Zeitschriftenartikel: „Simons' control mechanisms“

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Pandithasekara, Dasuni Nirmani, Erabaddage Ayoma Gayathri Sumanasiri und Áron Perényi. „Exploring the Impact of Sustainability Control Systems on Employees’ Green Creativity: The Mediating Role of Psychological Empowerment and Sustainability Learning Capabilities“. Sustainability 15, Nr. 6 (08.03.2023): 4806. http://dx.doi.org/10.3390/su15064806.

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This paper investigates how sustainability control systems (SCSs) drive employees’ green creativity (EGC) with the purpose of assisting organisations in the Sri Lankan manufacturing sector to improve their environmental sustainability performance. Managers and staff of manufacturing firms often lack awareness of environmental issues, which leads to unsustainable strategies. EGC has been identified as an important resource for devising sustainable strategies. SCSs drive employee behaviour and support EGC by fostering a creative workplace. Utilising Simons’ Levers of Controls (LoC) framework, a mediation model incorporating psychological empowerment (PE) and sustainability learning capabilities (SLCs) is tested to provide insights on how SCSs influence EGS. Survey data collected from 239 organisations in the Sri Lankan manufacturing sector were analysed using the PLS-SEM method. The results confirm the full mediating roles of PE and SLCs on the link between SCSs and EGC. This demonstrates the importance of empowering employees and enhancing their learning capabilities to encourage EGC. This study contributes to Simons’ LoC framework by incorporating sustainability dimensions into management control systems (MCSs), and extends the extant body of knowledge by providing a specific understanding of the mechanisms driving EGC through PE and SLCs.

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Zhao, Liang, Yang Bai, Jie Ma und Yonghui Wang. „Local Control Mechanisms of Implicit and Explicit Conflicts“. Experimental Psychology 62, Nr. 3 (07.05.2015): 153–60. http://dx.doi.org/10.1027/1618-3169/a000281.

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Congruency sequence effects are observed when the congruency effects following incongruent trials are smaller than those following congruent trials. It is typically assumed that such flexible adjustments are evidence of cognitively controlled dynamic modulations. The present study investigated whether cognitive control acts locally or globally when implicit and explicit conflicts exist simultaneously within a system. The implicit SNARC task and explicit Simon task were combined in a single task. The results showed that congruency effects of one type (e.g., SNARC effect) were only smaller following an incongruent trial of the same type (e.g., SNARC effect), but not when following an incongruent trial of the other type (e.g., Simon effect). These results indicate the operation of local control mechanisms triggered by implicit and explicit conflicts.

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BLUMENFELD, HENRIKE K., und VIORICA MARIAN. „Cognitive control in bilinguals: Advantages in Stimulus–Stimulus inhibition“. Bilingualism: Language and Cognition 17, Nr. 3 (21.11.2013): 610–29. http://dx.doi.org/10.1017/s1366728913000564.

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Bilinguals have been shown to outperform monolinguals at suppressing task-irrelevant information and on overall speed during cognitive control tasks. Here, monolinguals’ and bilinguals’ performance was compared on two nonlinguistic tasks: a Stroop task (with perceptualStimulus–Stimulus conflictamong stimulus features) and a Simon task (withStimulus–Response conflict). Across two experiments testing bilinguals with different language profiles, bilinguals showed more efficient Stroop than Simon performance, relative to monolinguals, who showed fewer differences across the two tasks. Findings suggest that bilingualism may engage Stroop-type cognitive control mechanisms more than Simon-type mechanisms, likely due to increased Stimulus–Stimulus conflict during bilingual language processing. Findings are discussed in light of previous research on bilingual Stroop and Simon performance.

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Soutschek, Alexander, Hermann J. Müller und Torsten Schubert. „Conflict-Specific Effects of Accessory Stimuli on Cognitive Control in the Stroop Task and the Simon Task“. Experimental Psychology 60, Nr. 2 (01.11.2013): 140–48. http://dx.doi.org/10.1027/1618-3169/a000181.

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Both the Stroop and the Simon paradigms are often used in research on cognitive control, however, there is evidence that dissociable control processes are involved in these tasks: While conflicts in the Stroop task may be resolved mainly by enhanced task-relevant stimulus processing, conflicts in the Simon task may be resolved rather by suppressing the influence of task-irrelevant information on response selection. In the present study, we show that these control mechanisms interact in different ways with the presentation of accessory stimuli. Accessory stimuli do not affect cognitive control in the Simon task, but they impair the efficiency of cross-trial control processes in the Stroop task. Our findings underline the importance of differentiating between different types of conflicts and mechanisms of cognitive control.

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Salzer, Yael, Daniela Aisenberg, Tal Oron-Gilad und Avishai Henik. „In Touch With the Simon Effect *The first two authors contributed equally.“ Experimental Psychology 61, Nr. 3 (01.11.2014): 165–79. http://dx.doi.org/10.1027/1618-3169/a000236.

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Cognitive control has been extensively studied using the auditory and visual modalities. In the current study, a tactile version of the Simon task was created in order to test control mechanisms in a modality that was less studied, to provide comparative and new information. A significant Simon effect – reaction time gap between congruent (i.e., stimulus and response in the same relative location) and incongruent (i.e., stimulus and response in opposite locations) stimuli – provided grounds to further examine both general and tactile-specific aspects of cognitive control in three experiments. By implementing a neutral condition and conducting sequential and distributional analysis, the present study: (a) supports two different independent mechanisms of cognitive control – reactive control and proactive control; (b) reveals facilitation and interference within the tactile Simon effect; and (c) proposes modality differences in activation and processing of the spatially driven stimulus-response association.

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Struys, Esli, Ghazal Mohades, Peggy Bosch und Maurits van den Noort. „Cognitive Control in Bilingual Children“. Swiss Journal of Psychology 74, Nr. 2 (Januar 2015): 65–73. http://dx.doi.org/10.1024/1421-0185/a000152.

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Studies comparing the cognitive control of bilingual and monolingual speakers are inconclusive about the nature and underlying mechanisms of differences in language-related processing. In the present study, in order to disentangle the impact of second-language onset age of acquisition and bilingualism on cognitive control, we compared a group of bilingual Dutch/French children who had started acquisition of both languages at birth (simultaneous bilingual group) to a group of children who had started acquisition of their second language at the age of 3 years (early bilingual group). Both groups had equal proficiency in the two languages. All participants completed an extensive language test battery in Dutch and French and conducted a linguistic (verbal fluency) and a nonlinguistic cognitive control task (the color Simon task). We found higher global accuracy rates for the simultaneous bilingual group on the Simon task. Surprisingly, we did not find any differences in mean reaction time between the two bilingual groups. In conclusion, this study finds no advantage in terms of verbal fluency, but does reveal that acquiring two languages from birth onward gives simultaneous bilingual children an advantage on the Simon task, even over early bilingual children and when second-language proficiency is held constant.

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Suarez, Isabel, Franck Vidal, Boris Burle und Laurence Casini. „A Dual-Task Paradigm to Study the Interference Reduction in the Simon Task“. Experimental Psychology 62, Nr. 2 (01.03.2015): 75–88. http://dx.doi.org/10.1027/1618-3169/a000275.

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Analyzing RT distributions in the Simon task reveals that congruency effects decrease for the longest RTs. Four experiments were carried out to examine whether this decrease of the congruency effect with response speed was under a top-down control or due to bottom-up mechanisms. We specifically manipulated the availability of attentional resources by requiring participants to perform a Simon task concurrently to different secondary tasks. RT distribution analysis (in particular delta functions) was performed under both single-task and dual-task conditions. Results show that the reduction of the interference effect with time could be affected when the Simon task was performed concurrently with a secondary task. Nonetheless, the type of the secondary task seems to be a critical factor. Therefore, the data suggest that the mechanisms responsible for the reduction of the interference effect with time are under some attentional control but the exact nature of these mechanisms remains to be explored.

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Mowery, Cody, Jacob Freimer, Jennifer Umhoefer, Christian Garrido, Ralf Schmidt, Zachary Steinhart, Benjamin Gowen et al. „CRISPRi and KO screens reveal integrated cis- and trans-regulation of the CD28, CTLA4, and ICOS locus in primary human T cells“. Journal of Immunology 208, Nr. 1_Supplement (01.05.2022): 56.17. http://dx.doi.org/10.4049/jimmunol.208.supp.56.17.

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Abstract Costimulation is essential for complete T cell activation, requiring the coordinated expression of various surface proteins including those encoded by CD28 family members CD28, CTLA4, and ICOS. Interestingly, these three genes lie adjacently in a topologically-associating domain (TAD) and are believed to have arisen through duplications of CD28, though they have evolved opposing functions and exhibit expression differences across cell states and T cell subsets. We hypothesized that distinct cis- and trans-regulatory circuits emerged to uniquely govern the expression of each gene. Therefore, we tiled CRISPR interference (CRISPRi) across the 1.44Mb TAD in primary human conventional (Tconv) and regulatory T (Treg) cells to functionally profile cis-regulatory elements (CREs) controlling expression of CD28, CTLA4, and ICOS. We find that inhibiting the transcriptional start site of one gene (but not gene KO) enhances the expression of an adjacent gene, potentially due to redirection of shared CREs to the un-inhibited promoter. Moreover, we find distinct CREs responsible for constitutive expression of CTLA4 in Treg cells but stimulation-responsiveness in Tconv cells. We also find evidence of a single CRE that negatively regulates CD28 at baseline but positively regulates CTLA4 upon restimulation. Lastly, we characterize mechanisms of CRE control by identifying upstream regulators of target genes via CRISPR knockout screening. Our work nominates ZNF217, a zinc finger protein with no known function in human T cells, as a novel negative regulator altering chromatin accessibility in the locus. Here, we present a framework for functional characterization of regulatory modules controlling loci of interest in primary human CD4+ T cells. CM is supported by NIAID F30 AI157167-01 and is a UCSF ImmunoX Computational Immunology Fellow. ZS is supported by the Parker Institute for Cancer Immunology scholarship. RS was supported by fellowships of the Austrian Exchange Service and the Austrian Society of Laboratory Medicine. C.J.Y. and AM are Chan Zuckerberg Biohub Investigators and members of the PICI. C.J.Y. is further supported by the National Institutes of Health (NIH) grant nos. R01AR071522, R01AI136972 and R01HG011239. AM is supported by National Institute of Diabetes and Digestive and Kidney Diseases DP3DK111914-01 (AM) Simons Foundation (AM) Burroughs Wellcome Fund, Career Award for Medical Scientists (AM) The Cancer Research Institute (CRI) Lloyd J. Old STAR grant (AM) Parker Institute for Cancer Immunotherapy, PICI (AM) Innovative Genomics Institute (IGI) National Institutes of Health grant P30 DK063720 (Parnassus Flow Cytometry Core, AM) National Institutes of Health grant S10 1S10OD021822-01 (Parnassus Flow Cytometry Core, AM) Investigator at the Chan Zuckerberg Biohub (AM) Gifts from Brook Byers, Barbara Bakar, Karen Jordan, Elena Radutzky

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Massaro, Maurizio, Andrea Moro und Mike Lucas. „Approcci formali e informali al controllo negli innovation network. La relazione tra Leve del Controllo e Fattori della Fiducia“. MANAGEMENT CONTROL, Nr. 1 (Mai 2012): 27–54. http://dx.doi.org/10.3280/maco2012-001003.

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In recent years, there has been a significant increase in inter-organisational collaboration resulting in the emergence of hybrid organisational forms. This has led to recognition that management control can no longer be confined to the boundaries of a single organisation. Management control systems (MCS) must encompass networks of organisations. Inter-organisational relationships require both formal and informal controls. The latter are essentially mechanisms for encouraging self regulation. Significant among these mechanisms is trust. In inter-organisational collaborations high levels of trust can impact on the nature and the role of MCS. This paper elaborates a model of the link between the constituents of trust (trust factors) and the design of the MCS. We show how different trust factors (ability, benevolence, integrity) impact on different MCS' approaches (belief, boundary, diagnostic and interactive systems) using Simon's (1995) levers of control framework. The model demonstrates that an understanding of these relationships, especially in the innovation networks, can help managers employ the most suitable approach to management control in organisational network.

