Journal articles on the topic 'Delayed-rational model'
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1
Alter, David M., and Tsu-Chin Tsao. "Two-Dimensional Exact Model Matching With Application to Repetitive Control." Journal of Dynamic Systems, Measurement, and Control 116, no. 1 (March 1, 1994): 2–9. http://dx.doi.org/10.1115/1.2900677.
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This paper concerns matching a system with time-delayed feedback to a rational transfer function model and its application to repetitive controller design. Necessary and sufficient conditions on the order of the plant, reference model, and controller are obtained for the existence of causal and stabilizing exact model matching solutions. The results are applied to robust repetitive controller design, in which a delayed feedback is introduced in the repetitive controller for rejecting periodic disturbances while simultaneously achieving input-output model matching. Furthermore, the 2-D model matching method also renders computationally efficient solutions. Also addressed are some subtle points on the selection of a low-pass filter required for robust stability. Finally, the approach is experimentally applied for turning noncircular shapes.
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Clatch, Lauren, and Eugene Borgida. "Behavioral Economics in Plea-Bargain Decision-Making: Beyond the Shadow-of-Trial Model." Review of Law & Economics 17, no. 2 (July 1, 2021): 349–83. http://dx.doi.org/10.1515/rle-2021-0069.
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Abstract Legal scholars have long assumed that plea bargains are contracts negotiated between rational actors who adhere to the dictates of the normative shadow-of-trial model. The two key features that rational actors presumably haggle over in the shadow of trial are the criminal charge (and associated sentence) and the probability of trial conviction. The behavioral economics theory of discounting, however, offers a theoretical foundation for testing the shadow-of-trial model. This article summarizes findings from experimental discounting studies in behavioral economics and psychological science – showing that these paradigms can be successfully applied to the plea-bargaining decision context wherein the likelihood of trial is uncertain and delayed, and the plea bargain is relatively certain and immediate. We suggest that the implications of applying discounting to plea bargaining are three-fold: (1) empirical evidence suggests that the shadow-of-trial model is too narrow; (2) the discounting of non-monetary losses may involve slightly different psychological processes than contexts involving monetary outcomes; and (3) probability of conviction and delay until trial constitute situational features that elicit guilty pleas despite a defendant’s factual innocence.
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Zhang, Zili, Jing Chen, and Yawen Mao. "Ridge regression and lasso regression based least squares algorithm for a time-delayed rational model via redundant rule." International Journal of Modelling, Identification and Control 40, no. 1 (2022): 11. http://dx.doi.org/10.1504/ijmic.2022.124075.
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Zhang, Zili, Jing Chen, and Yawen Mao. "Ridge regression and lasso regression based least squares algorithm for a time-delayed rational model via redundant rule." International Journal of Modelling, Identification and Control 40, no. 1 (2022): 11. http://dx.doi.org/10.1504/ijmic.2022.10048798.
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Ma, Junhai, and Hongliang Tu. "Complexity of a Duopoly Game in the Electricity Market with Delayed Bounded Rationality." Discrete Dynamics in Nature and Society 2012 (2012): 1–13. http://dx.doi.org/10.1155/2012/698270.
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According to a triopoly game model in the electricity market with bounded rational players, a new Cournot duopoly game model with delayed bounded rationality is established. The model is closer to the reality of the electricity market and worth spreading in oligopoly. By using the theory of bifurcations of dynamical systems, local stable region of Nash equilibrium point is obtained. Its complex dynamics is demonstrated by means of the largest Lyapunov exponent, bifurcation diagrams, phase portraits, and fractal dimensions. Since the output adjustment speed parameters are varied, the stability of Nash equilibrium gives rise to complex dynamics such as cycles of higher order and chaos. Furthermore, by using the straight-line stabilization method, the chaos can be eliminated. This paper has an important theoretical and practical significance to the electricity market under the background of developing new energy.
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Jackson, Mary, Susan W. Phalen, Micheline Lagranderie, Danielle Ensergueix, Pierre Chavarot, Gilles Marchal, David N. McMurray, Brigitte Gicquel, and Christophe Guilhot. "Persistence and Protective Efficacy of aMycobacterium tuberculosis Auxotroph Vaccine." Infection and Immunity 67, no. 6 (June 1, 1999): 2867–73. http://dx.doi.org/10.1128/iai.67.6.2867-2873.1999.
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ABSTRACT New vaccines against tuberculosis are urgently required because of the impressive incidence of this disease worldwide and the highly variable protective efficacy of the current vaccine. The possibility of creating new live vaccines by the rational attenuation of strains from the Mycobacterium tuberculosis complex was investigated. Two auxotrophic mutants of M. tuberculosis and M. bovis BCG were constructed by disruption of one of their purine biosynthetic genes. These mutants appeared unable to multiply in vitro within mouse bone-marrow derived macrophages. They were also attenuated in vivo in the mouse and guinea pig animal models. In guinea pigs, the two mutants induced strong delayed-type hypersensitivity response to purified protein derivative. In a preliminary experiment, the two mutants were compared to the BCG vaccine for their protective efficacy in a challenge against aerosolized virulent M. tuberculosisin the guinea pig model. Both mutants conferred some level of protection. These experiments demonstrate that the rational attenuation of M. tuberculosis could lead to the design of new candidate live vaccines against tuberculosis.
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Sun, Yuancheng, and Zhanhong Liang. "Fault Diagnosis and Fault Tolerant Control for Non-Gaussian Singular Time-Delayed Stochastic Distribution Systems with Disturbance Based on the Rational Square-Root Model." Journal of Control Science and Engineering 2016 (2016): 1–11. http://dx.doi.org/10.1155/2016/9563481.
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For the non-Gaussian singular time-delayed stochastic distribution control (SDC) system with unknown external disturbance where the output probability density function (PDF) is approximated by the rational square-root B-spline basis function, a robust fault diagnosis and fault tolerant control algorithm is presented. A full-order observer is constructed to estimate the exogenous disturbance and an adaptive observer is used to estimate the fault size. A fault tolerant tracking controller is designed using the feedback of distribution tracking error, fault, and disturbance estimation to let the postfault output PDF still track desired distribution. Finally, a simulation example is included to illustrate the effectiveness of the proposed algorithms and encouraging results have been obtained.
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Zybała, Andrzej. "Wokół kultury umysłowej w Polsce — jej źródła i przejawy." Kultura i Społeczeństwo 61, no. 4 (October 10, 2017): 103–23. http://dx.doi.org/10.35757/kis.2017.61.4.6.
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The author defines intellectual culture as a tendency to base decisions on objective analyses or the habit of investigating issues analytically. In the broader sense, intellectual culture may be considered to be the way the collective reacts to phenomena that appear in the real world. A high level of intellectual culture, in the author’s opinion, is shown by a modern form of thinking manifested in the ability to make use of abstracts and to take into account alternative systems of constructing opinions. On the basis of selected analyses of Polish scholars the author advances the hypothesis that Poland has failed to form proper institutional mechanisms favoring rational analysis in public life. The author demonstrates that this is the result of many factors, such as the long-lasting model of Sarmatian customs (including its providentialism), the strong and lasting influence of a radical form of romanticism, and also the nugatory influence of Enlightenment and positivist models. These factors have been accompanied by the unsuitability of educational and scholarly institutions, the delayed development of modern forms of economics, which force the use of rational calculations, and a structure of society that does not favor exchanges of ideas and deliberation.
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Prokhorchenko, Andrii, Dmytro Gurin, Iryna Lahuta, and Viktoriia Sunytska. "IMPROVEMENT OF THE PROCEDURE FOR SEARCHING RATIONAL TIME RESERVES FOR RECOVERY OF TRAIN MOVEMENT OF DIFFERENT CATEGORIES." Collected scientific works of Ukrainian State University of Railway Transport, no. 193 (October 5, 2021): 44–53. http://dx.doi.org/10.18664/1994-7852.193.2020.229812.
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This article improves the procedure for finding rational time reserves for theresumption of trains of different categories depending on the number of detained trains on the basisof the epidemiological SIR-model. A modified epidemiological SIR-model has been implemented forthe experimental railway line, which allows to take into account the interaction of trains of differentpriorities in the train schedule and the possibility of resumption of delayed trains due to the set timereserve. The adjustment of the delay rate transfer coefficients on the real data of train delays at theline has been performed. The solution of the system of differential equations of the SIR-model isproposed to be performed by the numerical Runge-Kutta method of the 4th order. Experimentalstudies of the impact of passenger train delays on the reliability of the regulatory schedule havebeen conducted. Experimental studies of the impact of passenger train delays on the reliability ofthe regulatory schedule have been conducted. The dependences of the number of detained trains ofdifferent categories on the change in the amount of time reserve for the resumption of trains ofdifferent categories are obtained. Rational time reserves for passenger, suburban and freight trainshave been established. These results were expertly assessed and confirm the adequacy of theobtained decisions in the practice of developing a regulatory schedule of trains at JSCUkrzaliznytsia. The application of the proposed approach will automate the complex process offinding rational values of compensation time in the threads of trains of different categories on therailway line and, as a consequence, increase the level of reliability of the regulatory train schedule.
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Sidenev, D. M., S. A. Savelyev, A. R. Valieva, A. R. Gaysina, and R. G. Khasanov. "Improving the Efficiency of the Heat Exchange Network of the Delayed Coking Plant." Chemistry and Technology of Fuels and Oils 631, no. 3 (2022): 22–26. http://dx.doi.org/10.32935/0023-1169-2022-631-3-22-26.
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Thermal integration of technological processes of oil refining is the most effective tool in the design and reconstruction of existing industrial facilities. The rational use of the heat of internal flows is especially important for energy-intensive processes of processing heavy oil residues, such as delayed coking. In this article, a model of the existing heat exchange network of the coke production process was constructed, for which a pinch analysis was carried out and the energy saving potential was determined. The analysis also revealed violations of the basic pinch rules made during the design of the existing circuit and proposed an option to increase its energy efficiency based on the re-linking of existing equipment without involving an additional heat exchange surface.
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Amirudin, Amirudin, Jumadil Saputra, Teuku Afrizal, M. Latip, and Α. Tarmizi. "Investigating the COVID-19 Self-Isolation Policy and Its Impact on Socioeconomic of Vulnerable Groups: An application of Rational and Non-Rational Thinking Models." WSEAS TRANSACTIONS ON ENVIRONMENT AND DEVELOPMENT 17 (June 1, 2021): 604–13. http://dx.doi.org/10.37394/232015.2021.17.58.
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The spread of the Corona Virus Disease (COVID-19) pandemic continues in impending world public health and bringing considerable human suffering. The present study investigates the vulnerable groups' reaction from informal sectors to the execution of the self-isolation policy of COVID-19 in Semarang City, Indonesia. This study is designed using a qualitative method with an ethnography approach. Using the binary opposition thinking pattern pioneered by Levi-Strauss, this study conducts the interview process with 25 informants in Semarang City. The data analysed using the response pattern of informants. We use the taxonomy analysis and finds three levels of vulnerability group; (a) jobs lost, (b) income decreased, and (c) delayed salary. The result of the analysis found that the group that obeys self-isolation is a rational thinking model. They stay at home, do not go to work, and no income. Also, the group who ignored self-isolation is a non-rational thinking model. They work, as usual, get their salaries, and believe that Covid-19 is a disaster; they pray for their safety to God. In conclusion, COVID 19 brings an economic impact on vulnerable groups in the forms of postponing, declining, and missing income. Even its circumstances are worse when self-isolation is forced. Thus, this study suggests that the government needs to assist vulnerable groups by focusing on strategic policies, such as strategies for survival, providing access to basic needs, and livelihood plans by providing access to improve livelihoods sustainably.
