripheral PD-1 blockade additionally resulted in a marked increase in CD3(+) T cells within the tumor microenvironment. This is the first immunologic characterization of preclinical models of molecular subtypes of medulloblastoma and demonstration that response to immune checkpoint blockade differs across subtype classification. Our findings also suggest that effective anti-PD-1 blockade does not require that systemically administered antibodies penetrate the brain tumor microenvironment. ©2015 American Association for Cancer Research.

  10. DNA damage response and spindle assembly checkpoint function throughout the cell cycle to ensure genomic integrity.

    Katherine S Lawrence

    2015-04-01

    Full Text Available Errors in replication or segregation lead to DNA damage, mutations, and aneuploidies. Consequently, cells monitor these events and delay progression through the cell cycle so repair precedes division. The DNA damage response (DDR, which monitors DNA integrity, and the spindle assembly checkpoint (SAC, which responds to defects in spindle attachment/tension during metaphase of mitosis and meiosis, are critical for preventing genome instability. Here we show that the DDR and SAC function together throughout the cell cycle to ensure genome integrity in C. elegans germ cells. Metaphase defects result in enrichment of SAC and DDR components to chromatin, and both SAC and DDR are required for metaphase delays. During persistent metaphase arrest following establishment of bi-oriented chromosomes, stability of the metaphase plate is compromised in the absence of DDR kinases ATR or CHK1 or SAC components, MAD1/MAD2, suggesting SAC functions in metaphase beyond its interactions with APC activator CDC20. In response to DNA damage, MAD2 and the histone variant CENPA become enriched at the nuclear periphery in a DDR-dependent manner. Further, depletion of either MAD1 or CENPA results in loss of peripherally associated damaged DNA. In contrast to a SAC-insensitive CDC20 mutant, germ cells deficient for SAC or CENPA cannot efficiently repair DNA damage, suggesting that SAC mediates DNA repair through CENPA interactions with the nuclear periphery. We also show that replication perturbations result in relocalization of MAD1/MAD2 in human cells, suggesting that the role of SAC in DNA repair is conserved.

  11. Indoor Smartphone Navigation Using a Combination of Wi-Fi and Inertial Navigation with Intelligent Checkpoints

    Hofer, H.; Retscher, G.

    2017-09-01

    For Wi-Fi positioning location fingerprinting is one of the most commonly employed localization technique. To achieve an acceptable level of positioning accuracy on the few meter level, i.e., to provide at least room resolution in buildings, such an approach is very labour consuming as it requires a high density of reference points. Thus, the novel approach developed aims at a significant reduction of workload for the training phase. The basic idea is to intelligently choose waypoints along possible users' trajectories in the indoor environment. These waypoints are termed intelligent checkpoints (iCPs) and serve as reference points for the fingerprinting localization approach. They are selected along the trajectories in such a way that they define a logical sequence with their ascending order. Thereby, the iCPs are located, for instance, at doors at entrances to buildings, rooms, along corridors, etc., or in low density along the trajectory to provide a suitable absolute user localization. Continuous positioning between these iCPs is obtained with the help of the smartphones' inertial sensors. While walking along a selected trajectory to the destination a dynamic recognition of the iCPs is performed and the drift of the inertial sensors is reduced as the iCP recognition serves as absolute position update. Conducted experiments in a multi-storey office building have shown that positioning accuracy of around 2.0 m are achievable which goes along with a reduction of workload by three quarter using this novel approach. The iCP concept and performance are presented and demonstrated in this paper.

  12. Motor proficiency in normal children and with learning difficulty: a comparative and correlational study based on the motor proficiency test of Bruininks-Oseretsky

    Nilson Roberto Moreira

    2008-06-01

    Full Text Available The aim of this investigation is to verify the difference between children with learning disabilities and children without learning disabilities through motor proficiency test of Bruininks and Ozeretsky (1978. The sample was constituted by 30 children, with 8-year average age, 15 males and 15 females, subdivided into two groups of 15 children from both sexes: children without learning disabilities attending 3rd grade and children with learning disabilities attending 2nd grade having failed a term once. All of them came from a middle class background, according to Grafar scale (adapted by Fonseca, 1991. All children presenting any other disabilities were excluded from the sample. Intelligence factor “G” was controlled by using a percentile, higher or equal to 50 (middle and high level, measured by Raven’s (1974 progressive combinations test. In motor proficiency, children with learning disabilities showed significant differences when compared with normal children of the same age, in all components of global, composed and fine motricity. The tests administered showed a strong correlation between the variables of the motor proficiency components. The results lead to the conclusion that there were significant differences in motor proficiency between normal children and children with learning disabilities, who showed specific motor difficulties evincing a more vulnerable motor profile and not the presence of neurological dysfunction signs.