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Forstmann, Birte U., Wery P. M. van den Wildenberg und K. Richard Ridderinkhof. „Neural Mechanisms, Temporal Dynamics, and Individual Differences in Interference Control“. Journal of Cognitive Neuroscience 20, Nr. 10 (Oktober 2008): 1854–65. http://dx.doi.org/10.1162/jocn.2008.20122.

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Functional magnetic resonance imaging (fMRI) methods may help in understanding processes of response capture and response inhibition in conflict tasks, such as the Simon task. However, data-driven approaches thus far have not yielded consistent insights into these processes. Here, a theory-driven approach is introduced that capitalizes on individual differences in the processes of central interest. Based on the so-called activation-suppression model, specific behavioral parameters for each individual derived from reaction time (RT) distribution analysis were computed and entered into model-based fMRI analyses. These parameters correspond closely to the processes of inappropriate location-driven response activation (capture) and the subsequent inhibition of this activation as detailed by the model. Data from 24 participants revealed activation in the pre-supplementary motor area, which covaried with the RT distribution measure of response capture. Activation in the right inferior frontal cortex was found to covary with the RT distribution measure of response inhibition. These results, which are consistent against the backdrop of the larger literature on cognitive control, could have been derived neither from the standard data-driven fMRI approach, nor from inspecting overall mean RT alone.

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Lafargue, Audrey M., Hailun Wang, Sivarajan T. Chettiar, Rajendra P. Gajula, Amol C. Shetty, Yang Song, Brian W. Simons et al. „Abstract 2968: TWIST1-induced suppression of oncogene-induced senescence in non-small cell lung cancer requires the transactivation domain of TWIST1“. Cancer Research 84, Nr. 6_Supplement (22.03.2024): 2968. http://dx.doi.org/10.1158/1538-7445.am2024-2968.

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Abstract Non-small cell lung carcinoma (NSCLC) is a major cause of cancer mortality. High expression of the epithelial-to-mesenchymal transition transcription factor TWIST1 is strongly associated with metastatic cancers and treatment resistance. Additionally, TWIST1 can upregulate O-GlcNAcylation which (1) is required to suppress fail-safe programs such as oncogene (KRasG12D)-induced senescence (OIS) to accelerate tumorigenesis in primary NSCLC tumors, and (2) is a potential modulator of DNA repair/radiation response. To decipher the domains and transcriptional targets required for tumorigenicity and radioresistance, we created a novel genetically engineered mouse model (GEMM) allowing tetracycline-inducible expression in the lung epithelium (via lung specific CCSP-reverse tetracycline transactivator (C)) of KRasG12D (R) with Twist1wt (T) or with Twist1F191G transactivation-null mutant (F). CRT mice had shorter tumor-free survival and more aggressive tumors compared to CR/CRF mice indicating that the Twist1 transactivation domain is required for Twist1-dependent tumorigenesis acceleration. Also, Twist1wt expression promoted radioresistance in cell lines and GEMMs. Contrary to CRT, CRF showed a progressive loss of Twist1F191G expression over time suggesting no functionality/no selective advantage. CRT lung tumors had higher proliferation (Ki67) and lower cell-cycle arrest (p16) compared to CR/CRF suggesting that the transactivation domain of Twist1 is important for the suppression of OIS. Supporting these data, we observed in non-cancer Human Bronchial Epithelial Cell (HBEC) that the co-expression of human TWIST1wt (HBEC-TWIST1wt) could suppress HRasG12V-induced senescence while the transactivation-null TWIST1F187G mutant (HBEC-TWIST1F187G) could not. Additionally, HBEC expressing HRasG12V-TWIST1wt had enhanced tumorigenic/invasive programs. Interestingly, we observed that the inhibition of O-GlcNAcylation rescued OIS in HBEC-HRasG12V-TWIST1wt while the stimulation of O-GlcNAcylation in HBEC-HRasG12V-TWIST1F187G suppressed OIS. Furthermore, TWIST1wt expression with HRasG12V modulated MYC downstream targets and the inhibition of MYC activity using the novel MYC inhibitor MYCi975 in HBEC-HRasG12V-TWIST1wt also rescued OIS induction. Altogether, these results suggest that TWIST1 may suppress OIS via MYC signaling and nominate MYCi975 as a means to activate latent OIS programs. In this context, MYC inhibiting strategies could serve as a therapeutic sensitizer for TWIST1-positive NSCLC. This work and our future studies on TWIST1 toward the control of OIS, O-GlcNAcylation and of mechanisms of radioresistance may help to identify new potential NSCLC therapeutic strategies. Citation Format: Audrey M. Lafargue, Hailun Wang, Sivarajan T. Chettiar, Rajendra P. Gajula, Amol C. Shetty, Yang Song, Brian W. Simons, Triet Nguyen, Christine Lam, Francesca A. Carrieri, Caleb Smack, Nick Connis, Dipanwita Dutta Chowdhury, Jinhee Chang, Danielle Council, Katriana Nugent, Ismaeel Siddiqui, Kekoa Taparra, Mohammad Rezaee, Natasha Zachara, Zachary S. Morris, Christopher McFarland, Sarki Abba Abdulkadir, Christine L. Hann, Phuoc T. Tran. TWIST1-induced suppression of oncogene-induced senescence in non-small cell lung cancer requires the transactivation domain of TWIST1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2968.

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Correa, Ángel, Paola Cappucci, Anna C. Nobre und Juan Lupiáñez. „The Two Sides of Temporal Orienting“. Experimental Psychology 57, Nr. 2 (01.11.2010): 142–48. http://dx.doi.org/10.1027/1618-3169/a000018.

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Would it be helpful to inform a driver about when a conflicting traffic situation is going to occur? We tested whether temporal orienting of attention could enhance executive control to select among conflicting stimuli and responses. Temporal orienting was induced by presenting explicit cues predicting the most probable interval for target onset, which could be short (400 ms) or long (1,300 ms). Executive control was measured both by flanker and Simon tasks involving conflict between incompatible responses and by the spatial Stroop task involving conflict between perceptual stimulus features. The results showed that temporal orienting facilitated the resolution of perceptual conflict by reducing the spatial Stroop effect, whereas it interfered with the resolution of response conflict by increasing flanker and Simon effects. Such opposite effects suggest that temporal orienting of attention modulates executive control through dissociable mechanisms, depending on whether the competition between conflicting representations is located at perceptual or response levels.

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Wylie, Scott A., K. Richard Ridderinkhof, Theodore R. Bashore und Wery P. M. van den Wildenberg. „The Effect of Parkinson's Disease on the Dynamics of On-line and Proactive Cognitive Control during Action Selection“. Journal of Cognitive Neuroscience 22, Nr. 9 (September 2010): 2058–73. http://dx.doi.org/10.1162/jocn.2009.21326.

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Processing irrelevant visual information sometimes activates incorrect response impulses. The engagement of cognitive control mechanisms to suppress these impulses and make proactive adjustments to reduce the future impact of incorrect impulses may rely on the integrity of frontal–basal ganglia circuitry. Using a Simon task, we investigated the effects of basal ganglia dysfunction produced by Parkinson's disease (PD) on both on-line (within-trial) and proactive (between-trial) control efforts to reduce interference produced by the activation of an incorrect response. As a novel feature, we applied distributional analyses, guided by the activation–suppression model, to differentiate the strength of incorrect response activation and the proficiency of suppression engaged to counter this activation. For situations requiring on-line control, PD (n = 52) and healthy control (n = 30) groups showed similar mean interference effects (i.e., Simon effects) on reaction time (RT) and accuracy. Distributional analyses showed that although the strength of incorrect response impulses was similar between the groups PD patients were less proficient at suppressing these impulses. Both groups demonstrated equivalent and effective proactive control of response interference on mean RT and accuracy rates. However, PD patients were less effective at reducing the strength of incorrect response activation proactively. Among PD patients, motor symptom severity was associated with difficulties in on-line, but not in proactive, control of response impulses. These results suggest that basal ganglia dysfunction produced by PD has selective effects on cognitive control mechanisms engaged to resolve response conflict, with primary deficits in the on-line suppression of incorrect responses occurring in the context of a relatively spared ability to adjust control proactively to minimize future conflict.

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Boutris, Panagiotis, Jessica Rees, Brodie Bevan und Cristina Izura. „Bilingualism and cognitive reserve: It’s a matter of top-down or bottom-up process“. Yearbook of the Poznan Linguistic Meeting 6, Nr. 1 (01.12.2020): 113–58. http://dx.doi.org/10.14746/yplm.2020.6.5.

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Cognitive performance declines with age following different trajectories. The cognitive trade-off, however, between age and cognitive reserve is still not clear. In addition, bilingualism has been thought to play a role in delaying cognitive decline by affecting cognitive control outside the scope of language. However, the effect has been unreliably reproduced and without exploring sufficiently the differences between cognitive functions that govern language control. In the current study 112 adults varying in age, level of bilingualism and cognitive reserve, completed a modified version of the Simon task, which engaged the mechanisms of interference suppression and shifting. Using ex-Gaussian analysis, the Simon effect was replicated in the normal component and the shifting effect was found in the exponential. Additional linear mixed-effects model analysis showed a significant “negative” effect of bilingualism on inhibition and a “positive” effect of cognitive reserve on shifting, both independent of age. Age affected similarly the speed of engagement of both executive functions irrespectively of language or cognitive background. Implications of a bilingual disadvantage and a beneficial effect of cognitive reserve during ageing are discussed.

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LILL, PHILIPP A., ANDREAS WALD und RONALD GLEICH. „AGILITY AND THE ROLE OF PROJECT — INTERNAL CONTROL SYSTEMS FOR INNOVATION PROJECT PERFORMANCE“. International Journal of Innovation Management 24, Nr. 07 (05.11.2019): 2050064. http://dx.doi.org/10.1142/s1363919620500644.

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As a reaction to the rapidly changing environment, organisations increasingly use agile project management (APM) methods to develop innovation. The associated process changes necessitate the adaption of organisational structures and control systems. This study draws on Simon’s Levers-of-Control framework (LOC) to explore the impact of different control levers on innovation project performance. Based on a survey of 316 project managers and product owners, the results suggest that the use of interactive project control systems and project-internal belief systems has a positive impact on the innovation outcome, regardless of the degree of agility of the project. Furthermore, we reveal that a strong project environment leads to increased use of control mechanisms on the project level and has a conducive impact on innovation project performance. The study is among the first to apply the LOC on the project level and integrate it into the agile context.

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Grisetto, Fanny, Pierre Le Denmat, Yvonne N. Delevoye-Turrell, Quentin Vantrepotte, Tanguy Davin, Andreea Dinca, Isabelle Desenclos-El Ghoulti und Clémence Roger. „Imbalanced weighting of proactive and reactive control as a marker of risk-taking propensity“. PLOS ONE 18, Nr. 1 (20.01.2023): e0277246. http://dx.doi.org/10.1371/journal.pone.0277246.

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According to the dual mechanisms of control (DMC), reactive and proactive control are involved in adjusting behaviors when maladapted to the environment. However, both contextual and inter-individual factors increase the weight of one control mechanism over the other, by influencing their cognitive costs. According to one of the DMC postulates, limited reactive control capacities should be counterbalanced by greater proactive control to ensure control efficiency. Moreover, as the flexible weighting between reactive and proactive control is key for adaptive behaviors, we expected that maladaptive behaviors, such as risk-taking, would be characterized by an absence of such counterbalance. However, to our knowledge, no studies have yet investigated this postulate. In the current study, we analyzed the performances of 176 participants on two reaction time tasks (Simon and Stop Signal tasks) and a risk-taking assessment (Balloon Analog Risk Taking, BART). The post-error slowing in the Simon task was used to reflect the spontaneous individuals’ tendency to proactively adjust behaviors after an error. The Stop Signal Reaction Time was used to assess reactive inhibition capacities and the duration of the button press in the BART was used as an index of risk-taking propensity. Results showed that poorer reactive inhibition capacities predicted greater proactive adjustments after an error. Furthermore, the higher the risk-taking propensity, the less reactive inhibition capacities predicted proactive behavioral adjustments. The reported results suggest that higher risk-taking is associated with a smaller weighting of proactive control in response to limited reactive inhibition capacities. These findings highlight the importance of considering the imbalanced weighting of reactive and proactive control in the analysis of risk-taking, and in a broader sense, maladaptive behaviors.