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Sen, Monokesh K., Mohammed S. M. Almuslehi, Peter J. Shortland, David A. Mahns, and Jens R. Coorssen. "Proteomics of Multiple Sclerosis: Inherent Issues in Defining the Pathoetiology and Identifying (Early) Biomarkers." International Journal of Molecular Sciences 22, no. 14 (July 9, 2021): 7377. http://dx.doi.org/10.3390/ijms22147377.
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Multiple Sclerosis (MS) is a demyelinating disease of the human central nervous system having an unconfirmed pathoetiology. Although animal models are used to mimic the pathology and clinical symptoms, no single model successfully replicates the full complexity of MS from its initial clinical identification through disease progression. Most importantly, a lack of preclinical biomarkers is hampering the earliest possible diagnosis and treatment. Notably, the development of rationally targeted therapeutics enabling pre-emptive treatment to halt the disease is also delayed without such biomarkers. Using literature mining and bioinformatic analyses, this review assessed the available proteomic studies of MS patients and animal models to discern (1) whether the models effectively mimic MS; and (2) whether reasonable biomarker candidates have been identified. The implication and necessity of assessing proteoforms and the critical importance of this to identifying rational biomarkers are discussed. Moreover, the challenges of using different proteomic analytical approaches and biological samples are also addressed.
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Liu, Mianfang, Shengwu Xiong, and Bixiang Li. "Dynamic route guidance strategy in a two-route pedestrian-vehicle mixed traffic flow system." International Journal of Modern Physics C 27, no. 09 (August 2016): 1650099. http://dx.doi.org/10.1142/s0129183116500996.
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With the rapid development of transportation, traffic questions have become the major issue for social, economic and environmental aspects. Especially, during serious emergencies, it is very important to alleviate road traffic congestion and improve the efficiency of evacuation to reduce casualties, and addressing these problems has been a major task for the agencies responsible in recent decades. Advanced road guidance strategies have been developed for homogeneous traffic flows, or to reduce traffic congestion and enhance the road capacity in a symmetric two-route scenario. However, feedback strategies have rarely been considered for pedestrian-vehicle mixed traffic flows with variable velocities and sizes in an asymmetric multi-route traffic system, which is a common phenomenon in many developing countries. In this study, we propose a weighted road occupancy feedback strategy (WROFS) for pedestrian-vehicle mixed traffic flows, which considers the system equilibrium to ease traffic congestion. In order to more realistic simulating the behavior of mixed traffic objects, the paper adopted a refined and dynamic cellular automaton model (RDPV_CA model) as the update mechanism for pedestrian-vehicle mixed traffic flow. Moreover, a bounded rational threshold control was introduced into the feedback strategy to avoid some negative effect of delayed information and reduce. Based on comparisons with the two previously proposed strategies, the simulation results obtained in a pedestrian-vehicle traffic flow scenario demonstrated that the proposed strategy with a bounded rational threshold was more effective and system equilibrium, system stability were reached.
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Schach, Sonja, Axel Lindner, and Daniel Alexander Braun. "Bounded rational decision-making models suggest capacity-limited concurrent motor planning in human posterior parietal and frontal cortex." PLOS Computational Biology 18, no. 10 (October 13, 2022): e1010585. http://dx.doi.org/10.1371/journal.pcbi.1010585.
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While traditional theories of sensorimotor processing have often assumed a serial decision-making pipeline, more recent approaches have suggested that multiple actions may be planned concurrently and vie for execution. Evidence for the latter almost exclusively stems from electrophysiological studies in posterior parietal and premotor cortex of monkeys. Here we study concurrent prospective motor planning in humans by recording functional magnetic resonance imaging (fMRI) during a delayed response task engaging movement sequences towards multiple potential targets. We find that also in human posterior parietal and premotor cortex delay activity modulates both with sequence complexity and the number of potential targets. We tested the hypothesis that this modulation is best explained by concurrent prospective planning as opposed to the mere maintenance of potential targets in memory. We devise a bounded rationality model with information constraints that optimally assigns information resources for planning and memory for this task and determine predicted information profiles according to the two hypotheses. When regressing delay activity on these model predictions, we find that the concurrent prospective planning strategy provides a significantly better explanation of the fMRI-signal modulations. Moreover, we find that concurrent prospective planning is more costly and thus limited for most subjects, as expressed by the best fitting information capacities. We conclude that bounded rational decision-making models allow relating both behavior and neural representations to utilitarian task descriptions based on bounded optimal information-processing assumptions.
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Amirudin, Amirudin, Mariusz Urbański, Jumadil Saputra, Muhamad Deni Johansyah, Latip Latip, Ahmad Tarmizi, and Teuku Afrizal. "The Impact of the COVID-19 Self-Isolation Policy on the Occupations of Vulnerable Groups." International Journal of Environmental Research and Public Health 18, no. 12 (June 15, 2021): 6452. http://dx.doi.org/10.3390/ijerph18126452.
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Today, the spread of the Coronavirus 2019 (COVID-19) pandemic continues to impact on world public health and bring about considerable human suffering partly due to government policies on reducing the spread. COVID-19 has significantly affected human health and it has impacted on the occupation of vulnerable groups such as tour guides, drivers and shop assistants. Of these, the present study aims to investigate the impact of the COVID-19 self-isolation policy on the occupation of vulnerable groups in Semarang City, Indonesia. To achieve this objective, this study uses a qualitative method with an ethnography approach considering a rational or non-rational thinking model. The binary opposition thinking pattern pioneered by Lévi-Strauss was used in the interview process with 25 informants in Semarang City, Indonesia. The data analyzed the response pattern of informants through the taxonomy analysis. Three levels of vulnerability among groups relating to occupation were identified; jobs lost, income decreased, and delayed salary. The result of the analysis found that the group who obeyed self-isolation was categorized as a rational thinking; these groups stay at home, do not go to work, and have no income. Besides that, the group who ignored self-isolation is categorized as non-rational thinking; they work, as usual, get their salary, and believe that the COVID-19 pandemic is a disaster and they pray for their safety to God. In conclusion, COVID-19 brings a significant impact on occupation in the forms of postponing, declining, and missing income besides the health effects among vulnerable groups in Semarang city, Indonesia. In avoiding COVID-19 infection, the circumstances of vulnerable groups are worse when self-isolation is required. Thus, this study suggests that the government needs to assist vulnerable groups by focusing on strategic policies, such as strategies for survival, providing access to basic needs, including health, and offering livelihood plans by providing access to medical services and other source of income.
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Radenovic, Cedomir, Milomir Filipovic, Dragojlo Selakovic, Mile Secanski, Vojka Babic, Zoran Camdzija, Snezana Jovanovic, Jovan Pavlov, and Milan Stevanovic. "The prestigious maize inbred lines with erect top leaves: The priority performance of the efficient photosynthetic model in breeding." Genetika 41, no. 1 (2009): 41–58. http://dx.doi.org/10.2298/gensr0901041r.
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This study conforms the hypothesis that there are elite maize inbred lines with erect top leaves that have a property of an efficient photosynthetic model and that as such are successfully used in the processes of breeding in which the number of plants is increased per area unit (plant density). This proof was established by the application of non- invasive photosynthetic-fluorescence method suitable for the evaluation of the efficiency of the photosynthetic model. The obtained photosynthetic and fluorescence properties of observed prestigious maize inbred lines with the erect top leaves are based on the effects and the nature of changes in chlorophyll fluorescence occurring in their thylakoid membranes. Their principal parameters are temperature dependence of the chlorophyll delayed fluorescence intensity, the Arrhenius plot for the determination of the phase transition in thylakoid membranes and the estimated activation energies. The displayed results on the size of an angle between the direction of the propagation of the above-ear leaf and the direction of the stalk propagation, as well as, results on the dynamics of grain dry-down during the maturation period, additionally indicate that traits of observed maize inbred lines with erect top leaves are the prominent base for more exact, rational and faster proceeding of current processes of breeding.
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Hasan, R. G. M., J. J. McGuirk, D. D. Apsley, and M. A. Leschziner. "A turbulence model study of separated 3D jet/afterbody flow." Aeronautical Journal 108, no. 1079 (January 2004): 1–14. http://dx.doi.org/10.1017/s0001924000004942.
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Three-dimensional RANS calculations and comparisons with experimental data are presented for subsonic and transonic flow past a non-axisymmetric (rectangular) nozzle/afterbody typical of those found in fast-jet aircraft. The full details of the geometry have been modelled, and the flow domain includes the internal nozzle flow and the jet exhaust plume. The calculations relate to two free-stream Mach numbers of 0-6 and 0-94 and have been performed during the course of a collaborative research programme involving a number of UK universities and industrial organisations. The close interaction between partners contributed greatly to the elimination of computational inconsistencies and to rational decisions on common grids and boundary conditions, based on a range of preliminary computations. The turbulence models used in the study include linear and non-linear eddy-viscosity models. For the lower Mach number case, the flow remains attached and all of the turbulence models yield satisfactory pressure predictions. However, for the higher Mach number, the flow over the afterbody is massively separated, and the effect of turbulence model performance is pronounced. It is observed that non-linear eddy-viscosity modelling provides improved shock capturing and demonstrates significant turbulence anisotropy. Among the linear eddy-viscosity models, the SST model predicts the best surface pressure distributions. The standard k -ε model gives reasonable results, but returns a shock location which is too far downstream and displays a delayed recovery. The flow field inside the jet nozzle is not influenced by turbulence modelling, highlighting the essentially inviscid nature of the flow in this region. However, the resolution of internal shock cells for identical grids is found to be dependent on the solution algorithm -specifically, whether it solves for pressure or density as a main dependent variable. Density-based time-marching schemes are found to return a better resolution of shock reflection. The paper also highlights the urgent need for more detailed experimental data in this type of flow.
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Radenovic, Cedomir, Milomir Filipovic, Milosav Babic, Goran Stankovic, Aleksandar Radojcic, Mile Secanski, Jovan Pavlov, Brankovic Radojcic, and Dragojlo Selakovic. "Actual prestigious properties of maize inbred lines: A good initial basis for the efficient development of new and yielding maize hybrids." Genetika 40, no. 2 (2008): 121–33. http://dx.doi.org/10.2298/gensr0802121r.
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This study conforms our hypothesis that there are elite maize inbred lines, which can be considered actual and prestigious as they have not only a property of the water status and a greater grain dry down rate during the maturation period, but also a property of the efficient photosynthetic-fluorescence model that is successfully used in the contemporary processes of breeding, and thereby in the development of new and yielding maize hybrids. Presented results obtained on the dynamics of grain dry down during the maturation period and on photosynthetic-fluorescence parameters (temperature dependence of the chlorophyll delayed fluorescence intensity, the Arrhenius plot for the determination of critical temperatures, i.e. phase transition temperatures and the activation energy) show that properties of the observed inbreeds are based on effects and nature of conformational and functional changes occurring in their thylakoid membranes and other chemical structures of grain tissues. Summarized results of studies on actual and prestigious properties of maize inbreeds will contribute to more exact, rational and expeditious proceedings of contemporary processes of breeding.