  13. Measuring Second Language Proficiency with EEG Synchronization: How Functional Cortical Networks and Hemispheric Involvement Differ as a Function of Proficiency Level in Second Language Speakers

    Reiterer, Susanne; Pereda, Ernesto; Bhattacharya, Joydeep

    2009-01-01

    This article examines the question of whether university-based high-level foreign language and linguistic training can influence brain activation and whether different L2 proficiency groups have different brain activation in terms of lateralization and hemispheric involvement. The traditional and prevailing theory of hemispheric involvement in…

  14. Ebola Preparedness: Diagnosis Improvement Using Rapid Approaches for Proficiency Testing.

    Lau, Katherine A; Theis, Torsten; Gray, Joanna; Rawlinson, William D

    2017-03-01

    The unprecedented 2015 Ebolavirus (EBOV) outbreak in West Africa was declared a public health emergency, making diagnosis and quality of testing a global issue. The accuracy of laboratory diagnostic capacity for EBOV was assessed in 2014 to 2016 using a proficiency testing (PT) strategy developed by the Royal College of Pathologists of Australasia Quality Assurance Programs (RCPAQAP) in Biosecurity. Following a literature search, EBOV-specific gene targets were ranked according to the frequency of their use in published methods. The most commonly used gene regions (nucleoprotein [NP], glycoprotein [GP], and RNA-dependent RNA polymerase [L]) were selected for the design of in vitro RNA transcripts to be included in the simulated EBOV specimens used for EBOV detection with PCR-based assays. Specimens were tested for stability and found to be stable on long-term storage (1 year) at -80°C and on shorter-term storage in lyophilized form (1 week at ambient temperature and a subsequent week at -80°C). These specimens were used in three EBOV PTs offered from April 2014 to March 2016. In the first and third PTs, all laboratories (3/3 and 9/9, respectively) correctly identified specimens containing EBOV RNA transcripts, while in the second PT, all but one laboratory (5/6) correctly confirmed the presence of EBOV. The EBOV PT panel was useful for ensuring the competency of laboratories in detecting EBOV in the absence of readily available clinical samples. The simulated EBOV specimen was safe, stable, and reliable and can be used in lyophilized form for future EBOV PT programs, allowing simplicity of transport. Copyright © 2017 American Society for Microbiology.

  15. Proficient brain for optimal performance: the MAP model perspective.

    Bertollo, Maurizio; di Fronso, Selenia; Filho, Edson; Conforto, Silvia; Schmid, Maurizio; Bortoli, Laura; Comani, Silvia; Robazza, Claudio

    2016-01-01

    Background. The main goal of the present study was to explore theta and alpha event-related desynchronization/synchronization (ERD/ERS) activity during shooting performance. We adopted the idiosyncratic framework of the multi-action plan (MAP) model to investigate different processing modes underpinning four types of performance. In particular, we were interested in examining the neural activity associated with optimal-automated (Type 1) and optimal-controlled (Type 2) performances. Methods. Ten elite shooters (6 male and 4 female) with extensive international experience participated in the study. ERD/ERS analysis was used to investigate cortical dynamics during performance. A 4 × 3 (performance types × time) repeated measures analysis of variance was performed to test the differences among the four types of performance during the three seconds preceding the shots for theta, low alpha, and high alpha frequency bands. The dependent variables were the ERD/ERS percentages in each frequency band (i.e., theta, low alpha, high alpha) for each electrode site across the scalp. This analysis was conducted on 120 shots for each participant in three different frequency bands and the individual data were then averaged. Results. We found ERS to be mainly associated with optimal-automatic performance, in agreement with the "neural efficiency hypothesis." We also observed more ERD as related to optimal-controlled performance in conditions of "neural adaptability" and proficient use of cortical resources. Discussion. These findings are congruent with the MAP conceptualization of four performance states, in which unique psychophysiological states underlie distinct performance-related experiences. From an applied point of view, our findings suggest that the MAP model can be used as a framework to develop performance enhancement strategies based on cognitive and neurofeedback techniques.