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Vissers, Marlies E., K. Richard Ridderinkhof, Michael X. Cohen und Heleen A. Slagter. „Oscillatory Mechanisms of Response Conflict Elicited by Color and Motion Direction: An Individual Differences Approach“. Journal of Cognitive Neuroscience 30, Nr. 4 (April 2018): 468–81. http://dx.doi.org/10.1162/jocn_a_01222.

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Goal-directed behavior requires control over automatic behavior, for example, when goal-irrelevant information from the environment captures an inappropriate response and conflicts with the correct, goal-relevant action. Neural oscillations in the theta band (∼6 Hz) measured at midfrontal electrodes are thought to form an important substrate of the detection and subsequent resolution of response conflict. Here, we examined the extent to which response conflict and associated theta-band activity depend on the visual stimulus feature dimension that triggers the conflict. We used a feature-based Simon task to manipulate conflict by motion direction and stimulus color. Analyses were focused on individual differences in behavioral response conflict elicited across different stimulus dimensions and their relationship to conflict-related midfrontal theta. We first confirmed the presence of response conflict elicited by task-irrelevant motion and stimulus color, demonstrating the usefulness of our modified version of the Simon task to assess different sensory origins of response conflict. Despite titrating overall task performance, we observed large individual differences in the behavioral manifestations of response conflict elicited by the different visual dimensions. These behavioral conflict effects were mirrored in a dimension-specific relationship with conflict-related midfrontal theta power, such that, for each dimension, individual midfrontal theta power was generally higher when experienced response conflict was high. Finally, exploratory analyses of interregional functional connectivity suggested a role for phase synchronization between frontal and parietal scalp sites in modulating experienced conflict when color was the task-relevant visual dimension. Highlighting the importance of an individual differences approach in cognitive neuroscience, these results reveal large individual differences in experienced response conflict depending on the source of visual interference, which are predicted by conflict-related midfrontal theta power.

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Lemaire, Patrick, und Thomas Hinault. „Age-Related Differences in Sequential Modulations of Poorer-Strategy Effects“. Experimental Psychology 61, Nr. 4 (01.12.2014): 253–62. http://dx.doi.org/10.1027/1618-3169/a000244.

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To determine how younger and older adults modulate execution of strategies across successive trials, we asked participants to accomplish a computational estimation task (i.e., provide approximate products to two-digit multiplication problems like 38 × 74). For each problem, they were cued to execute a better versus a poorer strategy. Their performance revealed sequential modulations of poorer-strategy effects (i.e., longer solution times and larger error rates when asked to execute a poorer than a better strategy). That is, poorer-strategy effects were smaller on current problems after using a poorer strategy on preceding problems than after using a better strategy. Moreover, sequential modulations of these poorer-strategy effects were smaller in older than in younger adults, especially older adults with low-cognitive control skills (as measured by conflict adaptation effects in the Simon task). Our findings suggest that these sequential modulations may result from executive control mechanisms, the efficiency of which is known to decrease in older adults. These findings have important implications regarding mechanisms underlying strategy execution and aging effects on strategic variations.

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Klostermann, André. „Does the Simon Effect Interfere with the Synergy Between Perception and Action?“ Perceptual and Motor Skills 128, Nr. 4 (02.06.2021): 1765–84. http://dx.doi.org/10.1177/00315125211022917.

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Research suggests that – particularly – the execution of precision-demanding far-aiming tasks necessitates an optimal coupling between perception and action. In this regard, the duration of the last fixation before initiating movement – i.e., the Quiet Eye (QE) – has been functionally related to subsequent motor performance. In the current study, we investigated potential mechanisms of QE by applying the Simon paradigm – i.e., cognitive interferences evoked by stimulus-effect incompatibilities over response selection. To this end, we had participants throw balls as precisely as possible, either with their left or right hand (hands condition, HC) or at left or right targets (targets condition, TC), respectively. Via monaural auditory stimuli, participants received information about the hand side and the target side, respectively, either with compatible (i.e., congruent stimulus-effect side) or incompatible (i.e., incongruent stimulus-effect side) stimulus-effect mappings. Results showed that participants reacted slower and showed later first fixation onsets at the target in incompatible vs. compatible trials, thus, replicating and extending the classical Simon effect. Crucially, in the HC, there were earlier QE onsets and longer QE durations in incompatible (vs. compatible) trials, suggesting an inhibition of cognitive interferences over response selection to preserve motor performance. These findings are in line with attentional explanations of QE, suggesting optimized attentional control with efficient management of limited cognitive resources (optimal-attentional-control explanation) or with the inhibition of alternative response parametrization (inhibition explanation).

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Ficarella, Stefania C., Andrea Desantis, Alexandre Zénon und Boris Burle. „Preparing to React: A Behavioral Study on the Interplay between Proactive and Reactive Action Inhibition“. Brain Sciences 11, Nr. 6 (22.05.2021): 680. http://dx.doi.org/10.3390/brainsci11060680.

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Motor preparation, based on one’s goals and expectations, allows for prompt reactions to stimulations from the environment. Proactive and reactive inhibitory mechanisms modulate this preparation and interact to allow a flexible control of responses. In this study, we investigate these two control mechanisms with an ad hoc cued Go/NoGo Simon paradigm in a within-subjects design, and by measuring subliminal motor activities through electromyographic recordings. Go cues instructed participants to prepare a response and wait for target onset to execute it (Go target) or inhibit it (NoGo target). Proactive inhibition keeps the prepared response in check, hence preventing false alarms. Preparing the cue-coherent effector in advance speeded up responses, even when it turned out to be the incorrect effector and reactive inhibition was needed to perform the action with the contralateral one. These results suggest that informative cues allow for the investigation of the interaction between proactive and reactive action inhibition. Partial errors’ analysis suggests that their appearance in compatible conflict-free trials depends on cue type and prior preparatory motor activity. Motor preparation plays a key role in determining whether proactive inhibition is needed to flexibly control behavior, and it should be considered when investigating proactive/reactive inhibition.

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Ivy, Julia. „Capabilities of Entrepreneurial Ventures that Successfully Navigate Regime Change: A Research Agenda“. International Journal of Business and Management Research 8, Nr. 3 (30.09.2020): 73–83. http://dx.doi.org/10.37391/ijbmr.080303.

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The study provides a framework and research agenda for investigating factors that contribute to the sustainability and growth of entrepreneurial ventures operating in environments of regime change. The suggested framework builds on Herbert Simon’s [1] science of design, as later extended to concepts of entrepreneurship as creation [2] and effectuation [3], in order to describe the nature of entrepreneurial actions in an environment of regime change. The framework integrates theory on organizational capabilities [4] to locate mechanisms behind entrepreneurs’ successful efforts to equip their ventures with capabilities for sustainability and growth. The study offers a pragmatism-driven methodology for studying ventures as artifacts created by entrepreneurs that practice the even-if principle of non-predictable control when navigating the challenges of regime change.

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Ali, Nilufa, David W. Green, Ferath Kherif, Joseph T. Devlin und Cathy J. Price. „The Role of the Left Head of Caudate in Suppressing Irrelevant Words“. Journal of Cognitive Neuroscience 22, Nr. 10 (Oktober 2010): 2369–86. http://dx.doi.org/10.1162/jocn.2009.21352.

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Suppressing irrelevant words is essential to successful speech production and is expected to involve general control mechanisms that reduce interference from task-unrelated processing. To investigate the neural mechanisms that suppress visual word interference, we used fMRI and a Stroop task, using a block design with an event-related analysis. Participants indicated with a finger press whether a visual stimulus was colored pink or blue. The stimulus was either the written word “BLUE,” the written word “PINK,” or a string of four Xs, with word interference introduced when the meaning of the word and its color were “incongruent” (e.g., BLUE in pink hue) relative to congruent (e.g., BLUE in blue) or neutral (e.g., XXXX in pink). The participants also made color decisions in the presence of spatial interference rather than word interference (i.e., the Simon task). By blocking incongruent, congruent, and neutral trials, we identified activation related to the mechanisms that suppress interference as that which was greater at the end relative to the start of incongruency. This highlighted the role of the left head of caudate in the control of word interference but not spatial interference. The response in the left head of caudate contrasted to bilateral inferior frontal activation that was greater at the start than at the end of incongruency, and to the dorsal anterior cingulate gyrus which responded to a change in the motor response. Our study therefore provides novel insights into the role of the left head of caudate in the mechanisms that suppress word interference.

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Fang, Liang, Dimin Li und Paul A. Welling. „Hypertension resistance polymorphisms in ROMK (Kir1.1) alter channel function by different mechanisms“. American Journal of Physiology-Renal Physiology 299, Nr. 6 (Dezember 2010): F1359—F1364. http://dx.doi.org/10.1152/ajprenal.00257.2010.

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The renal outer medullary K+ (ROMK) channel plays a critical role in renal sodium handling. Recent genome sequencing efforts in the Framingham Heart Study offspring cohort (Ji W, Foo JN, O'Roak BJ, Zhao H, Larson MG, Simon DB, Newton-Cheh C, State MW, Levy D, and Lifton RP. Nat Genet 40: 592–599, 2008) recently revealed an association between suspected loss-of-function polymorphisms in the ROMK channel and resistance to hypertension, suggesting that ROMK activity may also be a determinant of blood pressure control in the general population. Here we examine whether these sequence variants do, in fact, alter ROMK channel function and explore the mechanisms. As assessed by two-microelectrode voltage clamp in Xenopus oocytes, 3/5 of the variants (R193P, H251Y, and T313FS) displayed an almost complete attenuation of whole cell ROMK channel activity. Surface antibody binding measurements of external epitope-tagged channels and analysis of glycosylation-state maturation revealed that these variants prevent channel expression at the plasmalemma, likely as a consequence of retention in the endoplasmic reticulum. The other variants (P166S, R169H) had no obvious effects on the basal channel activity or surface expression but, instead, conferred a gain in regulated-inhibitory gating. As assessed in giant excised patch-clamp studies, apparent phosphotidylinositol 4,5-bisphosphate (PIP2) binding affinity of the variants was reduced, causing channels to be more susceptible to inhibition upon PIP2 depletion. Unlike the protein product of the major ROMK allele, these two variants are sensitive to the inhibitory affects of a G protein-coupled receptor, which stimulates PIP2 hydrolysis. In summary, we have found that hypertension resistance sequence variants inhibit ROMK channel function by different mechanisms, providing new insights into the role of the channel in the maintenance of blood pressure.

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Fernandez Cruz, Ana Lucia, Chien-Ming Chen, Ryan Sanford, D. Louis Collins, Marie-Josée Brouillette, Nancy E. Mayo und Lesley K. Fellows. „Multimodal neuroimaging markers of variation in cognitive ability in older HIV+ men“. PLOS ONE 16, Nr. 7 (27.07.2021): e0243670. http://dx.doi.org/10.1371/journal.pone.0243670.

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Objective This study used converging methods to examine the neural substrates of cognitive ability in middle-aged and older men with well-controlled HIV infection. Methods Seventy-six HIV+ men on antiretroviral treatment completed an auditory oddball task and an inhibitory control (Simon) task while time-locked high-density EEG was acquired; 66 had usable EEG data from one or both tasks; structural MRI was available for 43. We investigated relationships between task-evoked EEG responses, cognitive ability and immunocompromise. We also explored the structural correlates of these EEG markers in the sub-sample with complete EEG and MRI data (N = 27). Results EEG activity was associated with cognitive ability at later (P300) but not earlier stages of both tasks. Only the oddball task P300 was reliably associated with HIV severity (nadir CD4). Source localization confirmed that the tasks engaged partially distinct circuits. Thalamus volume correlated with oddball task P300 amplitude, while globus pallidus volume was related to the P300 in both tasks. Interpretation This is the first study to use task-evoked EEG to identify neural correlates of individual differences in cognition in men living with well-controlled HIV infection, and to explore the structural basis of the EEG markers. We found that EEG responses evoked by the oddball task are more reliably related to cognitive performance than those evoked by the Simon task. We also provide preliminary evidence for a subcortical contribution to the effects of HIV infection severity on P300 amplitudes. These results suggest brain mechanisms and candidate biomarkers for individual differences in cognition in HIV.

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Hoppe, Katharina, Edmund Wascher und Kristina Küper. „Feature Overlap and Relevance Determine Sequential Modulations in the Simon Task“. Journal of Psychophysiology 34, Nr. 2 (01.04.2020): 81–98. http://dx.doi.org/10.1027/0269-8803/a000239.