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Wempe, Michael Fitzpatrick. "New Insights into Ion Channels: Predicting hERG-Drug Interactions." International Journal of Molecular Sciences 23, no. 18 (September 14, 2022): 10732. http://dx.doi.org/10.3390/ijms231810732.
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Drug-induced long QT syndrome can be a very dangerous side effect of existing and developmental drugs. In this work, a model proposed two decades ago addressing the ion specificity of potassium channels is extended to the human ether-à-gogo gene (hERG). hERG encodes the protein that assembles into the potassium channel responsible for the delayed rectifier current in ventricular cardiac myocytes that is often targeted by drugs associated with QT prolongation. The predictive value of this model can guide a rational drug design decision early in the drug development process and enhance NCE (New Chemical Entity) retention. Small molecule drugs containing a nitrogen that can be protonated to afford a formal +1 charge can interact with hERG to prevent the repolarization of outward rectifier currents. Low-level ab initio calculations are employed to generate electronic features of the drug molecules that are known to interact with hERG. These calculations were employed to generate structure–activity relationships (SAR) that predict whether a small molecule drug containing a protonated nitrogen has the potential to interact with and inhibit the activity of the hERG potassium channels of the heart. The model of the mechanism underlying the ion specificity of potassium channels offers predictive value toward optimizing drug design and, therefore, minimizes the effort and expense invested in compounds with the potential for life-threatening inhibitory activity of the hERG potassium channel.
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Vallarola, Antonio, Massimo Tortarolo, Roberta De Gioia, Luisa Iamele, Hugo de Jonge, Giovanni de Nola, Enrica Bovio, et al. "A Novel HGF/SF Receptor (MET) Agonist Transiently Delays the Disease Progression in an Amyotrophic Lateral Sclerosis Mouse Model by Promoting Neuronal Survival and Dampening the Immune Dysregulation." International Journal of Molecular Sciences 21, no. 22 (November 12, 2020): 8542. http://dx.doi.org/10.3390/ijms21228542.
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Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease with no effective treatment. The Hepatocyte Growth Factor/Scatter Factor (HGF/SF), through its receptor MET, is one of the most potent survival-promoting factors for motor neurons (MN) and is known as a modulator of immune cell function. We recently developed a novel recombinant MET agonist optimized for therapy, designated K1K1. K1K1 was ten times more potent than HGF/SF in preventing MN loss in an in vitro model of ALS. Treatments with K1K1 delayed the onset of muscular impairment and reduced MN loss and skeletal muscle denervation of superoxide dismutase 1 G93A (SOD1G93A) mice. This effect was associated with increased levels of phospho-extracellular signal-related kinase (pERK) in the spinal cord and sciatic nerves and the activation of non-myelinating Schwann cells. Moreover, reduced activated microglia and astroglia, lower T cells infiltration and increased interleukin 4 (IL4) levels were found in the lumbar spinal cord of K1K1 treated mice. K1K1 treatment also prevented the infiltration of T cells in skeletal muscle of SOD1G93A mice. All these protective effects were lost on long-term treatment suggesting a mechanism of drug tolerance. These data provide a rational justification for further exploring the long-term loss of K1K1 efficacy in the perspective of providing a potential treatment for ALS.
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Xiao, Jianli, Hanli Xiao, Xinchang Zhang, and Xiang You. "Stability, Bifurcation, and Chaos Control of Two-Sided Market Competition." International Journal of Computer Games Technology 2022 (August 17, 2022): 1–10. http://dx.doi.org/10.1155/2022/6006450.
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Benefitting from the popular uses of internet technologies, two-sided market has been playing an increasing prominent role in modern times. Users and developers can interact with each other through two-sided platforms. The two-sided market structure has been investigated profoundly. Through building a dynamics two-sided market model with bounded rational, stability conditions of the two-sided market competition system are presented. With the help of bifurcation diagram, Lyapunov exponent, and strange attractor, the stability of the two-sided market competition model is simulated. At last, we use the time-delayed feedback control (TDFC) method to control the chaos. Our main results are as follows: (1) when the adjustment speed of two-sided increases, the system becomes bifurcation, and chaos state happens finally. When the system is stable, the consumer fee is positive while developer fee is negative. (2) When the user externality increases, the stable area of the system increases, and the difference in user externality leads the whole system more stable. When the system is stable, the developer fee decreases. (3) The stable area becomes larger when developer externality increases; when the system is stable, the user fee becomes lower and developer fee becomes higher when developer externality increases. (4) The TDFC method is presented for controlling the chaos; we find that the system becomes more stable under the TDFC method.
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Schweber, Sarah J., Alicia G. Rodriguez-LaRocca, Valerie Calvert, Emanuel Petricoin, Susan Band Horwitz, Eleni Andreopoulou, and Hayley M. McDaid. "Protein pathway activation mapping guided biomarker development to identify optimal combinations of MEK inhibitor with PI3K/mTOR pathway inhibitors for the treatment of triple-negative breast cancer." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 2612. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.2612.
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2612 Background: Activated MAPK and PI3K pathway signaling are associated with poor prognosis in triple negative breast cancer (TNBC). Although some TNBC cell models are sensitive to MEK inhibition, feedback activation of the PI3K pathway mediates resistance. Thus, suppression of both arms of the MAPK/PI3K/mTOR network is a rational approach to targeting TNBC. Here we explore the anti-tumor efficacy of combinations of MEK inhibitor with PI3K, AKT, or mTOR inhibitors with a focus on biomarker development. Methods: Combinations of the MEK inhibitor PD-0325901 with the PI3K inhibitor GDC-0941, AKT inhibitor MK-2206, dual mTORC 1/2 inhibitor Torin 1, or the rapalog temsirolimus were evaluated in TNBC cell lines. Synergy was assessed using the combination index method of Chou and Talalay. We utilized reverse-phase protein array to map the signaling architecture of the treated lines to verify target suppression and identify pharmacodynamic biomarkers. Results: All combinations demonstrated synergy that was mediated by both suppression of proliferation and cell death in a dose-dependent manner. Cell death was delayed, peaking at least 96 hours post-dosing, and was associated with sustained suppression of target proteins in both pathways, including pERKT202/Y204, pS6rpS235/236, p4EBP-1S65, and pPRAS40T246. However, suppression of pAKT (at T308 or S473) was variable and not consistently required for cell death. Pathway mapping identified a protein network ‘signature’ specific to all combination therapies that emerged at 72 hours and was associated with cell death. Thus, all combinations appear to share common downstream effectors. All combinations showed promising efficacy and will be evaluated in a human-in-mouse model of TNBC. Conclusions: These data support therapeutic strategies for TNBC that simultaneously inhibit both arms of the MAPK/PI3K/mTOR signaling network. For continued biomarker development, we stress the importance of studying the delayed effects of combination therapy. This strategy coupled with a protein network based approach uncovered a unique functional signaling ‘signature’.
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Charlet, Anne, Max Kappenstein, Philip Keye, Kathrin Kläsener, Cornelia Endres, Teresa Poggio, Sivahari P. Gorantla, et al. "The IL-3, IL-5, and GM-CSF common receptor beta chain mediates oncogenic activity of FLT3-ITD-positive AML." Leukemia 36, no. 3 (November 8, 2021): 701–11. http://dx.doi.org/10.1038/s41375-021-01462-4.
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AbstractFLT3-ITD is the most predominant mutation in AML being expressed in about one-third of AML patients and is associated with a poor prognosis. Efforts to better understand FLT3-ITD downstream signaling to possibly improve therapy response are needed. We have previously described FLT3-ITD-dependent phosphorylation of CSF2RB, the common receptor beta chain of IL-3, IL-5, and GM-CSF, and therefore examined its significance for FLT3-ITD-dependent oncogenic signaling and transformation. We discovered that FLT3-ITD directly binds to CSF2RB in AML cell lines and blasts isolated from AML patients. A knockdown of CSF2RB in FLT3-ITD positive AML cell lines as well as in a xenograft model decreased STAT5 phosphorylation, attenuated cell proliferation, and sensitized to FLT3 inhibition. Bone marrow from CSF2RB-deficient mice transfected with FLT3-ITD displayed decreased colony formation capacity and delayed disease onset together with increased survival upon transplantation into lethally irradiated mice. FLT3-ITD-dependent CSF2RB phosphorylation required phosphorylation of the FLT3 juxtamembrane domain at tyrosines 589 or 591, whereas the ITD insertion site and sequence were of no relevance. Our results demonstrate that CSF2RB participates in FLT3-ITD-dependent oncogenic signaling and transformation in vitro and in vivo. Thus, CSF2RB constitutes a rational treatment target in FLT3-ITD-positive AML.
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Garvey, Edward P., Andrew Sharp, Peter Warn, Christopher M. Yates, and Robert J. Schotzinger. "1346. The Tetrazole VT-1598 Is Efficacious in a Murine Model of Invasive Aspergillosis with a PK/PD Expected of a Mold-Active CYP51 Inhibitor." Open Forum Infectious Diseases 5, suppl_1 (November 2018): S411—S412. http://dx.doi.org/10.1093/ofid/ofy210.1177.
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Abstract Background VT-1598 is a novel fungal CYP51 inhibitor with potent in vitro activity against yeast, mold, and endemic pathogenic fungi (Wiederhold, JAC, 2017). Its tetrazole-based rational drug design imparts much greater selectivity vs. human CYPs (Yates, BMCL, 2017), which could reduce human CYP-related side effects and DDIs. We report here VT-1598’s in vivo activity in an invasive aspergillosis (IA) model. Methods MIC was determined as outlined in CLSI M38-A2. Plasma PK was measured after 4 days of oral doses in neutropenic ICR mice without fungal inoculation. In vivo antifungal activity was determined in a tail-vein IA model in neutropenic mice inoculated with A. fumigatus (AF) ATCC 204305 (N = 10 per dose). Two separate studies were conducted, with oral VT-1598 treatment starting either 48 hours prior (prophylaxis) or 5 hours postinoculation (delayed), with 4 days of postinoculation dosing, and kidney fungal burden measured 1 day post last dose by both CFU and qPCR. Drug control was 10 mg/kg AmBisome i.v. Results The MIC for VT-1598 against AF 204305 was 0.25 μg/mL. The plasma PK of VT-1598 was linearly proportional between the 5 and 40 mg/kg once-daily doses, with AUCs of 155 and 1,033 μg h/mL for the two doses, respectively. VT-1598 was similarly effective in reducing fungal burden when given in delayed treatment compared with prophylaxis, and both studies demonstrated a full dose–response (i.e., no to full reduction of fungal burden). When comparing fungal burdens of each dose group to the fungal burden at the start of treatment, the dose of VT-1598 to achieve fungal stasis ranged from 20.5 to 25.9 mg/kg and to achieve a 1-log10 fungal kill ranged from 30.9 to 50.5 mg/kg. Using the previously measured mouse plasma binding (>99.9%), the free AUC /MIC values for stasis and 1-log10 kill ranged from 2.1–2.7 and 3.2–5.2, respectively. These values are within the range of 1–11 that have been reported for posaconazole and isavuconazole (Lepak, AAC, 2013). Conclusion VT-1598 had potent antifungal activity in a murine model of IA. The PK/PD relationship was the same as clinically used mold-active CYP51 agents, suggesting that it could have similar clinical efficacy. If correct, the tetrazole-based greater selectivity may significantly differentiate VT-1598 from current IA therapies. Disclosures E. P. Garvey, Viamet Pharmaceuticals, Inc.: Employee, Salary. A. Sharp, Evotec (UK) Ltd.: Employee, Salary. P. Warn, Evotec (UK) Ltd.: Employee, Salary. C. M. Yates, Viamet Pharmaceuticals, Inc.: Employee, Salary. R. J. Schotzinger, Viamet Pharmaceuticals, Inc.: Board Member and Employee, Salary.