  16. Proficient brain for optimal performance: the MAP model perspective

    Maurizio Bertollo

    2016-05-01

    Full Text Available Background. The main goal of the present study was to explore theta and alpha event-related desynchronization/synchronization (ERD/ERS activity during shooting performance. We adopted the idiosyncratic framework of the multi-action plan (MAP model to investigate different processing modes underpinning four types of performance. In particular, we were interested in examining the neural activity associated with optimal-automated (Type 1 and optimal-controlled (Type 2 performances. Methods. Ten elite shooters (6 male and 4 female with extensive international experience participated in the study. ERD/ERS analysis was used to investigate cortical dynamics during performance. A 4 × 3 (performance types × time repeated measures analysis of variance was performed to test the differences among the four types of performance during the three seconds preceding the shots for theta, low alpha, and high alpha frequency bands. The dependent variables were the ERD/ERS percentages in each frequency band (i.e., theta, low alpha, high alpha for each electrode site across the scalp. This analysis was conducted on 120 shots for each participant in three different frequency bands and the individual data were then averaged. Results. We found ERS to be mainly associated with optimal-automatic performance, in agreement with the “neural efficiency hypothesis.” We also observed more ERD as related to optimal-controlled performance in conditions of “neural adaptability” and proficient use of cortical resources. Discussion. These findings are congruent with the MAP conceptualization of four performance states, in which unique psychophysiological states underlie distinct performance-related experiences. From an applied point of view, our findings suggest that the MAP model can be used as a framework to develop performance enhancement strategies based on cognitive and neurofeedback techniques.

  17. From novice to proficient general practitioner: a critical incident study.

    Sim, M G; Kamien, M; Diamond, M R

    1996-09-01

    To obtain information about any change in the performance or perceptions of doctors undertaking the Royal Australian College of General Practitioners (RACGP) Training Program, with advancing general practice experience. The critical incident technique' was used, which is a comparative qualitative analysis. It involved interviews at 12 to 18 months after the basic term interview. Eighteen Western Australian doctors, who had been interviewed in 1992, at the end of their first 6 months of general practice training and were now completing their advanced or mentor terms in the RACGP Training Program took part in the study. Doctors reported an average of 4.4 critical incidents in their first interview and 5.0 in their second interview. The major areas of positive change included relationships with patients and other health care professionals, including supervisors; paediatrics and orthopaedics skills; the skills of developing a therapeutic relationship to enhance patient compliance and the ability to manage complex cardiovascular and psychiatric problems without reliance on specialist referral; attitudes of responsibility for and enjoyment of long term care of patients and families; and reduced levels of anxiety over difficult problems. New or continuing areas of difficulty were found in gynaecology; pharmacotherapy and dermatology; the diagnosis of common complaints with uncommon presentations; the skill of managing difficult or angry patients; the organisation for the follow-up of patients with potentially severe disorders; and in managing feelings of guilt over missed diagnoses or poor management. An analysis of commonly occurring positive and negative critical incidents shows that RACGP Training Program doctors develop competence, confidence and reduced levels of performance anxiety with advancing experience. All but one doctor found the Training Program helpful in achieving these proficiencies. However, many ongoing areas of difficulty remain. The Critical Incident

  18. The Neurospora crassa UVS-3 epistasis group encodes homologues of the ATR/ATRIP checkpoint control system.

    Kazama, Yusuke; Ishii, Chizu; Schroeder, Alice L; Shimada, Hisao; Wakabayashi, Michiyoshi; Inoue, Hirokazu

    2008-02-01

    The mutagen sensitive uvs-3 and mus-9 mutants of Neurospora show mutagen and hydroxyurea sensitivity, mutator effects and duplication instability typical of recombination repair and DNA damage checkpoint defective mutants. To determine the nature of these genes we used cosmids from a genomic library to clone the uvs-3 gene by complementation for MMS sensitivity. Mutation induction by transposon insertion and RIP defined the coding sequence. RFLP analysis confirmed that this sequence maps in the area of uvs-3 at the left telomere of LG IV. Analysis of the cDNA showed that the UVS-3 protein contains an ORF of 969 amino acids with one intron. It is homologous to UvsD of Aspergillus nidulans, a member of the ATRIP family of checkpoint proteins. It retains the N' terminal coiled-coil motif followed by four basic amino acids typical of these proteins and shows the highest homology in this region. The uvsD cDNA partially complements the defects of the uvs-3 mutation. The uvs-3 mutant shows a higher level of micronuclei in conidia and failure to halt germination and nuclear division in the presence of hydroxyurea than wild type, suggesting checkpoint defects. ATRIP proteins bind tightly to ATR PI-3 kinase (phosphatidylinositol 3-kinase) proteins. Therefore, we searched the Neurospora genome sequence for homologues of the Aspergillus nidulans ATR, UvsB. A uvsB homologous sequence was present in the right arm of chromosome I where the mus-9 gene maps. A cosmid containing this genomic DNA complemented the mus-9 mutation. The putative MUS-9 protein is 2484 amino acids long with eight introns. Homology is especially high in the C-terminal 350 amino acids that correspond to the PI-3 kinase domain. In wild type a low level of constitutive mRNA is present for both genes. It is transiently induced upon UV exposure.