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Abstract. Subjects usually respond faster and more accurate in trials in which the response location corresponds to a task-irrelevant stimulus location compared to when not. Previous research has shown, that this so-called Simon effect is reduced after non-corresponding compared to after corresponding trials. As of now it is yet unclear what exact mechanisms drive such sequential modulations. One theory assumes a conflict adaptation mechanism that decreases the influence of incongruent information after non-corresponding trials via increased cognitive control. However, other authors claim that feature integration processes may be the underlying mechanism as the amount of feature overlap differs between different correspondence sequences. Unfortunately, this also means that in the standard Simon task the repetition of task features and correspondence sequences are not independent. In order to address this issue, we mapped four stimuli to two responses in the present EEG study. This way, we created a task, which allows for sequences in which the stimulus identity may change without alternating the required response. These sequences may either comprise a change of the stimulus position or not and the contribution of feature integration as well as conflict adaptation processes could thus be observed independently. Our results indicate that the repetition of task features affects performance to a stronger degree than the correspondence sequence and feature integration processes do. Yet, an impact of both could still be observed. The strongest effect of feature repetitions on task performance was observed for task-relevant features, especially for the imperative stimulus identity itself. The EEG results support these findings. The amplitudes of the fronto-central N2 and the parietal P3 decreased with increasing feature overlap from one trial to the next. The posterior lateralization, reflected by the posterior contralateral negativity (PCN), however, appears to reflect mainly changes in the stimulus location and stimulus–response (S–R) correspondence rather than feature repetitions per se.

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Abrasowicz, Gabriela. „Discourse on Corporeality and the Logic of Control in the Works of Contemporary post-Yugoslav Women Playwrights“. AM Journal of Art and Media Studies, Nr. 18 (15.04.2019): 51. http://dx.doi.org/10.25038/am.v0i18.296.

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The issue of corporeality is one of the dominant motifs in contemporary women’s playwriting in the countries formed after the collapse of Yugoslavia. At the turn of the 20th and 21st centuries women’s bodies function as a specific open register in their works, where real-life content is included. The body is also an instrument which detects the meanings of social actions and interactions. According to the authors – mainly from Serbia, Croatia, Bosnia and Herzegovina, and Montenegro – the body becomes a constantly-transforming palimpsestic, multi-layered body-text which delivers information about the logic of control. The body-centric perspective here is connected with the problematization of the characters’ reactions to some mechanisms of normalization, classification, and increasing productivity of the bodies in their population. The changes in the configuration of control modes and everyday practices in some areas of women’s life activity are presented. The female authors, e.g.: Milena Bogavac, Maja Pelević (Serbia), Lada Kaštelan, Ivana Sajko (Croatia), Jasna Šamić, Elma Tataragić (Bosnia and Herzegovina), Nataša Nelević (Montenegro), Simona Semenič (Slovenia) illustrate some rituals and transgressions concerning procreation, female visual representations and the body losing its fitness and becoming isolated. In their artistic descriptions the authors confirm the relationship between the cultural and psychological inscription of the female body and female difference in language and text. Article received: December 13, 2018; Article accepted: January 23, 2019; Pulbished online: April 15, 2019; Original scholarly paperHow to cite this article: Abrasowicz, Gabriela. "Discourse on Corporeality and the Logic of Control in the Works of Contemporary post-Yugoslav Women Playwrights." AM Journal of Art and Media Studies 18 (2019): 51–64. doi: 10.25038/am.v0i18.296

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Pinheiro, Pedro, und Goran Putnik. „Organizational efficiency prospects for management in Industry 4.0“. FME Transactions 49, Nr. 4 (2021): 773–83. http://dx.doi.org/10.5937/fme2104773p.

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Industry 4.0 emerges as a tool to help organizations manage. Often identified with the Internet of Things and Cyber-Physical Systems, Industry 4.0 appears as a solution to many of the difficulties plaguing manufacturing. The history of management theories, e.g. by Taylor, Fayol, or Simon, shows that deterministic solutions do not ensure the permanent success of organizations. In manufacturing, the economy overlaps the technological, social, environmental, and cultural dimensions that influence organizations. This paper assesses the possible benefits for the efficiency of the organizations resulting from the implementation of Industry 4.0. To fulfill this purpose, the effects on the hierarchical structures of organizations are investigated, namely those related to specialization, authority, and span of control. The results show that technological advances and efficiency of industry 4.0, which are relevant for the economy, still do not respond satisfactorily to social needs that require changes in the behavior of the management system.

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Umbu Henggu, Krisman, und Yopi Nurdiansyah. „Review dari Metabolisme Karbohidrat, Lipid, Protein, dan Asam Nukleat“. QUIMICA: Jurnal Kimia Sains dan Terapan 3, Nr. 2 (02.08.2022): 9–17. http://dx.doi.org/10.33059/jq.v3i2.5688.

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Artikel review ini mengulas tentang prinsip dan proses metabolisme karbohidrat, lipid, protein dan asam nukeat pada organisme. Telaah pustaka yang disajikan dalam review ini bersumber pada jurnal ilmiah maupun buku terakreditasi yang relevan. Lintasan metabolisme karbohidrat, lipid, protein, asam nukleat terdiri atas tiga bentuk lintasan yakni katabolik, anabolik dan amfibolik. Lintasan tersebut umumnya terjadi pada mitokondria melalui siklus Krebs. Katabolisme protein, karbohidrat dan lemak dapat menjadi derivat asam amino, glukosa, gliserol dan asam lemak yang mampu dikonversi menjadi energi maupun cadangan energi untuk proses pertumbuhan dan perkembangan sel. Demikian sebaliknya proses anabolisme dapat memanfaatkan derivat makro molekul (asam amino, glukosa, fruktosa, asam lemak) menjadi makro molekul (protein, karbohidrat dan lipid). Proses metabolisme karbohidrat secara khusus melalui glikolisis, glikogenesis dan glukoneogenesis. Sedangkan metabolisme lemak melalui proses asetil-KoA terkarboksilase dan menghasilkan malonil-KoA hingga berlanjut pada proses pembentukan asam lemak melalui proses enzimatis (elongase dan desaturase). Demikian pula pada metabolisme protein yang diawali dengan pemecahan makro molekul dalam bentuk peptida menjadi monomer terkecil (asam amino) secara enzimatis (melibatkan enzim protease) dan menjadi salah satu sumber energi dalam pembentukan ATP untuk perkembangan sel. Sebaliknya anabolisme protein tersebut didasari oleh proses transmisi dan aminasi. Metabolisme asam nukleat melibatkan proses sintesis purin dan pirimidin sebagai nukleotida secara de novo. Proses metabolisme asam nukleat melaui proses enzimatik (housekeeping) yang sangat bertanggungjawab terhadap fungsi katabolisme dan anabolisme. Referensi: [1] Wali, J. A., Milner, A. J., Luk, A. W., Pulpitel, T. J., Dodgson, T., Facey, H. J., ... & Simpson, S. J. (2021). Impact of dietary carbohydrate type and protein–carbohydrate interaction on metabolic health. Nature Metabolism, 3(6), 810-828. [2] Staples, J. F. (2016). Metabolic flexibility: hibernation, torpor, and estivation. Compr. Physiol, 6(2), 737-71. [3] O’Neill, L. A. (2015). A broken krebs cycle in macrophages. Immunity, 42(3), 393-394. [4] Rajendran, M., Dane, E., Conley, J., & Tantama, M. (2016). Imaging adenosine triphosphate (ATP). The Biological Bulletin, 231(1), 73-84. [5] Luo, L., & Liu, M. (2016). Adipose tissue in control of metabolism. Journal of endocrinology, 231(3), R77-R99. [6] Poggiogalle, E., Jamshed, H., & Peterson, C. M. (2018). Circadian regulation of glucose, lipid, and energy metabolism in humans. Metabolism, 84, 11-27. [7] Purba, D. H., Marzuki, I., Dailami, M., Saputra, H. A., Mawarti, H., Gurning, K., ... & Purba, A. M. V. (2021). Biokimia. . Bandung (ID): Yayasan Kita Menulis Press [8] Park, S., Jeon, J. H., Min, B. K., Ha, C. M., Thoudam, T., Park, B. Y., & Lee, I. K. (2018). Role of the pyruvate dehydrogenase complex in metabolic remodeling: differential pyruvate dehydrogenase complex functions in metabolism. Diabetes & metabolism journal, 42(4), 270-281. [9] Adeva-Andany, M. M., Pérez-Felpete, N., Fernández-Fernández, C., Donapetry-García, C., & Pazos-García, C. (2016). Liver glucose metabolism in humans. Bioscience reports, 36(6). [10] Murray, Robert K. Daryl K. Granner; Victor W. Rodwell. Biokimia Harper Ed.27. Jakarta. EGC;2009 : 152-94 [11] Jones, J. G. (2016). Hepatic glucose and lipid metabolism. Diabetologia, 59(6), 1098-1103. [12] Chen, L., Zhang, Z., Hoshino, A., Zheng, H. D., Morley, M., Arany, Z., & Rabinowitz, J. D. (2019). NADPH production by the oxidative pentose-phosphate pathway supports folate metabolism. Nature metabolism, 1(3), 404-415. [13] Shi, L., & Tu, B. P. (2015). Acetyl-CoA and the regulation of metabolism: mechanisms and consequences. Current opinion in cell biology, 33, 125-131. [14] Chandel, N. S. (2021). Lipid metabolism. Cold Spring Harbor Perspectives in Biology, 13(9), a040576. [15] Tsikas, D. (2017). Assessment of lipid peroxidation by measuring malondialdehyde (MDA) and relatives in biological samples: Analytical and biological challenges. Analytical biochemistry, 524, 13-30. [16] Merino-Ramos, T., Vázquez-Calvo, Á., Casas, J., Sobrino, F., Saiz, J. C., & Martín-Acebes, M. A. (2016). Modification of the host cell lipid metabolism induced by hypolipidemic drugs targeting the acetyl coenzyme A carboxylase impairs West Nile virus replication. Antimicrobial agents and chemotherapy, 60(1), 307-315. [17] Schmitt, S., Castelvetri, L. C., & Simons, M. (2015). Metabolism and functions of lipids in myelin. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids, 1851(8), 999-1005. [18] Cerk, I. K., Wechselberger, L., & Oberer, M. (2018). Adipose triglyceride lipase regulation: an overview. Current Protein and Peptide Science, 19(2), 221-233. [19] Whitford, D. (2013). Proteins: Structure And Function. John Wiley & Sons. [20] Gropper, S. S., & Smith, J. L. (2012). Advanced Nutrition And Human Metabolism. Cengage Learning. [21] Bender, D. A. (2012). Amino acid metabolism. John Wiley & Sons. [22] Chargaff, E. (Ed.). (2012). The nucleic acids. Elsevier. [23] Kochetkov, N. (Ed.). (2012). Organic Chemistry of Nucleic Acids: Part B. Springer Science & Business Media. [24] Wang, L. (2016). Mitochondrial purine and pyrimidine metabolism and beyond. Nucleosides, Nucleotides and Nucleic Acids, 35(10-12), 578-594.

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Anderson, Jack. „Doping, sport and the law: time for repeal of prohibition?“ International Journal of Law in Context 9, Nr. 2 (Juni 2013): 135–59. http://dx.doi.org/10.1017/s1744552313000050.

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AbstractThis article concerns the legal issues that surround the prohibition of doping in sport. The current policy on the use of performance enhancing drugs (PEDs) in sport is underpinned by both a paternalistic desire to protect athletes' health and the long-term integrity or ‘spirit’ of sport. The policy is put into administrative effect globally by the World Anti-Doping Agency (WADA), which provides the regulatory and legal framework through which the vast majority of international sports federations harmonise their anti-doping programmes. On outlining briefly both the broad administrative structures of international sport's various anti-doping mechanisms, and specific legal issues that arise in disciplinary hearings involving athletes accused of doping, this article questions the sustainability of the current ‘zero tolerance’ approach, arguing, by way of analogy to the wider societal debate on the criminalisation of drugs, and as informed by Sunstein and Thaler's theory of libertarian paternalism, that current policy on anti-doping has failed. Moreover, rather than the extant moral and punitive panic regarding doping in sport, this article, drawing respectively on Seddon's and Simon's work on the history of drugs and crime control mentality, contends that, as an alternative, harm reductionist measures should be promoted, including consideration of the medically supervised use of certain PEDs.