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Singh, Renu, Michelle C. Swick, Kimberly R. Ledesma, Zhen Yang, Ming Hu, Lynn Zechiedrich, and Vincent H. Tam. "Temporal Interplay between Efflux Pumps and Target Mutations in Development of Antibiotic Resistance in Escherichia coli." Antimicrobial Agents and Chemotherapy 56, no. 4 (January 9, 2012): 1680–85. http://dx.doi.org/10.1128/aac.05693-11.
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ABSTRACTThe emergence of resistance presents a debilitating change in the management of infectious diseases. Currently, the temporal relationship and interplay between various mechanisms of drug resistance are not well understood. A thorough understanding of the resistance development process is needed to facilitate rational design of countermeasure strategies. Using anin vitrohollow-fiber infection model that simulates human drug treatment, we examined the appearance of efflux pump (acrAB) overexpression and target topoisomerase gene (gyrAandparC) mutations over time in the emergence of quinolone resistance inEscherichia coli. Drug-resistant isolates recovered early (24 h) had 2- to 8-fold elevation in the MIC due toacrABoverexpression, but no point mutations were noted. In contrast, high-level (≥64× MIC) resistant isolates with target site mutations (gyrAS83L with or withoutparCE84K) were selected more readily after 120 h, and regression ofacrABoverexpression was observed at 240 h. Using a similar dosing selection pressure, the emergence of levofloxacin resistance was delayed in a strain withacrABdeleted compared to the isogenic parent. The role of efflux pumps in bacterial resistance development may have been underappreciated. Our data revealed the interplay between two mechanisms of quinolone resistance and provided a new mechanistic framework in the development of high-level resistance. Early low-level levofloxacin resistance conferred byacrABoverexpression preceded and facilitated high-level resistance development mediated by target site mutation(s). If this interpretation is correct, then these findings represent a paradigm shift in the way quinolone resistance is thought to develop.
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Momot, Volodymyr Ye, Olena M. Lytvynenko, and S. Zairzhanov. "SPECIFICS OF GAINING ECONOMIC INDEPENDENCE BY REFUGEES FROM UKRAINE." Academic Review 1, no. 58 (February 15, 2023): 205–19. http://dx.doi.org/10.32342/2074-5354-2023-1-58-15.
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The article examines the problems of the emergence and development of the flow of refugees from Ukraine during the first half of 2022 as a complex phenomenon that depends on rational (economic) and irrational (social-psychological) factors. The phenomenological model, created on the basis of the Burgers’ equation, which reproduces the process of the involvement of the new refugees to the flow and the resistance of the environment to the formation of this flow, made it possible to analyze such subtle effects as the existence of a hub country, where the initial accumulation of refugees takes place, followed by redistribution, and the influence of infrastructure problems in the exit country. Transitional regimes from the infrastructural problems prevailing in the country of exit to the predominant influence of the hub-country effects are also considered. It is concluded that the entry to new levels of the refugee flow could be achieved due to the effects of emotional and economic (rational) behavior of refugees replenishing the hub, i.e., a stepwise development of the refugee flow is possible if new hubs would be created, or the existing hub will be freed up from overloading. On the basis of mathematical modeling, it is shown that in the case when the refugee flow is restrained by infrastructural problems in the exodus country, the exit to the stationary regime is delayed. Identification of the proposed model was carried out based on the empirical data on the refugee flow development using the apparatus of incorrect problems of the mathematical physics. A comparison of the dynamic effects of the refugee flow development from Ukraine with similar processes in Syria and Iraq was carried out, which allowed for identification of the zones of influence of infrastructure problems and the hub effect in the refugee flow development. The use of the concept of refugees’ economic independence (self-sufficiency), which was developed in 2018 by the Office of the United Nations High Commissioner for Refugees, was proposed as a basis for policy formation in the field of refugee assistance. The consequences of the discrete use of this concept in the case of refugees from Syria are analyzed, and the dynamics of employment opportunities for these refugees in countries with similar and different socio-cultural conditions were compared. A conclusion was made about the fundamental difference in the employment trends in those types of countries. The authors formulated proposals regarding the utilization of the Monte Carlo methods and the learning model for researching the peculiarities of the process of Ukrainian refugees achieving a certain level of economic independence (self-sufficiency), determining the typical time of reaching such a level, obtaining the distribution of probabilities of getting the first job depending on the initial competencies and skills of refuges, their education, experience, and foreign languages mastery.
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McDonald, Anna G., Maureane Hoffman, Ulla Hedner, Harold R. Roberts, and Dougald M. Monroe. "Restoring Initial Thrombin Generation Does Not Normalize Cutaneous Wound Healing in Hemophilia B." Blood 108, no. 11 (November 16, 2006): 1030. http://dx.doi.org/10.1182/blood.v108.11.1030.1030.
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Abstract We recently described abnormal wound healing in a mouse model of hemophilia B (Hoffman et al, Blood 2006; DOI 10.1182/blood-2006-05-020495). Specifically: epithelial closure was delayed in hemophilia B mice; hemophilic animals, unlike wild type, developed subcutaneous hematomas; macrophage influx was delayed compared to wild-type mice; and, surprisingly, angiogenesis was enhanced in the hemophilia B mice. We hypothesized that restoring the initial hemostatic burst of thrombin generation following wounding by administration of a single dose of factor IX (FIX) replacement or factor VIIa (FVIIa) bypassing therapy would not only prevent bleeding, but correct the subsequent wound healing process. One dose of therapy was given thirty minutes prior to placement of a single three mm punch biopsy wound on the dorsal skin of each wild type, untreated hemophilia B, and treated hemophilia B mouse. The size of the wounds was measured daily until full epithelial closure. The time course of epithelial closure in treated hemophilia B was intermediate between wild type and untreated hemophilia B. FVIIa-treated hemophilia B began to heal earlier than FIX-treated. Skin from the wound site was collected at different days and examined histologically. Macrophage influx was earlier in treated hemophilia B mice compared to untreated hemophilia B, likely a due to the increased thrombin and fibrin acting as chemotactic agents. The macrophage influx in FVIIa-treated HB was significantly greater at certain time points than in FIX-treated mice, possibly reflecting some signaling effect of TF/FVIIa in addition to its effects on thrombin generation. With the earlier influx in macrophages, hemoglobin was degraded to storage iron at earlier time points. However, tissue iron continued to persist in treated hemophilia B mice similar to untreated hemophilia B, suggesting continued rebleeding. FIX treatment led to significantly more angiogenesis than FVIIa. The reasons for this difference remain to be determined. Untreated and some treated hemophilia B mice developed subcutaneous hematomas both before and after wound closure. The early hematomas are likely caused by a combination of the initial wounding trauma and vulnerability to bleeding related to the high level of vascularity within the granulation tissue. We propose the late hematomas are due to a cycle of bleeding, leading to more inflammation with production of more pro-angiogenic cytokines, leading to greater angiogenesis with its attendant risk of bleeding. In conclusion, restoring initial hemostatic thrombin generation did not normalize cutaneous wound healing in a hemophilia B mouse model. While the time frame of healing may not be the same in human and murine hemophiliacs, our findings suggest that this model could be helpful in rational determination of treatment schedules for replacement or bypassing therapy following injury or surgery.
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Anderson, Kristin G., Shannon K. Oda, Breanna M. Bates, Edison Y. Chiu, Madison G. Burnett, Magdalia L. Suarez Gutierrez, Nicolas M. Garcia, Andrew W. Daman, and Philip D. Greenberg. "Engineering adoptive T cell therapy to co-opt Fas ligand-mediated death signaling in solid tumors." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 246.8. http://dx.doi.org/10.4049/jimmunol.204.supp.246.8.
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Abstract Over half of patients diagnosed with high grade serous ovarian cancer will die within five years, highlighting the need for therapy innovation. Engineering T cells to target proteins uniquely overexpressed in tumors has the potential to limit tumor growth without toxicity—mesothelin (Msln) is a rational immunotherapy target as it contributes to the malignant/invasive phenotype and has limited expression in healthy cells. T cells were engineered to express a high-affinity Msln-specific T cell receptor (TCRMsln) and adoptively transferred into a disseminated ID8VEGF murine model, which recapitulates many features of human ovarian cancer. TCRMsln+ T cells preferentially accumulated within established tumors, delayed tumor growth, and significantly prolonged survival. However, T cell persistence and anti-cancer activity were limited by elements in the tumor microenvironment (TME), including Fas Ligand (FasL) that can induce apoptosis in infiltrating lymphocytes expressing Fas receptor (Fas). To overcome this potential T cell evasion mechanism, we generated a panel of immunomodulatory fusion proteins (IFPs) containing the Fas extracellular binding domain fused to a co-stimulatory domain, replacing the natural death domain. Relative to T cells modified with only TCRMsln, T cells that expressed both TCRMsln and a Fas IFP preferentially infiltrated tumors and expanded/persisted in the TME of tumor-bearing mice. Moreover, adoptive immunotherapy with TCRMsln+IFP+ T cells significantly prolonged survival in tumor-bearing mice, relative to TCRMsln+ only T cells. As many solid tumors overexpress FasL, IFPs may provide an opportunity to enhance engineered adoptive T cell therapy against many malignancies.
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Timm, Michael, Linda Wellik, Teresa Kimlinger, Jessica Haug, Michael Kline, S. Vincent Rajkumar, Philip Greipp, and Shaji Kumar. "Thymoglobulin (Polyclonal Rabbit Anti Thymocyte Globulin) Has In Vivo Activity in a Mouse Model of Myeloma." Blood 108, no. 11 (November 16, 2006): 3487. http://dx.doi.org/10.1182/blood.v108.11.3487.3487.