  19. Vaccination targeting human HER3 alters the phenotype of infiltrating T cells and responses to immune checkpoint inhibition.

    Osada, Takuya; Morse, Michael A; Hobeika, Amy; Diniz, Marcio A; Gwin, William R; Hartman, Zachary; Wei, Junping; Guo, Hongtao; Yang, Xiao-Yi; Liu, Cong-Xiao; Kaneko, Kensuke; Broadwater, Gloria; Lyerly, H Kim

    2017-01-01

    Expression of human epidermal growth factor family member 3 (HER3), a critical heterodimerization partner with EGFR and HER2, promotes more aggressive biology in breast and other epithelial malignancies. As such, inhibiting HER3 could have broad applicability to the treatment of EGFR- and HER2-driven tumors. Although lack of a functional kinase domain limits the use of receptor tyrosine kinase inhibitors, HER3 contains antigenic targets for T cells and antibodies. Using novel human HER3 transgenic mouse models of breast cancer, we demonstrate that immunization with recombinant adenoviral vectors encoding full length human HER3 (Ad-HER3-FL) induces HER3-specific T cells and antibodies, alters the T cell infiltrate in tumors, and influences responses to immune checkpoint inhibitions. Both preventative and therapeutic Ad-HER3-FL immunization delayed tumor growth but were associated with both intratumoral PD-1 expressing CD8 + T cells and regulatory CD4 + T cell infiltrates. Immune checkpoint inhibition with either anti-PD-1 or anti-PD-L1 antibodies increased intratumoral CD8 + T cell infiltration and eliminated tumor following preventive vaccination with Ad-HER3-FL vaccine. The combination of dual PD-1/PD-L1 and CTLA4 blockade slowed the growth of tumor in response to Ad-HER3-FL in the therapeutic model. We conclude that HER3-targeting vaccines activate HER3-specific T cells and induce anti-HER3 specific antibodies, which alters the intratumoral T cell infiltrate and responses to immune checkpoint inhibition.

  20. Pch2 acts through Xrs2 and Tel1/ATM to modulate interhomolog bias and checkpoint function during meiosis.

    Hsuan-Chung Ho

    2011-11-01

    Full Text Available Proper segregation of chromosomes during meiosis requires the formation and repair of double-strand breaks (DSBs to form crossovers. Repair is biased toward using the homolog as a substrate rather than the sister chromatid. Pch2 is a conserved member of the AAA(+-ATPase family of proteins and is implicated in a wide range of meiosis-specific processes including the recombination checkpoint, maturation of the chromosome axis, crossover control, and synapsis. We demonstrate a role for Pch2 in promoting and regulating interhomolog bias and the meiotic recombination checkpoint in response to unprocessed DSBs through the activation of axial proteins Hop1 and Mek1 in budding yeast. We show that Pch2 physically interacts with the putative BRCT repeats in the N-terminal region of Xrs2, a member of the MRX complex that acts at sites of unprocessed DSBs. Pch2, Xrs2, and the ATM ortholog Tel1 function in the same pathway leading to the phosphorylation of Hop1, independent of Rad17 and the ATR ortholog Mec1, which respond to the presence of single-stranded DNA. An N-terminal deletion of Xrs2 recapitulates the pch2Δ phenotypes for signaling unresected breaks. We propose that interaction with Xrs2 may enable Pch2 to remodel chromosome structure adjacent to the site of a DSB and thereby promote accessibility of Hop1 to the Tel1 kinase. In addition, Xrs2, like Pch2, is required for checkpoint-mediated delay conferred by the failure to synapse chromosomes.