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Woodard, Tyler, Viju Gupta, Simona Miceska, Bisiayo Fashemi, Wendy Zhang und Dineo Khabele. „Abstract 795: Entinostat restores responsiveness to Olaparib in ID8 TP53 null and ID8 TP53 null/BRCA2 null mouse ovarian cancer cell lines“. Cancer Research 82, Nr. 12_Supplement (15.06.2022): 795. http://dx.doi.org/10.1158/1538-7445.am2022-795.

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Abstract Poly (adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi) reduce disease progression in patients diagnosed with ovarian cancer. The anticancer effects of PARPi are most effective in tumors with BRCA mutations and homologous recombination (HR) deficiency (HRD). One mechanism of PARPi resistance is through restoration of HR repair. Our group has shown that entinostat (an HDACi) potentiates the effects of olaparib (a PARPi). The objective of this study was to investigate mechanisms of intrinsic PARPi resistance by studying the combination of entinostat and olaparib in HR proficient and HR deficient mouse ovarian cancer cell lines. We used the ID8 TP53 null (HR proficient) and ID8 TP53 null/BRCA2 null (HR deficient) mouse ovarian cancer cell lines that harbor molecular features consistent with human high-grade serous ovarian cancer. To recapitulate an ongoing clinical trial using this drug combination, cells were pre-treated with 0.25 µM Entinostat or control for 24 hours, followed by 24 or 72 hours of drug treatment [0.5 µM Entinostat, 10 µM of Olaparib, the combination of both, or control]. Clonogenicity assays were used to assess colony formation and MTS assays were used to measure cell viability and proliferation. We then performed immunofluorescence (IF) staining for RAD51 (a marker for HR repair), γH2AX (a marker of DNA damage) and Ki67 (a marker of proliferation). As expected in the clonogenicity assay, there was no statistically significant difference in cell survival between the olaparib treated ID8 TP53 null (HR proficient) cells and vehicle-treated controls (p= 0.0993; paired t test). Alternatively, the ID8 TP53 null/BRCA2 null (HR deficient) cell line treated with olaparib alone reduced cell viability compared to control (p=0.0245; paired t test). Clonogenicity assays also demonstrated that the combination of entinostat and olaparib reduced colony formation compared to control in the ID8 TP53 null cell line (p<0.0001; one-way ANOVA). MTS assays corroborated this treatment effect (p< 0.0001; two way ANOVA). Preliminary data suggests that compared to controls and each drug alone, IF staining for RAD51 and Ki67 expression was reduced in cells treated with combination therapy. Also preliminarily, there was increased number of γH2AX foci in combination treatment compared to controls and each drug alone. Entinostat restores responsiveness to olaparib in ID8 TP53 null HR proficient mouse ovarian cancer cells that molecularly resemble high-grade serous ovarian carcinoma. These results suggest this drug combination can overcome intrinsic resistance to PARPi and provide additional preclinical support for clinical investigation of this combination for the treatment of HR proficient ovarian cancer. Citation Format: Tyler Woodard, Viju Gupta, Simona Miceska, Bisiayo Fashemi, Wendy Zhang, Dineo Khabele. Entinostat restores responsiveness to Olaparib in ID8 TP53 null and ID8 TP53 null/BRCA2 null mouse ovarian cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 795.

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Hobbs, Gabriela, Cansu Cimen Bozkus, Erin Moshier, Mikaela Dougherty, Michal Bar-Natan, Lonette Sandy, Kathryn Johnson et al. „PD-1 inhibition in advanced myeloproliferative neoplasms“. Blood Advances 5, Nr. 23 (03.12.2021): 5086–97. http://dx.doi.org/10.1182/bloodadvances.2021005491.

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Abstract Myelofibrosis (MF) is a clonal stem cell neoplasm characterized by abnormal JAK-STAT signaling, chronic inflammation, cytopenias, and risk of transformation to acute leukemia. Despite improvements in the therapeutic options for patients with MF, allogeneic hematopoietic stem cell transplantation remains the only curative treatment. We previously demonstrated multiple immunosuppressive mechanisms in patients with MF, including increased expression of programmed cell death protein 1 (PD-1) on T cells compared with healthy controls. Therefore, we conducted a multicenter, open-label, phase 2, single-arm study of pembrolizumab in patients with Dynamic International Prognostic Scoring System category of intermediate-2 or greater primary, post-essential thrombocythemia or post-polycythemia vera myelofibrosis that were ineligible for or were previously treated with ruxolitinib. The study followed a Simon 2-stage design and enrolled a total of 10 patients, 5 of whom had JAK2V617mutation, 2 had CALR mutation, and 6 had additional mutations. Most patients were previously treated with ruxolitinib. Pembrolizumab treatment was well tolerated, but there were no objective clinical responses, so the study closed after the first stage was completed. However, immune profiling by flow cytometry, T-cell receptor sequencing, and plasma proteomics demonstrated changes in the immune milieu of patients, which suggested improved T-cell responses that can potentially favor antitumor immunity. The fact that these changes were not reflected in a clinical response strongly suggests that combination immunotherapeutic approaches rather than monotherapy may be necessary to reverse the multifactorial mechanisms of immune suppression in myeloproliferative neoplasms. This trial was registered at www.clinicaltrials.gov as #NCT03065400.

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Simon, M. Celeste. „Abstract IA017: Impact of oxygen and nutrient availability on sarcoma tumor neighborhood“. Clinical Cancer Research 28, Nr. 18_Supplement (15.09.2022): IA017. http://dx.doi.org/10.1158/1557-3265.sarcomas22-ia017.

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Abstract Molecular oxygen (O2) sustains intracellular bioenergetics and is consumed by numerous biochemical reactions, making it essential for most species on Earth. Accordingly, decreased oxygen concentration (hypoxia) is a major stressor that generally subverts life of aerobic species and is a prominent feature of pathological states encountered in bacterial infection, inflammation, wounds, cardiovascular defects and cancer. Therefore, key adaptive mechanisms to cope with hypoxia have evolved in mammals. Systemically, these adaptations include increased ventilation, cardiac output, blood vessel growth and circulating red blood cell numbers. On a cellular level, ATP- consuming reactions are suppressed, and metabolism is altered until oxygen homeostasis is restored. A critical question is how mammalian cells sense oxygen levels to coordinate diverse biological outputs during hypoxia. The best- studied mechanism of response to hypoxia involves hypoxia inducible factors (HIFs), which are stabilized by low oxygen availability and control the expression of a multitude of genes, including those involved in cell survival, angiogenesis, glycolysis and invasion/metastasis. Importantly, changes in oxygen can also be sensed via other stress pathways as well as changes in metabolite levels and the generation of reactive oxygen species by mitochondria. Collectively, this leads to cellular adaptations of protein synthesis, energy metabolism, mitochondrial respiration, lipid and carbon metabolism as well as nutrient acquisition. These mechanisms are integral inputs into fine- tuning the responses to hypoxic stress. Citation Format: M. Celeste Simon. Impact of oxygen and nutrient availability on sarcoma tumor neighborhood [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr IA017.

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O'Reilly, Eileen Mary, Maeve Aine Lowery, Kenneth H. Yu, Marinela Capanu, Zsofia Kinga Stadler, Andrew S. Epstein, Talia Golan et al. „Randomized phase II study of gemcitabine (G), cisplatin (C) with or without veliparib (V) (arms A, B) and a phase II single-arm study of single-agent veliparib (arm C) in patients with BRCA or PALB2-mutated pancreas adenocarcinoma (PC).“ Journal of Clinical Oncology 31, Nr. 15_suppl (20.05.2013): TPS4144. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.tps4144.

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TPS4144 Background: Germline mutations in BRCA1, 2 predispose to PC (Lal, G. Cancer Res, 2000). 5-8% PC have BRCA 1,2 mutations; higher in Ashkenazi Jewish (10-15%). Pre-clinical data demonstrates that platinums and poly-ADP ribose polymerase inhibitors (PARPi) have activity in BRCA-mutated PC models. Early clinical data supporting (Lowery, M. Oncol, 2011). We are evaluating the role of platinum agents and PARPi, veliparib (ABT-888), in BRCA or PALB2-mutated PC. Methods: Arm A, B: Includes non-randomized phase to optimize V dose combined with G, C (Arm A). Subsequently randomized phase II study will evaluate G, C +/- V. Primary endpoint: RECIST 1.1 response rate (RR) G, C, V (Arm A) and G, C (Arm B). Secondary endpoints: Progression-free survival, safety, disease-control rate, overall survival and correlatives involving pre, post biopsies to evaluate mechanisms of sensitivity, resistance to platinums, PARPi. Arm C: Evaluates single-agent V in previously-treated PC. Primary and secondary endpoints similar. Eligibility: BRCA, PALB2-mutated, measurable, stage III/IV PC; Untreated (Arm A, B), ≤ 2 lines therapy (Arm C); ECOG 0-1 (Arm A, B), ECOG 0-2 (Arm C). Treatment Plan: Arm A, B: V PO BID d1-12 (Arm A), q 3 weeks, G 600mg/m2 IV, C 25mg/m2IV, both d3, 10, q 3 weeks (Arm A, B). Arm C: V 400mg PO BID d1-28 q 4 weeks. Biostatistics: Arms A, B: Simon’s 2-stage minimax design per arm. Unacceptable RR 10%, promising 30%, type I, II errors 10%. N= 16 stage I, +N= 9 (stage II). If ≥ 5/25, then promising. If both arms promising, option to add N= 10, allows distinction between RR 20% and 40%, 83% power. Arm C: Simon’s 2-stage, single-arm, uninteresting RR 10%, promising if ≥ 28%. N= 15 stage I, +N= 18 (stage II). Promising RR ≥ 6/33. Total N 47- 95. Contingency for slow accrual. Progress to Date: Accrual: Arm A (non-randomized): 13 screened, N= 5 enrolled. Arm C: 9 screened, N= 4 enrolled. Israeli, Canadian, other U.S. sites opening 2013. Funding and acknowledgements: National Cancer Institute, Lustgarten Foundation. NCT01585805. Clinical trial information: NCT01585805.

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Prabhakar, S., und A. K. Goel. „Learning about novel operating environments: Designing by adaptive modelling“. Artificial Intelligence for Engineering Design, Analysis and Manufacturing 10, Nr. 2 (April 1996): 151–56. http://dx.doi.org/10.1017/s0890060400001438.

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According to Simon (1983), machine learning is a process that improves the performance of an intelligent system. The performance task of a design system is to arrive at a structural description of a device given its functional description. Machine learning can occur, to improve the performance of the design system, in a number of ways. The learning can make the process of arriving at a known structure to function mapping faster, either by improving the control strategy or by learning new world knowledge needed for the structure to function mapping. It can also improve the performance of the design system by allowing it to come up with new structure to function mappings. The latter kinds of learning leads to innovative designs. The work presented in this paper, EnviroAdapt, belongs to the latter category. EnviroAdapt has the performance task of designing devices along with their operating environments. The EnviroAdapt learns about the novel environments and designs devices for these environments. This learning process is enabled by adapting the previous designs of devices along with their operating environments. This adaptation process makes use of abstracting general mechanisms from the previous designs, then instantiating them in the context of new design problem. Both of these processes are driven by the characteristics of the new design problem that requires a device to operate within a novel operating environment.

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Danesi, Marcel. „The Language of Power: Casini and Bancheri's In-Depth Analysis of Italian in Immigration and Global Contexts“. Italica 99, Nr. 2 (01.06.2022): 282–98. http://dx.doi.org/10.5406/23256672.99.2.08.

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Abstract This review article looks at a groundbreaking book in sociolinguistics by Simone Casini and Salvatore Bancheri, What Is the Language of Power? Theoretical Reflections on Italian, Italiese and Other Languages, which focuses on the forms and uses of Italian in immigrant communities, as well as the role of the Italian language in the global village in which we now reside. Based on research conducted on the kind of Italian that takes shape in immigrant communities, called “Italiese,” one of the main insights that can be gleaned from this penetrating book is that the language that emerges in immigrant communities is a product of creative mechanisms, enlisted unconsciously to render the native language (or dialect) adapted to solving everyday communicative problems that pertain to the new environment socially and conceptually. By making the English input conform to the native language, structurally and semantically, the result is a code that allows for direct access to the new reality on its own terms. The book also relates the ways in which Italiese is constructed and employed to the history of Italian itself, ending with a broad examination of the roles that the language should be playing in an international context today. As such, it provides an expansive theoretical framework for assessing the factors that contribute to making a language, such as Italian, an instrument of control over any environment, real or virtual—hence, a “language of power.”