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Abstract Background: Multiple myeloma remains incurable with current approaches and newer therapies are needed to improve the outcome of these patients. While monoclonal antibody based therapies have been successful in some of the hematological malignancies, such approaches have had limited efficacy in the setting of myeloma. Thymoglobulin (polyclonal rabbit antithymocyte globulin, Genzyme) (Thymo) has been extensively evaluated in the setting of allogeneic blood and marrow transplantation and solid organ transplants. Given the polyclonal nature of this product, with antibodies against different B cell antigens, we evaluated the in vitro and in vivo activity of Thymo in myeloma. Methods: MM cell lines were cultured in RPMI 1640 containing 10% fetal bovine serum supplemented with L-Glutamine, penicillin, and streptomycin. The KAS-6/1 cell line was also supplemented with 1 ng/ml IL-6. Cytotoxicity following drug treatment was measured using the MTT viability assay. Apoptosis was measured by flow cytometry using Annexin V/PI in cell lines and Apo 2.7 in primary patient plasma cells. Shifts in expression of a variety of different B cell and plasma cell antigens were examined on several different myeloma cell lines following Thymo treatment in order to identify the potential antigenic targets. In vivo activity of thymo was evaluated in a SCID plasmacytoma model injected with RPMI myeloma cell lines. Results: rATG was cytotoxic in vitro to several MM cell lines (RPMI 8226, U266, OPM1, OPM2) including the IL-6 dependent cell line Kas6/1 with LC50 of around 1 mg/mL. Additionally, thymo was cytotoxic MM cell lines resistant to conventional agents such as doxorubicin (Dox40), melphalan (LR5) and dexamethasone (MM1R). Thymo induced apoptosis in MM cell lines and in patient derived primary myeloma cells. When tested in combination with other anti-myeloma agents an additive effect was seen with doxorubicin, PS341 and melphalan. Using competitive flow cytometry, we identified CD138, CD38, Cd45, CD126, CD49d (VLA4), as well as CD20 as antigens likely to be targeted by Thymo. Tumor bearing mice injected with Thymo at two different doses (5 mg/kg and 10 mg/kg for five days) had significantly delayed tumor growth compared to non-injected mice, and this translated into a better survival for these mice. Mice receiving 10 mg/kg dose had a slower tumor growth compared to 5 mg/kg dose (Figure). Conclusions: Thymoglobulin has promising in vitro and in vivo activity in the setting of myeloma. These studies will provide the rational for future clinical development of this agent in myeloma alone or in combination with other agents. Based on these results, we are in the process of initiating a clinical trial combining Thymo with Melphalan. Figure Figure
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Gopalakrishnapillai, Anilkumar, Anne Kisielewski, Yang Zhang, Bruce Ruggeri, Peggy Scherle, E. Anders Kolb, and Sonali P. Barwe. "Evaluating the Efficacy of PRMT5 Inhibitor C220 in Patient-Derived Xenograft Models of Pediatric Acute Myeloid Leukemia." Blood 138, Supplement 1 (November 5, 2021): 1170. http://dx.doi.org/10.1182/blood-2021-151671.
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Abstract Pediatric acute myeloid leukemia (AML) is the deadliest malignancy in children. Despite maximally intensive therapy, inclusive of chemotherapy and hematopoietic stem cell transplant, approximately 20% of patients experience recurrent disease. These patients are also burdened with treatment-related toxicities. Significant improvements in survival in pediatric AML patients necessitate the incorporation of rational targeted therapies with reduced toxicity. Recent studies demonstrate that PRMT5 knockout or inhibition in syngeneic mouse models of KMT2A (MLL) rearranged leukemic cells increased disease latency (Serio et al., Oncogene, 37:450, 2018; Kaushik et al., Leukemia, 32:499, 2018), indicating that PRMT5 is a potential therapeutic target in pediatric AML. However, there are no reports testing the efficacy of PRMT5 in PDX models of pediatric AML. We evaluated the preclinical efficacy of C220, a potent and selective PRMT5 inhibitor (PRMT5i) (Pastore et al., Cancer Discovery, 10:1742, 2020) in three distinct patient-derived xenograft (PDX) models of KMT2A rearranged AML. Based on the model used for the study, 3-5 million AML cells were injected intravenously in NSG-B2m mice. Disease progression was monitored by evaluating the percentage of human cells in mouse peripheral blood at periodic intervals by flow cytometry. At 2-3 weeks post transplantation, when human cells were detectable in peripheral blood, mice were randomly assigned to control (n=4-5) or treatment (n=2) groups. C220 was administered daily p.o. at a dose of 15 mg/kg for seven days with a break of two days. Mice were dosed with 2-3 additional cycles (indicated in the figure by shaded areas) based on their health status. Mice were monitored daily for experimental endpoints that included body condition score and human cell percentages in peripheral blood. Kaplan-Meier survival plots were generated based on the time when mice were euthanized because they met experimental endpoints. Chronic dosing of C220 prolonged survival and delayed the rise in percentage of human AML cells in mouse peripheral blood in all 3 PDX models (Fig. 1B, D, F). In the NTPL-146 model (KMT2A-MLLT1 fusion), a 135-day improvement in median survival was observed with C220-treatment (Fig. 1A). In the DF-2 (KMT2A-MLLT10 fusion) and DF-5 (KMT2A-MLLT4 fusion) models, which showed a faster engraftment compared to NTPL-146, there was a 5.5-day and 18-day improvement in median survival respectively (Fig. 1C, E). The improvement in median survival was statistically significant in all models (*P<0.05). In conclusion, C220 was effective in controlling leukemia progression and improving survival in KMT2A rearranged PDX models of pediatric AML. Figure 1 Figure 1. Disclosures Gopalakrishnapillai: Geron: Research Funding. Zhang: Prelude Therapeutics: Current Employment. Ruggeri: Prelude Therapeutics: Current Employment, Current equity holder in publicly-traded company. Scherle: Prelude Therapeutics: Current Employment, Current equity holder in publicly-traded company. Barwe: Prelude Therapeutics: Research Funding.
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Saddawi-Konefka, Robert, Aoife O’Farrell, Farhoud Faraji, Michael Allevato, Zhiyong Wang, Victoria Wu, Bryan Yung, et al. "601 Sequencing immunotherapy before lymphatic ablation unleashes cDC1-dependent antitumor immunity in HNSCC." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A631. http://dx.doi.org/10.1136/jitc-2021-sitc2021.601.
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BackgroundDespite the proven efficacy of immune checkpoint inhibitor (ICI) therapy in the recurrent/metastatic setting for head and neck squamous cell carcinoma (HNSCC), clinical trials of ICI combined with curative-intent therapies have yielded equivocal results [1–4]. Collectively, this highlights gaps in our understanding of rational immune oncology (IO) treatment sequencing and suggests that the efficacy ICI may be disrupted by standard therapies, which necessarily compromise regional lymphatics.MethodsWe employ a preclinical model of tobacco-signature HNSCC to identify sequences of therapy that maximize durable response. By mapping the cervical lymphatic basins in the mouse, we define patterns of active antitumor immunosurveillance. Additionally, we establish tumors with distinct patterns of regional lymphatic drainage and develop a murine neck dissection (ND) model.ResultsWe find that cervical lymphatic ablation, with ND or stereotactic body radiation therapy, in tumor bearing animals abolishes the response to ICI therapy, significantly impacting overall survival. Examination of the tumor immune microenvironment following ND reveals dramatic changes with a ten-fold increase in CD45 cells and exclusion of cytotoxic and antigen-specific lymphocytes. By examining the lymphatics removed at the time of ND, we find that conventional type I dendritic cells (cDC1s) and type I interferon (IFN-I) signaling are significantly increased, suggesting that these effectors are lost after curative-intent therapy. Depleting IFN-I or cDC1s blocks the response to ICI similar to lymphatic ablation. We find that successful primary response to ICI leads to durable immunity, conferred by systemically distributed memory T cells, not impaired by delayed ND. Lastly, we discover a rational IO treatment sequence by delivering neoadjuvant ICI followed by ND. Neoadjuvant ICI leads to complete tumor response, accumulation of nodal cDC1, and durable immunity. Surprisingly, the incidence of nodal metastasis at early timepoints reveals a similar burden of nodal disease between control and ICI-treated animals that decreases at late timepoints only with ICI treatment (44% vs 15%, n=25, p=0.033). This suggests that ICI also drives active immunosurveillance in regional, tumor-draining lymphatics, challenging the landmark findings from the definitive clinical trial demonstrating the benefit of elective versus therapeutic neck dissection for oral SCC patients with clinically negative necks.ConclusionsThis work demonstrates the necessity of preserving tumor-draining lymphatics during the tumor response to ICI therapy in HNSCC. Overall, we define rational IO treatment sequences to achieve optimal primary tumor response, durable antitumor immunity and immunosurveillance of regional metastatic disease. These findings can inform future clinical trials investigating combination IO therapy and treatment sequencing.ReferencesHarrington, K. J. et al. Nivolumab versus standard, single-agent therapy of investigator’s choice in recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141): health-related quality-of-life results from a randomised, phase 3 trial. Lancet Oncology 18, 1104–1115 (2017).Burtness, B. et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet (London, England) 394, 1915–1928 (2019).Lee, N. Y. et al. Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol 22, 450–462 (2021).D’Cruz, A. K. et al. Elective versus Therapeutic Neck Dissection in Node-Negative Oral Cancer. New England Journal of Medicine 373, 521–529 (2015).
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Hajihassani, Omid, Ali Vaziri-Gohar, Mehrdad Zarei, Jonathan Hue, Helen Cheng, Anusha Mudigonda, Erryk Katayama, Hallie Graor, and Jordan Winter. "Abstract 3021: Understanding the effects of a ketogenic diet against pancreatic cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3021. http://dx.doi.org/10.1158/1538-7445.am2022-3021.
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Abstract With an overall survival of less than 3%, pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer-related death in the U.S. at its advanced stages. With the most promising therapeutics, the overall survival after a stage IV PDAC diagnosis is only at 11.1 months. The marginal effects of current therapeutics emphasize the importance of developing new approaches to treat PDAC. In a wide range of cancer subtypes, a ketogenic diet has shown encouraging effects as combination therapy. However, the underlying anti-tumorigenic pathways involved in this diet alone are still not well understood. The ketogenic diet’s core elements and direct physiologic effects (ketone bodies, fatty acids, low glucose, low insulin levels) potentially alter PDAC biology that span from redox homeostasis to mitochondrial metabolism, and epigenetic modifications. We hypothesized that in carefully controlled in vitro and in vivo experiments, KD components delay growth of PDAC. Additionally, we hypothesize that understanding the underlying drivers of the anti-tumor effects of a ketogenic diet could be leveraged into the rational design of combination therapies that augment these anti-tumor effects. We show that in the subcutaneous mouse model of PDAC, tumor growth is markedly delayed under ketogenic diet restrictions Furthermore, in PDAC cell culture models, we observed anti-cancer effects when the ketogenic diet core elements are isolated. Specifically, fatty acids and ketone bodies inhibit PDAC cell growth, particularly under high glucose conditions. These effects are somewhat attenuated under low glucose, suggesting that these elements result in competing effects on PDAC cells (i.e., support some pro-survival pathways while inhibiting others). Future studies seek to better delineate the mechanistic impact of the principal ketogenic diet elements on metabolic pathways with a focus on mitochondrial metabolism, as well effects on epigenetic signaling. Citation Format: Omid Hajihassani, Ali Vaziri-Gohar, Mehrdad Zarei, Jonathan Hue, Helen Cheng, Anusha Mudigonda, Erryk Katayama, Hallie Graor, Jordan Winter. Understanding the effects of a ketogenic diet against pancreatic 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 3021.
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Petrovic, Mina. "Changes of marital behavior and family patterns in post-socialist countries: Delayed, incomplete or specific second demographic transition?" Stanovnistvo 49, no. 1 (2011): 53–78. http://dx.doi.org/10.2298/stnv1101053p.
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The paper starts by questioning the theory of second demographic transition (SDT) and its universal relevance in the field of marriage behavior and family organization in low fertility context, arguing for more differentiated approaches. With an aim to illustrate the contextual specifics of post-socialist countries in general and of Serbia in particular, the author claims that analyzed changes have not just been delayed or incomplete in comparison to more developed European countries, but shaped by specific modernization processes, which led to rationally developed strategies in overcoming structural risks, although, without ideational changes typical to the theory of SDT. Slow changes in marital behavior and family organization in Serbia are illustrated in recent sociological (empirical) research findings. The perceived changes are linked to specific structural risks (war, slow transformation and enduring economic hardships, weak state and low trust in institutions, etc) and value characteristics (persistence of materialism and traditionalism, but with increasing ambivalence). The connection between structural and ideational changes is considered through social stratification variable by relying on Coale's model on necessary preconditions for behavioral changes as well as on social deprivation concept. Having in mind upper social strata (more educated and better off), the value changes precede the behavioral that are adapted to economic uncertainty, which still force more traditional marital and family patterns. Therefore, there is a rank of different options, from extended family (for a short period at the beginning of marriage or after divorce) to separated leaving (of married partners) in parental households (due to refusing the extended family option thus creating quite specific "living apart together" form), combined with dominant strategy of prolonging the marriage. Hence, for upper social strata, marriage is still a universal but negotiable institution since more alternative options (although attractive and in accordance to changing values) are deemed irrational (have no obvious benefit). As regards the lower social strata (less educated and worse off), marriage is more in accordance with their higher inclination to traditional values, but general value liberalization legitimizes possible failures (divorces, extra marital births), which, even if not desired or economically rational, happen due to lower capacity to command life. For that reason, cohabitations and extra marital births are more common among actors at the lower end of the stratification ladder. The paper concludes that adaptive strategies related to traditional patterns of family organization dominate in Serbia, which might be illustrated by the fact that every third of one parent families lives in extended families. Even with significant structural changes (and economic improvements) in Serbia in the near future it is realistic to expect familism as an influential context, which suggests the spreading of cohabitation primarily as a pre- marital option (but more desired than forced).
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Magnani, John L., Arun Sarkar, Yonhong Li, Scarlett Goon, Bea Wagner, Jungshan Chang, Beat Ernst, Paul S. Frenette, and John T. Patton. "GMI-1070: A Small Pan-Selectin Antagonist That Inhibits Leukocyte Adhesion and Migration in Multple Disease Models In Vivo." Blood 110, no. 11 (November 16, 2007): 2410. http://dx.doi.org/10.1182/blood.v110.11.2410.2410.
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Abstract Rational design of glycomimetic inhibitors based on the bioactive conformation of functional carbohydrates provides new therapeutic opportunities for the development of small molecule drugs with improved activity, pharmacokinetics, and bioavailability relative to native ligands. In designing more active glycomimetic selectin inhibitors, the low enthalpy (ΔH0) of the reaction is compensated by pre-forming the bioactive conformation thereby improving the entropy (ΔS0), known as S/H compensation. Modifications of the molecule that also stabilize the core structure, further improve ΔS0 and binding activity. To improve ΔH0, second site interactions were explored. To address the requirements for P and L-selectins, interactions were combined for both carbohydrate and sulfate-binding domains to produce heterobifunctional molecules. By stabilizing the bioactive core and exploring second site molecular interactions, we have produced a family of pan-selectin antagonists, one of which (GMI-1070) is now in development and scale-up synthesis as a lead compound. GMI-1070 is a potent inhibitor of E, P, and L-selectins in vitro and inhibits E and P-selectin-mediated leukocyte adhesion to endothelial monolayers under flow conditions. More importantly, GMI-1070 is active in several animal models of diseases requiring leukocyte adhesion and migration such as: a delayed-type hypersensitivity (DTH) response, cardiac ischemia/reperfusion injury, and vaso-occlusive crisis in sickle cell disease. GMI-1070 significantly inhibited infarct size in an ischemia/reperfusion cardiac injury model in rats. A single dose at 10mg/kg gave maximal inhibition. The effects of GMI-1070 on T-cell migration was studied in a DTH model. Mice were sensitized with oxazolone on the abdomen and then, 7 days later challenged on the ear. Donors T-cells from a different cohort of similarly sensitized mice were fluorescently labeled and injected into the test cohorts at the time of administration of GMI-1070. Three hours following injection, migration of fluorescent T-cells to the challenged area was determined. Selectin-dependent T-cell migration in the DTH response was completely eliminated with a dose of 10mg/kg of GMI-1070, suggesting the potential clinical application in diseases involving skin homing T-cells such as graft vs. host disease (GVHD) after bone marrow transplantation, and other inflammatory skin diseases. We have also shown that acute myelogenous leukemia (AML) cells adhere to endothelial cells under flow in a selectin-dependent mechanism suggesting that graft vs. leukemia as well as graft vs. host may be affected by treatment with GMI-1070. GMI-1070 was also tested in a model of vaso-occlusive crisis in sickle cell disease using Berkeley sickle cell mice. Blood flow was restored to normal values and adhesion of sickle red blood cells to adherent leukocytes was essentially eliminated as determined intravital microscopy using a dose of 20mg/kg administered at the time of elicitation of the vaso-occlusive challenge (TNFα) and at the start of intravital microscopy (70 minutes later). Based on the encouraging results in disease models, we are advancing the clinical development of GMI-1070 into Phase 1 studies to support indications which include the treatment of sickle cell patients in vaso-occlusive crisis.
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Smith, Eric L., Maria Lia Palomba, Jae H. Park, and Renier J. Brentjens. "A Systemic Xenograft Model of Waldenström’s Macroglobulinemia Demonstrates the Potent Anti-Tumor Effect of Second Generation CD19 Directed Chimeric Antigen Receptor Modified T Cells in This Disease." Blood 124, no. 21 (December 6, 2014): 4484. http://dx.doi.org/10.1182/blood.v124.21.4484.4484.
Full textAbstract:
Abstract Chimeric antigen receptor (CAR) modified T-cell therapy consists of ex-vivo genetic manipulation of autologous lymphocytes in order to establish robust T-cell mediated anti-tumor immunity. Our group was the first to design and evaluate a CAR targeted toward the B cell antigen CD19 in mice. Currently we utilize a second generation CAR comprised of a single-chain variable fragment (scFv) derived from an antibody against CD19 fused to the CD3 ζ chain and the CD28 intracellular signaling domain (19-28z) to provide the necessary signal 1 and signal 2 for enhanced T-cell activation and persistence. We have gone on to test the safety and efficacy of 19-28z CAR T-cells in patients with chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL). We observed rapid complete molecular remissions in the first 14/16 patients treated with relapsed/refractory ALL. We hypothesize that contributing to the enhanced efficacy seen in ALL, when compared to solid tumors or extra-medullary CLL, is the fact that ALL is a bone marrow predominant disease, which may provide a microenvironment more amenable to T-cell therapy. Waldenström’s Macroglobulinemia (WM) is an ideal disease to test 19-28z CAR-modified T-cell therapy, as it is often bone marrow predominant, and WM cells from patient samples typically uniformly express high levels of CD19. Furthermore, despite recent progress made with novel BCR-directed therapy, complete eradication of the WM clone from the bone marrow niche remains elusive, therefore providing an ideal clinical scenario for treatment consolidation via alternative cytotoxic methods such as cellular immunotherapy. Using the human WM cell line, BCWM.1, we evaluated the in vitro efficacy of 19-28z CAR-modified T-cells when compared to mock transduced T cells or T cells transduced with an irrelevant second generation CAR directed towards the ovarian antigen MUC16. In a 4 hour co-culture assay, we observed significant cytotoxicity, even at low effector:target ratios (52% lysis at 1:1; 92% lysis at 10:1; p<0.01). This corresponded to increased secretion of INFγ and IL-2, markers of T-cell activation (p<0.01). We then conducted in vivo studies using sublethally irradiated SCID/beige mice to generate a systemic model of WM via tail vein injection of 1x106 luciferase transduced BCWM.1 cells. This model is characterized by tumor growth in the bone marrow followed by rapid spread to the liver, lungs, kidney, and CNS. Mice were monitored by weekly bioluminescent imaging (BLI) and ultimately were sacrificed when they developed hind leg paralysis. 19-28z CAR modified T-cells administered at day 7, after tumor establishment, when compared to non-treated and irrelevant CAR-modified T cell controls, delayed the progression of disease and doubled the median survival time of the mice after treatment (p=0.001). Taken together, the pre-clinical efficacy demonstrated in this abstract and the clinical features of WM, listed above, provide the rational for testing 19-28z CAR modified T cells clinically for WM. We have now opened a clinical trial for patients with relapsed or refractory WM, in which chemotherapy preconditioning is followed by a single dose of 19-28z CAR modified autologous T-cells (NCT00466531). Disclosures Brentjens: Juno Therapeutics: Consultancy, Scientific co-founder and Stock holder Other.
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Kwag, Daehun, Byung Sik Cho, Gi June Min, Sung-Soo Park, Silvia Park, Jae-Ho Yoon, Sung-Eun Lee, et al. "Effects of Delayed Treatment on Patients with Acute Myeloid Leukemia; Treatment Delay Matters in Younger Patients." Blood 136, Supplement 1 (November 5, 2020): 19–20. http://dx.doi.org/10.1182/blood-2020-143361.