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Einstein, David Johnson, Atish Dipankar Choudhury, Philip James Saylor, Lillian Werner, Mark G. Erlander, Maya Ridinger und Glenn Bubley. „A phase II study of onvansertib (PCM-075) in combination with abiraterone and prednisone in patients with metastatic castration-resistant prostate cancer.“ Journal of Clinical Oncology 37, Nr. 7_suppl (01.03.2019): TPS336. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.tps336.

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TPS336 Background: Metastatic castration-resistant prostate cancer (mCRPC) remains a leading cause of cancer-related deaths worldwide. Although abiraterone (abi) in either the castration-sensitive or castration-resistant setting increases survival, resistance is universal and limits the efficacy of subsequent hormonal therapies. Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase that regulates mitotic functions and promotes the progression of cells through mitosis, and it is highly upregulated in prostate cancer following castration. PLK1 inhibition enhances the efficacy of abi in cell line models as well as patient-derived tumor xenografts via several mechanisms. Onvansertib (PCM-075; Trovagene, Inc.) is the first orally available PLK1-specific inhibitor. In phase 1 testing, onvansertib demonstrated a manageable safety profile, with transient hematologic effects as its most prominent, yet reversible, toxicity. Methods: The goal of this phase 2 study (NCT03414034) is to observe the effects of onvansertib in combination with abi + prednisone on disease control, as assessed by prostate-specific antigen (PSA) decline or stabilization after 12 weeks of study treatment, in subjects with mCRPC and early resistance to abi. Patients will be enrolled at time of PSA progression while on standard abi. A completed 3-patient safety lead-in phase tested the safety of the combination of onvansertib with abi, and the accruing expansion phase will treat 29 more patients with onvansertib (24 mg/m2 orally on days 1-5 of a 21-day cycle) plus abi (administered orally and continuously once daily with prednisone) until time of radiographic or symptomatic progression. With 32 patients, there will be 90% power to detect a change in disease-control rate from 10% (null) to 30% (alternative). Based on a Simon’s two-stage optimal design, the study will terminate early if < 2 of the first 13 patients achieve disease control. Exploratory analyses include evaluations of predictive genomic biomarkers in circulating tumor cells and circulating tumor DNA, including alterations of oncogenes and tumor suppressors implicated in PLK1 sensitivity within preclinical models. Clinical trial information: NCT03414034.

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Einstein, David Johnson, Atish Dipankar Choudhury, Philip James Saylor, Lillian Werner, Mark G. Erlander, Maya Ridinger und Glenn Bubley. „A phase II study of onvansertib in combination with abiraterone and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC).“ Journal of Clinical Oncology 38, Nr. 6_suppl (20.02.2020): TPS266. http://dx.doi.org/10.1200/jco.2020.38.6_suppl.tps266.

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TPS266 Background: Metastatic CRPC remains a leading cause of cancer-related deaths worldwide. Although abiraterone (abi) in either the castration-sensitive or castration-resistant setting increases survival, resistance is universal and generally occurs within 9-16 months of initiating treatment. Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase that regulates mitotic functions and progression, and it is highly upregulated in prostate cancer following castration. PLK1 inhibition enhances the efficacy of abi in cell line models and patient-derived tumor xenografts via several mechanisms. Onvansertib (PCM-075; Trovagene, Inc.) is the first orally available PLK1-specific inhibitor. In phase 1 testing, onvansertib demonstrated a manageable safety profile, with transient and reversible hematologic effects. Methods: The goal of this phase 2 study (NCT03414034) is to observe the effects of onvansertib in combination with abi + prednisone on disease control, as assessed by prostate-specific antigen (PSA) decline or stabilization after 12 weeks of study treatment, in subjects with mCRPC and early resistance to abi. Patients will be enrolled at time of PSA progression while on standard abi. A safety lead-in phase has been completed at one dosing schedule (24 mg/m2 on days 1-5 of a 21-day cycle) and is ongoing at a second dosing schedule (18 mg/m2 on days 1-5 of a 14-day cycle). Expansion phases are ongoing on both arms. In addition, a more continuous dosing schedule has been proposed (12 mg/m2 on days 1-14 of a 21-day cycle). With 32 patients in each arm, there will be 90% power to detect a change in disease-control rate from 10% (null) to 30% (alternative). Based on a Simon’s two-stage optimal design, the study will terminate early if <2 of the first 13 patients achieve disease control. Exploratory analyses include evaluation of the presence of the androgen receptor variant 7 (AR-V7) and other genomic alterations in circulating tumor cells and circulating tumor DNA that may be associated with response to treatment. Clinical trial information: NCT03414034.

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Contoux, C., G. Ramstein und A. Jost. „Modelling the mid-Pliocene Warm Period climate with the IPSL coupled model and its atmospheric component LMDZ5A“. Geoscientific Model Development 5, Nr. 3 (28.06.2012): 903–17. http://dx.doi.org/10.5194/gmd-5-903-2012.

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Abstract. This paper describes the experimental design and model results of the climate simulations of the mid-Pliocene Warm Period (mPWP, ca. 3.3–3 Ma) using the Institut Pierre Simon Laplace model (IPSLCM5A), in the framework of the Pliocene Model Intercomparison Project (PlioMIP). We use the IPSL atmosphere ocean general circulation model (AOGCM), and its atmospheric component alone (AGCM), to simulate the climate of the mPWP. Boundary conditions such as sea surface temperatures (SSTs), topography, ice-sheet extent and vegetation are derived from the ones imposed by the Pliocene Model Intercomparison Project (PlioMIP), described in Haywood et al. (2010, 2011). We first describe the IPSL model main features, and then give a full description of the boundary conditions used for atmospheric model and coupled model experiments. The climatic outputs of the mPWP simulations are detailed and compared to the corresponding control simulations. The simulated warming relative to the control simulation is 1.94 °C in the atmospheric and 2.07 °C in the coupled model experiments. In both experiments, warming is larger at high latitudes. Mechanisms governing the simulated precipitation patterns are different in the coupled model than in the atmospheric model alone, because of the reduced gradients in imposed SSTs, which impacts the Hadley and Walker circulations. In addition, a sensitivity test to the change of land-sea mask in the atmospheric model, representing a sea-level change from present-day to 25 m higher during the mid-Pliocene, is described. We find that surface temperature differences can be large (several degrees Celsius) but are restricted to the areas that were changed from ocean to land or vice versa. In terms of precipitation, impact on polar regions is minor although the change in land-sea mask is significant in these areas.

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Nguyen, Anthony T., Tahir B. Dar, Jolene Viramontes, Satchel Stevens, Julie K. Jang, Emily Y. Ko, Diana J. Lu et al. „Abstract 6409: Non-redundant mechanisms of immune resistance to radiotherapy converge on innate immunity“. Cancer Research 83, Nr. 7_Supplement (04.04.2023): 6409. http://dx.doi.org/10.1158/1538-7445.am2023-6409.

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Abstract Multiple studies have demonstrated synergy between immune checkpoint blockade (ICB) and radiotherapy (RT) in preclinical murine models; however, randomized trials of RT/ICB have been inconsistent in patients with solid tumors. To better understand this discordance, we hypothesized that there are non-redundant inhibitory immune pathways that restrain the efficacy of RT beyond T-cell oriented immune checkpoints. To this end, we performed scRNA-seq and CITE-seq analysis of the EO771 syngeneic murine model of breast cancer to characterize the immune landscape following RT±ICB. We found that ICB reprograms the immune response to RT by shifting tumor-associated macrophages (TAMs) from a lipid-associated phenotype (APOE, FABP5) to an M1-like interferon-stimulated state (CXCL10, ISG15). However, ICB also promoted the late recruitment of intratumoral neutrophils, which drive resistance to RT in other contexts. To evaluate whether neutrophils may be limiting antitumor immunity to RT/ICB, we depleted intratumoral neutrophils using two separate antibodies, anti-Ly6G and anti-Gr-1. Compared to RT/ICB alone, both neutrophil depletion strategies enhanced tumor control and prolonged survival in advanced EO771 tumors (P<0.001). Given that indiscriminate neutrophil depletion is not a viable therapeutic strategy, we tested alternative immune targeting approaches to alter the TAM response to RT/ICB. By scRNA-seq, we found that RT strongly upregulated several innate immune checkpoints on TAMs (e.g., SIRPα, SLAMF3/7, LRP1). Accordingly, we disrupted the SIRPα-CD47 interaction with anti-CD47 antibodies and characterized the impact on response to RT/ICB. Anti-CD47 significantly improved tumor regression and survival when combined with RT/ICB (P<0.001). We then used scRNA-seq and CITE-seq to understand why disruption of SIRPα-CD47 improved antitumor responses to RT/ICB. We found that anti-CD47 depleted an entire cluster of chronically inflamed TAMs, expressing pro-inflammatory markers (IL1A, NOS2) and chemokines (CCL3, CXCL1/2/3). Furthermore, anti-CD47 reduced the recruitment of intratumoral neutrophils and depleted a cluster of pathologically activated neutrophils (PMNs), termed myeloid-derived suppressor cells (PMN-MDSCs), expressing WFDC17, PTGS2, S100A8/9. Lastly, anti-CD47 enhanced the recruitment of tumor-infiltrating lymphocytes including central memory TCF7+ T cells and CD19+ B cells. By inference and analysis of cell-cell communication (CellChat), we found that anti-CD47 strengthened the interactions between myeloid cells and T cells compared to RT/ICB alone. Collectively, our data indicate that innate immune cells, in particular neutrophils and chronically inflamed TAMs, promote resistance to RT/ICB in the EO771 model. These data suggest that inhibition of CD47-SIRPα is a promising therapeutic strategy to overcoming immune resistance through the elimination of PMN-MDSCs. Citation Format: Anthony T. Nguyen, Tahir B. Dar, Jolene Viramontes, Satchel Stevens, Julie K. Jang, Emily Y. Ko, Diana J. Lu, Eric M. Chung, Samuel C. Zhang, Katelyn M. Atkins, Mitchell Kamrava, Howard M. Sandler, Jlenia Guarnerio, Simon Knott, Zachary S. Zumsteg, David M. Underhill, Stephen L. Shiao. Non-redundant mechanisms of immune resistance to radiotherapy converge on innate immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6409.

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Baer, Hallie, Jessica Simon, Lara McKean-Baste, Alicia N. Ray, Heather Green, Grace Maresh, Xin Zhang, David Marjolin, Jennifer Paruch und Li Li. „Abstract 1487: Role of micro-RNA199a-3p in lymph node stromal extracellular vesicles on tumorigenesis in colorectal cancer“. Cancer Research 82, Nr. 12_Supplement (15.06.2022): 1487. http://dx.doi.org/10.1158/1538-7445.am2022-1487.