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Introduction Acute myeloid leukemia (AML) has been considered as a hematological emergency. However, debates on how much the time from diagnosis to treatment (TDT) can be justified to choose the optimal treatment in AML have been raised due to the increased possibility of customized treatment with novel targeted agents based on genetic abnormalities tested by newly applicable diagnostic tools. Three recent studies with a large data set from Western countries showed conflicting results about the relationship between TDT and prognosis. Thus, we evaluated the influence of TDT on patients' outcomes from a large data set of Asian patients. Methods We retrospectively evaluated a cohort of AML patients aged 18 and older who visited the Catholic Hematology Hospital in Korea and received anthracycline-based intensive chemotherapy from 2002 to 2016. A total of 1313 patients were included in this analysis, of which 1282 were used for analysis, excluding 26 patients with incomplete documentation and with more than 90 days of TDT. Patients under the age of 60 (Young group, YG) and patients over 60 years of age (Elderly group, EG) were analyzed as an individual cohort. In both cohorts, the effects of TDT on complete remission (CR/CRi), early death (ED), and overall survival (OS) were analyzed. The TDT was analyzed as a continuous variable to minimize the loss of information, while also grouped into four ordinal groups of 1-5, 6-10, 11-15, and 16- to visualize data and find appropriate cutoff. In order to adjust for the influence of established prognostic variables on the outcomes, we used multivariate regression models. In both univariate and multivariate analyses, the transformation of variables or relaxing the linearity such as restricted cubic splining (RCS) were considered to reflect the data properly and not to violate the model assumptions. When TDT was treated as an ordinal variable, the effects of TDT on CR/CRi and ED were evaluated by Cochran-Armitage trend tests, and the effect on OS was checked by the log-rank test. Results Median age of YG (n=1104) and EG (n=178) were 40 years (interquartile range, IQR; 32-49) and 63 years (IQR; 61-64), respectively. Median TDT of both groups was 8 in days (IQR; 6-11 in YG and 6-13 in EG). When TDT was categorized into 4 groups, patients with higher WBC count tended to belong to earlier TDT groups in both YG and EG cohorts, and secondary AML patients were more placed in the later TDT groups especially in YG cohort. Univariate analyses of TDT in YG showed that TDT had significant correlation with CR/CRi rate, ED rate, and OS. Odds ratio (OR) of CR/CRi per one day treatment delay was -0.0206 (95% CI; -0.0412~-0.0000), and OR of ED per one day delay was 0.0439 (95% CI; 0.0126~0.0752) (Table 1 and Figure 1). RCS method was applied on OS model, so a single value of the hazard ratio (HR) per one day treatment delay was not available, but we could say HR of patients of TDT 2 versus (vs.) patients of TDT 16 was 0.6063 (95% CI; 0.4450-0.8259) in our model (Figure 2). Even after TDT was treated as a grouped variable, TDT was still significant on the ED rate and OS in YG. Especially, High ED rate and low 2-year OS of a group of TDT more than 15 days were noticed (Table 1). In EG, there was no significant effect of TDT on all patients' outcomes (Table 1). Multivariate analyses including age, WBC, AML type, MRC risk, and HSCT status showed that, in YG, TDT effect on CR/CRi rate turned to be insignificant, but TDT still acted as a significant variable for ED and OS. In EG, there was no significant effects of TDT on ED and OS, as like univariate analyses. When the treatment course was divided into 'during induction', 'between induction and HSCT', and 'after HSCT' in YG, there was no significant difference in the rate of death between TDT groups except for the deaths during the induction period (Table 3 and Figure 3). Conclusion Our data revealed the effects of TDT on OS and ED in YG, which were significant in multivariate analyses adjusting the effects of other variables. When the timing of death was divided in YG, the only ED was significantly different between TDT groups, especially in the group with more than 15 days of TDT. These results suggest that TDT matters in YG and delayed initiation of treatment over 15 days after diagnosis would increase risk of early mortalities. On the other hand, little effects of TDT on EG provide a rational for sufficient evaluation of comorbidity and functional impairments to select appropriate initial treatment. Disclosures Kim: Takeda: Research Funding; ILYANG: Consultancy, Honoraria, Research Funding; Sun Pharma.: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Lee:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kim:Abbvie: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme: Honoraria; SL VaxiGen: Consultancy, Honoraria; Yuhan: Consultancy, Honoraria; AML Global Portal: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astella: Consultancy, Membership on an entity's Board of Directors or advisory committees; BL&H: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Hanmi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.
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Bojarczuk, Kamil, Kirsty Wienand, Jeremy A. Ryan, Linfeng Chen, Mariana Villalobos-Ortiz, Elisa Mandato, Joanna Stachura, et al. "Targeted Inhibition of PI3K α/δ Is Synergistic with BCL-2 Blockade in Genetically Defined Subtypes of DLBCL." Blood 132, Supplement 1 (November 29, 2018): 39. http://dx.doi.org/10.1182/blood-2018-99-113647.
Full textAbstract:
Abstract Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous disease that is transcriptionally classified into germinal center B-cell (GCB) and activated B-cell (ABC) subtypes. A subset of both GCB- and ABC-DLBCLs are dependent on B-cell receptor (BCR) signaling. Previously, we defined distinct BCR/PI3K-mediated survival pathways and subtype-specific apoptotic mechanisms in BCR-dependent DLBCLs (Cancer Cell 2013 23:826). In BCR-dependent DLBCLs with low baseline NF-κB activity (GCB tumors), targeted inhibition or genetic depletion of BCR/PI3K pathway components induced expression of the pro-apoptotic HRK protein. In BCR-dependent DLBCLs with high NF-κB activity (ABC tumors), BCR/PI3K inhibition decreased expression of the anti-apoptotic NF-κB target gene, BFL1. Our recent analyses revealed genetic bases for perturbed BCR/PI3K signaling and defined poor prognosis DLBCL subsets with discrete BCR/PI3K/TLR pathway alterations (Nat Med 2018 24:679). Cluster 3 DLBCLs (largely GCB tumors) exhibited frequent PTEN deletions/mutations and GNA13 mutations. Cluster 5 DLBCLs (largely ABC tumors) had frequent MYD88L265P and CD79B mutations that often occurred together. These DLBCL subtypes also had different genetic mechanisms for deregulated BCL2 expression - BCL2 translocations in Cluster 3 and focal (18q21.33) or arm level (18q) BCL2 copy number gains in Cluster 5. These observations prompted us to explore the activity of PI3K inhibitors and BCL2 blockade in genetically defined DLBCLs. We utilized a panel of 10 well characterized DLBCL cell line models, a subset of which exhibited hallmark genetic features of Cluster 3 and Cluster 5. We first evaluated the cytotoxic activity of isoform-specific, dual PI3Kα/δ and pan-PI3K inhibitors. In in vitro assays, the PI3Kα/δ inhibitor, copanlisib, exhibited the highest cytotoxicity in all BCR-dependent DLBCLs. We next assessed the transcriptional abundance of BCL2 family genes in the DLBCLs following copanlisib treatment. In BCR-dependent GCB-DLBCLs, there was highly significant induction of the pro-apoptotic HRK. In BCR-dependent ABC-DLBCLs, we observed significant down-regulation of the anti-apoptotic BFL1 protein and another NF-κB target gene, BCLxL (the anti-apoptotic partner of HRK). We then used BH3 profiling, to identify dependencies on certain BCL2 family members and to correlate these data with sensitivity to copanlisib. BCLxL dependency significantly correlated with sensitivity to copanlisib. Importantly, the BCLxL dependency was highest in DLBCL cell lines that exhibited either transcriptional up-regulation of HRK or down-regulation of BCLxL following copanlisib treatment. In all our DLBCL cell lines, PI3Kα/δ inhibition did not alter BCL2 expression. Given the genetic bases for BCL-2 deregulation in a subset of these DLBCLs, we next assessed the activity of the single-agent BCL2 inhibitor, venetoclax, in in vitro cytotoxicity assays. A subset of DLBCL cell lines was partially or completely resistant to venetoclax despite having genetic alterations of BCL2. We postulated that BCR-dependent DLBCLs with structural alterations of BCL2 might exhibit increased sensitivity to combined inhibition of PI3Kα/δ and BCL2 and assessed the cytotoxic activity of copanlisib (0-250 nM) and venetoclax (0-250 nM) in the DLBCL cell line panel. The copanlisib/venetoclax combination was highly synergistic (Chou-Talalay CI<1) in BCR-dependent DLBCL cell lines with genetic bases of BCL2 deregulation. We next assessed copanlisib and venetoclax activity in an in vivo xenograft model using a DLBCL cell line with PTENdel and BCL2 translocation (LY1). In this model, single-agent copanlisib did not delay tumor growth or improve survival. Single-agent venetoclax delayed tumor growth and improved median survival (27 vs 51 days, p<0.0001). Most notably, we found that the combination of copanlisib and venetoclax delayed tumor growth significantly longer than single-agent venetoclax (p<0.0001). Additionally, the combined therapy significantly increased survival in comparison with venetoclax alone (median survival 51 days vs not reached, p<0.0013). Taken together, these results provide in vitro and in vivo pre-clinical evidence for the rational combination of PI3Kα/δ and BCL2 blockade and set the stage for clinical evaluation of copanlisib/venetoclax therapy in patients with genetically defined relapsed/refractory DLBCL. Disclosures Letai: AbbVie: Consultancy, Other: Lab research report; Flash Therapeutics: Equity Ownership; Novartis: Consultancy, Other: Lab research report; Vivid Biosciences: Equity Ownership; AstraZeneca: Consultancy, Other: Lab research report. Shipp:AstraZeneca: Honoraria; Merck: Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding.
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McKim, William A. "Positive reinforcement, the matching law and morality." Behavioral and Brain Sciences 19, no. 4 (December 1996): 587–88. http://dx.doi.org/10.1017/s0140525x00043168.
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AbstractAddictive behavior has never seemed rational because it persists in spite of drastic aversive consequences. This is a particular problem for models of addiction such as operant psychology which hold that behavior is controlled by its consequences. Inspite of claims to the contrary, Heymans target article illustrates how operant psychology resolves this contradiction. By using the matching law, Heyman suggests a mechanism that explains why delayed aversive events may not control behavior, and a conceptual framework in which we can understand successful therapies.
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Saddawi-Konefka, Robert, Aoife O’Farrell, Andrew Sharabi, Joseph Califano, J. Silvio Gutkind, and Robert Saddawi-Konefka. "436 Rational sequencing of immune-oncology therapies achieves durable response and immunologic memory." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A462. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0436.
Full textAbstract:
BackgroundOncologically-sound standard of care therapy often indicates ablation of draining lymphatic basins to eradicate repositories of metastatic disease. However, emerging cancer immunotherapies often necessitate intact secondary lymphoid organs to achieve maximum effect. Therefore, multimodal immune-oncology (IO) therapeutic approaches introduce an inherent paradox into the clinical management of the cancer patient: how to reconcile the clinical benefit of lymphatic ablation with the destruction of an indispensable immune organ.MethodsHere, we leverage a novel preclinical model of tobacco-signature head and neck squamous cell carcinoma (HNSCC) to examine the impact of lymphatic ablation on the efficacy of immunotherapy and to identify sequences of therapy that maximize durable response without compromising oncologically-sound standard of care therapy.ResultsWe show that cervical lymphatic ablation in tumor bearing animals abolishes the response to CTLA- 4 blockade by eradicating lymph-node associated conventional dendritic cells and restricting CD8 T cell priming and subsequent tumor infiltration. By modelling recurrent HNSCC, we find that upfront, elective cervical lymphatic ablation eliminates the tumor response to adjuvant CTLA-4 blockade in contrast to a lymphatic-sparing approach, which preserves sensitivity to CTLA-4 blockade. In the neoadjuvant setting, we show that delayed, but not early, cervical lymphatic ablation leads to durable response after CTLA-4 blockade. Lastly, we demonstrate that a successful tumor response to CTLA-4 blockade begets long-lasting immunologic memory, resistant to delayed cervical lymphatic ablation.ConclusionsCollectively, this work addresses an inherent paradox in the delivery of combination IO therapy, informs optimal sequencing of multimodal therapy and affords a premise for the introduction of CTLA-4 blockade into the clinical management of HNSCC.
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Mizukawa, Benjamin, Eric O'Brien, Wei Liu, Daniel Moriera Ridsdale, Mark Wunderlich, Yi Zheng, and James C. Mulloy. "Maintenance Of Bone Marrow Residency and Self-Renewal Of Leukemic Stem Cells By Cdc42 Gtpase." Blood 122, no. 21 (November 15, 2013): 2889. http://dx.doi.org/10.1182/blood.v122.21.2889.2889.