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Abstract Introduction: MicroRNAs (miRNAs) are short non-coding RNAs implicated in post-transcriptional regulation of gene expression. Abnormal expression of miRNAs in cancer is associated with enhanced tumorigenesis and metastatic potential. Our previous data has shown that extracellular vesicles (EV) secreted by human lymph node stromal cells (LNSC) enhance tumorigenesis in colorectal cancer (CRC). By systemic searching and modifying miRNAs carried by EV through overexpression and inhibition on LNSC, we aim to demonstrate their effect on CRC progression in vitro and orthotopic mouse model. Methods: Total microRNA sequencing was analyzed using in-silico computer prediction models. Four overexpressed miRNAs in the LNSC-EV were selected (miR-155-5p, miR-199a-3p, mi-143-3p, and mi-214-3p). Tumor cell proliferation assay was performed using a CRC SW620 cell line transfected with selected miRNA mimics or inhibitors or controls. In our mouse model, miRNA transfected SW620 cells tagged with luciferase/RFP, were injected into the rectal submucosa of NOD/SCID mice. Tumor growth and metastases were observed by weekly bioluminescent imaging (BLI). At week 7, tumors were weighed and BLI of the tumors and organs were recorded. Immunohistochemistry staining was performed on the paraffin sections of tumors, livers and lung collected from these mice. Results: In vitro proliferation assays, cells transfected with the mimic of miRNA 199a-3p significantly increased CRC SW620 cell proliferation (p<0.01) while cells treated with the inhibitor showed decreased proliferation (p<0.05). In our orthotopic mouse model, mice with SW620 cells transfected with the mimic had increased frequencies of tumorigenesis (94% vs. 14%) and liver and lung metastasis comparing to control group (56% vs 9.5%, 50% vs 0%). Mice injected with SW620 cells transfected with the miRNA inhibitor had decreased tumor growth compared to the negative control (p<0.05). Conclusion: Our study shows that miRNAs carried in LNSC-EV are crucial for CRC progression. Specifically, inhibition of miRNA-199a-3p may serve as a therapeutic target in the treatment of CRC. Understanding the role and mechanisms of this miRNA in CRC could lead to the improved management of patients with CRC. Citation Format: Hallie Baer, Jessica Simon, Lara McKean-Baste, Alicia N. Ray, Heather Green, Grace Maresh, Xin Zhang, David Marjolin, Jennifer Paruch, Li Li. Role of micro-RNA199a-3p in lymph node stromal extracellular vesicles on tumorigenesis in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1487.

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Ishii, Toru, Makoto Kawai, Christina Chick, Isabelle Cotto, Joachim Hallmayer und Ruth O'hara. „0789 Sleep Spindle Density is Associated with Core Symptom Severity in Autism Spectrum Disorder“. SLEEP 46, Supplement_1 (01.05.2023): A348. http://dx.doi.org/10.1093/sleep/zsad077.0789.

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Abstract Introduction Converging evidence suggests that dysregulation of thalamocortical interactions, mediated by the thalamic reticular nucleus (TRN), contributes to the expression of autism spectrum disorder (ASD). Risk genes for ASD have been found to affect the TRN early in development. Two hallmarks of NREM sleep –slow oscillations (SO) and sleep spindles– reflect TRN function and distinct thalamic/thalamocortical circuits. While studies demonstrate disrupted sleep quality that correlates with symptoms in children with ASD, studies of spindles in ASD have produced inconsistent findings. It is yet unclear if and how spindle properties are associated with ASD symptoms. Herein, based on studies implicating TRN-mediated thalamocortical dysregulation in ASD, we hypothesized that 1) sleep spindles are reduced in ASD; 2) spindle abnormalities correlate with worse clinical symptoms and cognition. Methods Forty participants with ASD (32 males, age: 11.8 ± 3.2; range 6-15) and 46 typically developing (TD) controls (32 males, age: 11.2 ± 2.3; range 6-15) participated in the study. All participants underwent ambulatory overnight polysomnography (PSG) for sleep assessment after systematic desensitization. The Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview-Revised (ADI-R) were used to assess core behavioral symptoms. Results Spindle density was significantly lower in ASD compared to TD participants (ASD: 2.5 ± 2.0; TD: 3.0 ± 2.1; d= 0.45, p=0.01). In the ASD group, less spindle density was associated with more severe behavioral symptoms, as measured by the total ADOS score (R2=0.15, p=0.01) and the three main subscales of the ADI-R (reciprocal social interaction: R2=0.22, p=0.002; communication and language: R2=0.19, p=0.003; and restricted and repetitive, stereotyped interests and behaviors: R2=0.14, p=0.01). Conclusion Alterations in the maturational trajectory of spindles are related to the core symptoms of ASD individuals. The results have the potential to identify novel biomarkers that index distinct aspects of ASD pathophysiology and point to multiple neural mechanisms underlying disease heterogeneity. The study may contribute to producing novel evidence to elucidate the bidirectional relationship between sleep and ASD. Support (if any) Simons Foundation Autism Research Initiative grant (177986).

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D'Angelo, Egidio, Paola Rossi, Simona Armano und Vanni Taglietti. „Evidence for NMDA and mGlu Receptor-Dependent Long-Term Potentiation of Mossy Fiber–Granule Cell Transmission in Rat Cerebellum“. Journal of Neurophysiology 81, Nr. 1 (01.01.1999): 277–87. http://dx.doi.org/10.1152/jn.1999.81.1.277.

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D'Angelo, Egidio, Paola Rossi, Simona Armano, and Vanni Taglietti. Evidence for NMDA and mGlu receptor-dependent long-term potentiation of mossy fiber–granule cell transmission in rat cerebellum. J. Neurophysiol. 81: 277–287, 1999. Long-term potentiation (LTP) is a form of synaptic plasticity that can be revealed at numerous hippocampal and neocortical synapses following high-frequency activation of N-methyl-d-aspartate (NMDA) receptors. However, it was not known whether LTP could be induced at the mossy fiber–granule cell relay of cerebellum. This is a particularly interesting issue because theories of the cerebellum do not consider or even explicitly negate the existence of mossy fiber–granule cell synaptic plasticity. Here we show that high-frequency mossy fiber stimulation paired with granule cell membrane depolarization (−40 mV) leads to LTP of granule cell excitatory postsynaptic currents (EPSCs). Pairing with a relatively hyperpolarized potential (−60 mV) or in the presence of NMDA receptor blockers [5-amino-d-phosphonovaleric acid (APV) and 7-chloro-kynurenic acid (7-Cl-Kyn)] prevented LTP, suggesting that the induction process involves a voltage-dependent NMDA receptor activation. Metabotropic glutamate receptors were also involved because blocking them with (+)-α-methyl-4-carboxyphenyl-glycine (MCPG) prevented potentiation. At the cytoplasmic level, EPSC potentiation required a Ca2+ increase and protein kinase C (PKC) activation. Potentiation was expressed through an increase in both the NMDA and non-NMDA receptor-mediated current and by an NMDA current slowdown, suggesting that complex mechanisms control synaptic efficacy during LTP. LTP at the mossy fiber–granule cell synapse provides the cerebellar network with a large reservoir for memory storage, which may be needed to optimize pattern recognition and, ultimately, cerebellar learning and computation.

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Roksandić, Miodrag M. „On: “3-D seismic imaging and seismic attribute analysis of genetic sequences deposited in low‐ accommodation conditions” (B. A. Hardage, D. L. Carr, D.E. Lancaster, J. L. Simmons Jr., D. S. Hamilton, R. Y. Elphick, K. L. Oliver, and R. A. Johns, GEOPHYSICS, 61, 1351–1362)“. GEOPHYSICS 62, Nr. 6 (November 1997): 1996–98. http://dx.doi.org/10.1190/1.1444300.

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The paper deals with the results of a multidisciplinary study of the Bend Conglomerate (Middle Pennsylvanian fluvio‐deltaic clastics) in a portion of Boonsville gas field in the Fort Worth Basin of North‐Central Texas, especially with those related to the Caddo sequence, at the top of the Bend Conglomerate. The purpose of the study was “to determine how modern geophysical, geological, and engineering techniques could be combined to understand the mechanisms by which fluvio‐deltaic depositional processes create reservoir compartmentalization in a low‐ to moderate‐accommodation basin.” According to Hardage et al. (1996), complexly arranged key chronostratigraphic surfaces are major controls on compartmentalization and architecture of reservoirs. These key chronostratigraphic surfaces are flooding surfaces, maximum flooding surfaces, and erosion surfaces.

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Kutsenko, T., D. Nasiedkin, L. Latyshenko und M. Gavrylenko. „Relation of success in study of foreign language with speed of interhemispheric transfer of information“. Bulletin of Taras Shevchenko National University of Kyiv. Series: Problems of Physiological Functions Regulation 26, Nr. 1 (2019): 25–30. http://dx.doi.org/10.17721/1728_2624.2019.26.25-30.

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Bilingual speakers seem to outreach monolingual speakers in performing non-verbal tasks for testing executive functions, such as Simon, Flanker and Stroop tasks, as well as in capacity of working memory. Other researchers have doubts about these cognitive benefits of bilinguals and multilinguals. The study used a combined test with the tasks of the Stroop, Poffenberger, Sperry in native (Ukrainian) and foreign (English) languages. Schoolboys of lyceum were the subjects surveyed (14-15 years old). Stimuli (the word "Green" or "Red", "Blue" or "Yellow" written in relevant or irrelevant color) were exposed on the right or left from the center of the screen. In the case of congruence the word and its semantic meaning should press one button by the ipsilateral hand ("yes"), while in the case of mismatch – the other button by the contralateral one ("no"). Latent periods of response to stimuli, which reflect the speed of the interhemispheric transfer of information, were taken into account. Correlation analysis of the success in study in the nine subjects of the three blocks (humanities, natural and formal disciplines) reveal a direct correlation of speed of reaction when performing the complex Stroop test in both the native and English languages with the success in the learning English language, what may indicate on special dependence of the success from interhemispheric interaction. In order for the foreign language to be automated and become "all the more native", it is need the fast access of the executive structures of the brain, such as the front-parietal neural network, to the linguistic neural networks, presented in both hemispheres. According to literature, the inhibitory control mechanism from the dorsolateral prefrontal cortex as the key structure of the front-parietal brain system may be one of several mechanisms underlying bilingual superiority. The results obtained by us complement this conception, indicating the importance of the speed of interhemispheric interaction.

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Koffler, Daniel, Jacob Eckstein, Joseph Herman, Diana Martins-Welch, Nagashree Seetharamu, Maged Ghaly, Nina Kohn et al. „Efficacy of ketamine mouthwash in the management of oral and pharyngeal toxicity associated with head and neck chemoradiotherapy: protocol for a phase II, Simon’s two-stage trial“. BMJ Open 13, Nr. 4 (April 2023): e064809. http://dx.doi.org/10.1136/bmjopen-2022-064809.

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IntroductionCurative intent treatment of head and neck cancer (HNC) is frequently radiation therapy over 7 weeks with concurrent chemotherapy. This regimen is effective but carries a burden of toxicity leading to severe pain and treatment breaks portending inferior outcomes. Conventional palliation methods include opioids, anticonvulsants and local anaesthetics. Breakthrough toxicities are nevertheless ubiquitous and present an urgent unmet need. Ketamine is an inexpensive drug with mechanisms of analgesia outside the opioid pathway including N-methyl-D-aspartate (NMDA) receptor antagonism and a pharmacologically unique property of opioid desensitisation. Systemic ketamine is validated in randomised controlled trials for efficacy in reducing pain and/or opioid burden in the oncologic setting. Literature supports peripherally administered ketamine for pain control without systemic toxicity. These data support our rationale of using ketamine mouthwash to decrease acute toxicity of curative treatment of HNC, the efficacy of which is our aim to elucidate.Methods and analysisThis is a phase II, Simon’s two-stage trial. Patients have pathologically confirmed HNC and an intended regimen of 70 Gy of radiation with concurrent cisplatin. The protocol is initiated on diagnosis of grade 3 mucositis and consists of 2 weeks of 4 times daily (QID) ketamine mouthwash use. The primary endpoint is pain response defined as a combination of pain score and opioid use. 23 subjects will be enrolled in stage 1. If statistical criteria are met, 33 subjects will be enrolled in stage 2. Secondary endpoints include daily pain, daily opioid use, dysphagia at baseline and completion, nightly sleep quality, feeding tube placement and any unscheduled treatment breaks.Ethics and disseminationAll trial data will be stored in an Institutional Review Board (IRB) approved database. The protocol is registered under Northwell IRB registration number #22-0292 and U.S. Food and Drug Administration (FDA) Investigational New Drug (IND) approval has been granted under IND number 161609. Results are intended to be published in an open-source journal and further data, statistics and source documents are available on request.Trial registration numberNCT05331131.

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Sweetenham, John W., Basit Iqbal Chaudhry, Benjamin Teng, Andrew Yue und Nora Connor. „The use of quasi-experimental design methods to evaluate and improve the impact of acute care centers on oncologic emergencies.“ Journal of Clinical Oncology 39, Nr. 15_suppl (20.05.2021): e13515-e13515. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e13515.

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e13515 Background: Reducing avoidable hospital and emergency department (ED) use are national priorities in cancer care. Acute care centers (ACCs) that expand access for patients with oncologic emergencies are increasingly implemented as alternatives to inpatient and ED care. The impact of these ACCs is uncertain. Additionally, how to rigorously evaluate these interventions and to iteratively improve their effectiveness remains unclear as infrastructure interventions such as ACCs are not amenable to experimental manipulation. Methods: We are developing a novel quasi-experimental framework for evaluating and improving the effectiveness of an ACC intervention at the Simmons Comprehensive Cancer Center (SCCC) of the University of Texas Southwestern. SCCC covers one of the largest geographic regions of any academic medical center in the country, creating challenges addressing access to care. Drawing on the Andersen model for healthcare utilization we hypothesize that ACC effectiveness is mediated through enabling factors, particularly distance. Our initial evaluation framework draws on an untreated control group design with multiple pretest and post-test samples. The control group is comprised of patients living in zip codes farther away from the ACC. Additional analytic work will assess the feasibility of adding a matching cohort group structure based on factors such as onset of illness and matching individual patient episodes based on risk adjustment parameters. If the ACC is later expanded to other sites, the design can be further developed by adding a switching replications methodology to augment the quasi-experiment. Data collection draws on claims data provided through SCCC’s participation in Medicare’s Oncology Care Model (OCM). Results: Over OCM’s initial four performance periods (each six months long), all-cause risk adjusted hospitalization rates for SCCC patients ranged from 25.2% to 27.2%. All-cause risk adjusted OCM ED use ranged from 28.1 to 29.9%. Seeking to improve performance for both, SCCC leadership initially implemented a temporary urgent care clinic in August 2018. This initial prototype clinic was formalized into an operational ACC in August 2020. Evaluation of the impact of this ACC intervention is ongoing. Conclusions: ACCs represent potentially important means to reduce avoidable hospital and ED use. However, complex infrastructure interventions are not amenable to experimental evaluations assessing their impact, and it remains difficult to gain insights into how to tailor services through these interventions to support patients with oncologic urgencies and emergencies. Quasi-experimental approaches when integrated alongside ACC interventions represent promising mechanisms of evaluation and continuous quality improvement.

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Kashapov, Mergalyas M., und Anastasiya A. Volchenkova. „Theory of mind of adolescents in the context of inclusive education“. Vestnik of Kostroma State University. Series: Pedagogy. Psychology. Sociokinetics 27, Nr. 2 (30.07.2021): 118–27. http://dx.doi.org/10.34216/2073-1426-2021-27-2-118-127.

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Topicality of the study is due to the need for practice in understanding and substantiating the psychological foundations of the formation of such a personality trait of adolescents as tolerance, as well as in identifying other personal characteristics of adolescents as predictors of the formation of tolerance. The purpose of the article is a generalised theoretical presentation of the empirical results of a pilot study of the personality traits of adolescents in the context of inclusive education. Achieving this goal makes it possible to reveal the psychological mechanisms of the adolescent's social behaviour. The study of the problem of the mental model as a predictor of the formation of tolerance in adolescents in the context of inclusive education was carried out within the framework of the methodological principles developed by Simon Baron-Cohen, as well as in the framework of the system-subject approach of Yelena Sergiyenko, in which the traditions of the systemic (Boris Lomov, Alexei Leontiev, Vladimir Shadrikov) and the subject-activity (Sergei Rubinstein, Kseniya Abul'khanova, Andrey Brushlinskiy, Viktor Znakov) approaches in psychology are creatively integrated. The article presents and substantiates the results of an empirical study of the mental model as a predictor of the formation of tolerance in adolescents in the context of inclusive education. In the course of applying the procedure of regression analysis, on the basis of the mental model, the basic personality predictors of the formation of tolerance in adolescents – “self-control in communication”, “self-attitude” and “situational anxiety” were identified. The resulting regression model explains the possibility of influencing the general index of tolerance through the indicated personal characteristics. The mental model makes it possible to conceptualise the inner world of a teenager. The article substantiates new research opportunities for studying the ability of adolescents to understand their own mental world and the mental world of another. The conclusion is made about the high productivity of using the mental model, its research capabilities in the study of individual personality traits, and, in particular, in the formation of adolescent tolerance in the context of inclusive education.

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Yakou, Marina H., Sonia Ghilas, Kelly Tran, Yang Liao, Shoukat Afshar-Sterle, Anita Kumari, Kevin Schmid et al. „Abstract 2698: TCF-1 is a critical regulator of intraepithelial lymphocytes in colorectal carcinoma“. Cancer Research 84, Nr. 6_Supplement (22.03.2024): 2698. http://dx.doi.org/10.1158/1538-7445.am2024-2698.

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Abstract Tissue-resident immune cells reside within the gastrointestinal tract known as intraepithelial lymphocytes (T-IELs), including αβ and γδ T-IELs. This unique population of T cells constantly survey and are critical in maintaining the gastrointestinal epithelium. We show that T-IELs in various regions of the gastrointestinal tract have distinct features. T-IELs in the small intestine exhibit high expression of cytotoxic molecules important for cancer defense while colon T-IELs are distinctively regulated by the transcription factor, TCF-7/TCF-1, which suppresses their effector and cytotoxic properties, including reduced expression of granzymes, and their abundance is dependent on the microbiome. Targeted deletion of TCF-1 in γδ T-IELs using pre-clinical mouse models resulted in a distinct effector profile and reduced colon tumor burden. Furthermore, TCF-1 expression was significantly reduced in γδ T-IELs present in human colorectal cancers compared with normal healthy colon, strongly correlating with an enhanced γδ T-IEL effector phenotype and improved patient survival. Further investigation aims to elucidate diverse mechanisms by which TCF-1 controls tissue-specific anti-tumor immunity and uncover the important factors controlling TCF-1 expression. Our study underscores the necessity to consider tumor and organ microenvironment-specific factors in optimizing immunotherapy, advancing our understanding of T cell function in the colon to pave the way for innovative CRC treatments. Citation Format: Marina H. Yakou, Sonia Ghilas, Kelly Tran, Yang Liao, Shoukat Afshar-Sterle, Anita Kumari, Kevin Schmid, Christine Dijkstra, Chantelle Inguanti, Simone Ostrouska, Jordan Wilcox, Maxine Smith, Pavitha Parathan, Amr Allam, Hai-Hui Xue, Gabrielle T. Belz, John M. Mariadason, Andreas Behren, Grant R. Drummond, Roland Ruscher, David S. Williams, Bhupinder Pal, Wei Shi, Matthias Ernst, Dinesh Raghu, Lisa A. Mielke. TCF-1 is a critical regulator of intraepithelial lymphocytes in colorectal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2698.

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Ciombor, Kristen Keon, Tyler J. Zemla, Joleen M. Hubbard, Jingquan Jia, Olumide B. Gbolahan, Andrea Sousa, Luke Wilson et al. „A phase II single-arm study of the FGFR inhibitor pemigatinib in patients with metastatic colorectal cancer (mCRC) harboring FGF/FGFR alterations.“ Journal of Clinical Oncology 41, Nr. 4_suppl (01.02.2023): 139. http://dx.doi.org/10.1200/jco.2023.41.4_suppl.139.

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139 Background: The fibroblast growth factor receptor (FGFR) pathway plays a key role in cellular proliferation, migration, survival and angiogenesis. Aberrant signaling through FGFR in colorectal cancer and other malignancies results from gene amplification or mutation, chromosomal translocation or ligand-dependent activation of the receptors. Pemigatinib is an oral inhibitor of FGFR1-3 with proven efficacy in FGFR-altered cholangiocarcinoma and myeloid/lymphoid neoplasms, among others. We hypothesized that pemigatinib would improve response rates compared to historical controls in patients with refractory FGF/FGFR-altered mCRC. Methods: ACCRU-GI-1701 was a multicenter, single-arm, Simon’s two-stage phase II clinical trial (NCT04096417) of the FGFR inhibitor pemigatinib in patients (pts) with FGF/FGFR-altered mCRC. Eligible pts had received prior fluoropyrimidine, oxaliplatin, irinotecan, and anti-VEGF/anti-EGFR/anti-PD-1 if eligible. Pts received pemigatinib 13.5 mg once daily on d1-21 of each cycle, with option to escalate to 18 mg in c2 if well tolerated. The primary endpoint was (unconfirmed) objective response (OR). A sample size of 21 evaluable pts would provide 82% power to detect a true OR rate of 20% or greater compared to a historical control of 5 % with a one-sided type I error rate of 0.1. A prespecified interim analysis for futility was planned after 12 evaluable patients. Results: A total of 14 patients were enrolled in the first stage of the study, and all were evaluable for the primary endpoint. No OR were observed (out of 12) crossing the futility boundary and resulting in permanent closure of the study. Among all enrolled patients, median age was 60.5 years, 71.4% were male, 92.9% Caucasian, 42.9% with no prior exposure to TAS-102 or regorafenib, and 64.3% with left-sided primary tumors. Treated patients all had tumors with FGFR1-4 mutations and/or FGF/FGFR amplifications by tissue- and/or blood-based molecular testing; no FGFR translocations were present. OR rate for this study was 0% (95% CI, 0-23.2%), with one patient achieving stable disease as best response. Median progression-free survival was 9.1 weeks (95% CI, 7.9-not evaluable [NE]), and median overall survival was 7.9 months (95% CI, 3.4-NE). Grade 3+ adverse events (AE) were seen in 42.9% of treated patients (including 1 grade 5 AE). Most commonly occurring AEs of any grade were anemia, hyperphosphatemia, alkaline phosphatase increased, aspartate aminotransferase increase, and fatigue. Conclusions: Pemigatinib demonstrated evidence of safety but not clinical activity in this population of patients with FGF/FGFR-altered mCRC. It is unknown whether pemigatinib would be active in mCRC patients with FGFR translocations/fusions as these were not represented in our trial. Translational studies are planned to investigate mechanisms of resistance to this therapy. Clinical trial information: NCT04096417 .

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Chelis, Leonidas, Nikolaos Xenidis, Kiriakos Amarantidis, Nikolaos Diamantopoulos, Anastasios L. Boutis, Triantafyllia Koukaki, Prodromos Michailidis et al. „The importance of sequence in rescheduling bevacizumab and chemotherapy administration in the first-line treatment of metastatic colorectal carcinoma (mCRC).“ Journal of Clinical Oncology 32, Nr. 3_suppl (20.01.2014): 617. http://dx.doi.org/10.1200/jco.2014.32.3_suppl.617.

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617 Background: One of the proposed mechanisms of action for bevacizumab is by reducing the interstitial fluid pressure (IFP) allowing an increased penetration and uptake of chemotherapy agents in tumors. Clinical and laboratory data suggest that the decrease of IFP occurs after a few days of bevacizumab administration and intratumoral delivery of chemotherapy increase when bevacizumab precedes chemotherapy. We hypothesized that altering the schedule of BEV/FOLFOX regimen would improve the efficacy of the regimen and increase objective response rate. Methods: Patients (pts) with mCRC or locally advanced colorectal cancer, with ECOG PS 0-2 were eligible. The treatment schedule was Bevacizumab 5mg/Kg on day 1, standard FOLFOX-4 regimen on days 8-9 at cycles repeated every 14 days. Prior 5-FU/oxaliplatin adjuvant treatment was allowed. The pts were treated for 6 months or until reaching a plateau of response. Standard RECIST v1.1 response evaluation criteria were used. Primary endpoint of the study was the percentage of objective response rate, PR+CR (ORR), secondary end points were PFS, OS and toxicity. A Simon two step, minimax, statistical design was used: the minimum accepted ORR was 45% (p0) and the estimated ORR was 65% (p1). Results: Thirty (n=30) pts were enrolled. The median age was 69.5 years, the performance status was 0 (40%), 1 (40%), 2 (20%), the median follow up was 20.75 months and the K-RAS status was wild type for 63.5% and mutant for 36.5%. Seven pts (23.3%) had received prior adjuvant chemotherapy. Five pts had convertible metastatic disease. Four CR (13.33%), 18 PR (60%), 7 SD (23.33%), and one PD (3.3%) were observed for a total ORR of 73.3% and disease control rate (CR+PR+SD) of 96.7%. Four out of five (80%) pts with convertible disease achieved a R0 resection. The PFS was 12.8 months and OS has not been reached yet. One patient experienced a grade 4 event (febrile neutropenia). The study met its primary endpoint and therefore is considered positive. Conclusions: Delivering bevacizumab before chemotherapy in the first-line treatment of mCRC represents a very effective and promising schedule which warrants further investigation in randomized clinical trials.

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