Full textAbstract:
Abstract The leukemic stem cell (LSC) depends on specific interactions with extracellular matrix, soluble factors, and cellular components of the microenvironment, or niche. These interactions promote LSC self-renewal and survival, thus contributing to chemoresistance and treatment failure. Understanding the signaling pathways that promote LSC maintenance in response to niche interactions may reveal novel targets for therapy. Recent studies indicate a critical role for the small Rho GTPase, Cdc42, in the maintenance of normal hematopoietic stem and progenitor cells (HSPCs). Cdc42 coordinates actin cytoskeleton organization, adhesion, migration, self-renewal, cell polarity, proliferation, and survival of normal HSPCs in response to niche signaling through multiple cell surface receptors, including CXCL12/CXCR4, SCF/KIT, and fibronectin/integrin. Cdc42 activity is increased in both murine and human models of MLL-AF9 (MA9) acute myeloid leukemia (AML). Cdc42 expression is also increased in human patient AML samples across cytogenetic subtypes, compared to normal hematopoietic cell subsets, in analysis of curated datasets in the HemaExplorer database. In earlier work, we have shown that Cdc42 inhibition leads to peripheral mobilization of leukemia cells out of the marrow niche (Blood 114, 13). In the present study, we investigate whether Cdc42 inhibition also disrupts intrinsic LSC self-renewal. To interrogate Cdc42 in LSC self-renewal, MA9 cell lines were established following transduction of bone marrow HSPCs harvested from tamoxifen-inducible Cdc42 knockout mice, with Cre null donors as controls. Upon tamoxifen (TAM) treatment, Cdc42KO-MA9 cells had decreased CFU and small, diffuse colony morphology. Mice transplanted with untreated MA9 cells were divided to receive injections of TAM vs control. The Cdc42KO-MA9 cohort remains alive at over 180 days post-transplant, whereas vehicle control mice died of AML with latency similar to Cre null MA9 cell recipients (p<0.005). In vivo deletion of Cdc42 from MA9 leukemia in secondary recipients prolonged disease latency (p<0.005). AML cells recovered from vehicle control mice showed decreased growth in culture, reduced CFU content, and increased apoptosis following treatment with TAM to delete Cdc42. Cdc42KO-MA9 leukemia cells also had higher side scatter and Gr-1 expression, and decreased c-Kit, suggesting differentiation. These data indicate that Cdc42 is required for murine LSC maintenance. We used Tet-inducible shRNA targeting of Cdc42 in human cell lines expressing MA9 and mutant NRas (MA9/NRas). Cdc42 knockdown reduced MA9/NRas colony-forming ability, blocked actin polymerization and migration in response to CXCL12, and induced apoptosis. MA9/NRas cells co-expressing inducible Cdc42 shRNA and luciferase were transplanted into NSGS mice on doxycycline chow to induce knockdown. Bioluminescence imaging showed delayed AML progression in the knockdown group compared to non-targeting shRNA and regular chow controls. Thus, Cdc42 deficiency in human MA9 LSC reproduces the phenotype seen in the mouse genetic model. We used a novel small-molecule Cdc42-activity specific inhibitor, CASIN, to test pharmacologic inhibition of Cdc42 in AML. Consistent with knockdown data, in vitro CASIN treatment blocked MA9 cell colony-forming ability, actin polymerization, and migration. CASIN treatment led to specific induction of apoptosis in MA9 cells, while normal human umbilical cord blood CD34+ cells showed no significant toxicity in the dose range tested. Together, these studies show that Cdc42 signaling is critical to intrinsic LSC self-renewal and engagement of the niche, and Cdc42 inhibition represents a rational therapeutic principle to target LSC maintenance. Disclosures: No relevant conflicts of interest to declare.
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Brookes, Paul, Andrew Tompkins, Kimberly Morse, Shannon Hilchey, Suhail Salim, Denise Ray, Richard Phipps, and Steven H. Bernstein. "The Triterpenoids 2-cyano-3,12-dioxooleana-1,9-dien-28-oic Acid (CDDO) and Their Imidazole (CDDO-Im) and Dinitrile Derivatives (DI-CDDO) Elicit Apoptosis through a Novel Mitochondrial Pathway." Blood 106, no. 11 (November 16, 2005): 2426. http://dx.doi.org/10.1182/blood.v106.11.2426.2426.
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Abstract We have recently shown that B-cell non Hodgkin’s lymphoma express the transcription factor PPARγ and undergo apoptosis upon exposure to PPARγ ligands. The synthetic triterpenoid CDDO is a specific ligand for PPARγ, and CDDO and its derivatives, CDDO-Im and DI-CDDO, induce diffuse large cell lymphoma (DLCL) death (OCI Ly10 and OCI Ly19 cells), with a potency of DI-CDDO>CDDO-Im>CDDO, suggesting that such agents have therapeutic potential in lymphoma. The natural PPARγ ligand, 15d-PGJ2 (which also elicits DLCL death), has previously been shown to inhibit mitochondrial complex I, enhance mitochondrial reactive oxygen species (ROS) generation, and react with protein thiols. Given that CDDO is structurally similar to 15d-PGJ2 we hypothesized that CDDO-induced cell death may similarly be mediated via complex I inhibition, ROS generation, thiol oxidation, and opening of a large membrane pore complex in the mitochondrial membrane, termed the “permeability transition” (PT) pore. Studies on isolated rat liver mitochondria however showed that none of the CDDO-derivatives inhibited complex I activity or affected mitochondrial protein thiols. However, all three compounds did induce PT pore opening and mitochondrial swelling, with a concurrent loss of mitochondrial membrane potential, in a Ca2+ dependent manner (potency DI-CDDO>CDDO-Im>CDDO). This is consistent with a previously shown role for Ca2+ in CDDO-induced cell death. Interestingly, this mitochondrial swelling was not inhibited by the classical PT pore inhibitor cyclosporin A (CsA). This is supported by our findings that the induction of OCI-Ly19 cell death by CDDO was also not inhibited by CsA, or by another classical PT pore inhibitor, nortriptyline. These phenomena may be partially explained by invoking the “unregulated PT pore”. In addition to the classical PT pore, a non-CsA sensitive “unregulated PT pore” also exists, which is generated by the aggregation of misfolded mitochondrial membrane proteins that are induced by oxidants and thiol reactive agents. That exposure of mitochondria to CDDO results in the formation of “unregulated PT pores” is supported by our findings that the proteosome inhibitor PS341, potentiates CDDO-induced cell death, suggesting the involvement of a protein folding response. The temporal role of ROS in CDDO-induced cell death was also investigated, and it was found that the antioxidant N-acetyl-cysteine did not inhibit PT pore opening, but did inhibit cell death. This is consistent with our observation that ROS generation in isolated mitochondria was not immediately triggered by CDDO, but rather increased at delayed time points, placing it downstream of PT pore opening. This proposes the following novel model of a direct mitochondrial effect of CDDO and its derivatives: \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \[CDDO{\rightarrow}\ mitochondrial\ protein\ misfolding\ {\rightarrow}\ unregulated\ PT\ pore\ formation\ {\rightarrow}\ ROS\ {\rightarrow}\ cell\ death\] \end{document} In summary: CDDO and its derivatives have direct effects on mitochondria, and represent novel therapeutic approaches for the treatment of patients with DLCL; and combinations of CDDO and its derivatives with proteosome inhibitors represent a rational combination to test in the context of clinical trials.
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Krueger, Michael J., Matthew Minus, Wei Liu, Xin Long, Alexandra M. Stevens, Mikhail I. Kolosov, Edward Allan R. Sison, David John Tweardy, Zachary T. Ball, and Michele S. Redell. "A Novel STAT3 Inhibitor Has Potent Activity in Preclinical Models of Acute Myeloid Leukemia That Incorporate the Stromal Environment." Blood 126, no. 23 (December 3, 2015): 569. http://dx.doi.org/10.1182/blood.v126.23.569.569.
Full textAbstract:
Abstract Background: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with relapse rates approaching 40% in children. Aberrant activation of the Signal Transducer and Activator of Transcription 3 (STAT3) pathway is implicated in promoting many cancer phenotypes, including AML. Additionally, the important role of STAT3 in microenvironment-mediated chemoresistance is well established. Therefore, STAT3 is an important target for the development of new agents. Like other transcription factors, the structure of the STAT3 protein does not easily lend itself to the development of a small molecule inhibitor that is both potent and specific. Several commercially available and academic STAT3 inhibitors have been reported, but none is yet suitable for broad clinical application. We have developed a novel class of naphthalene sulfonamide small molecule STAT3 inhibitors with efficacy in AML cell lines and primary samples (e.g. C188-9 [Redell, et al, 2011, Blood 117:5701-9]). Rational optimization steps have yielded a new lead compound, MM-206, with improved stability in cellular contexts. Our aim is to evaluate the activity of MM-206 in preclinical AML models that include the bone marrow stromal environment. Inhibition of STAT3 activity: MM-206 potently inhibited the STAT3 SH2 domain-phosphopeptide interaction, with IC50 1.2 μM by surface plasmon resonance assays. Further, MM-206 attenuated phosphorylation of G-CSF-induced STAT3 as measured by intracellular flow cytometry. AML cell lines were treated with increasing doses of MM-206 for 30 minutes, followed by stimulation with G-CSF to induce STAT3 phosphorylation (pY705). The IC50 values for inhibition of phosphorylation were 1-3 µM, indicating potent inhibitory activity in cells. Similarly, MM-206 inhibited G-CSF-induced PIM1 transcription in a dose dependent manner in AML cell lines. Anti-leukemia activity in vitro: MM-206 demonstrated dose-dependent induction of apoptosis in AML cell lines and pediatric AML samples, even in the presence of bone marrow stromal cells. Cell lines and patient samples were cultured alone or co-cultured with mOrange-transduced HS5 or HS27A stromal cells, then treated with increasing doses of MM-206 for 24 hours. Cells were stained with Annexin V-FITC and apoptosis in the mOrange-negative cells was quantified by FACS. EC50 values were consistent with the doses for inhibition of phosphorylation, ranging from 1 - 10 µM. The increase in EC50s in the stroma co-cultured AML cells, compared to AML cells cultured alone, was ~3-fold, indicating only moderate environment-derived protection against this compound. In complementary experiments, luciferase-transduced AML cell lines were cultured alone or with stromal cells, treated with MM-206 for 24 hours, then AML cell viability was assessed by luminescence. Again, IC50s were in the range of 3 µM for all cell lines tested. There was no difference in potency for cells on stroma in the luminescence assay. In contrast to the anti-AML activity, EC50s were >30 µM in cell line models of acute lymphoblastic leukemia, a disease not typically associated with STAT3-dependent survival. Anti-leukemia activity in vivo: We engrafted NSG mice with luciferase-expressing MV4-11 AML cells. After 2 weeks, mice were randomized to receive MM-206 (30 mg/kg) or vehicle, ip daily Monday-Friday, for 2 or 4 weeks. MM-206 treatment delayed disease progression, as evidenced by significantly lower luminescence values (p<0.001, Fig. 1). Mice treated with MM-206 for 4 weeks (n=8) had significantly reduced blast percent in the bone marrow and significantly prolonged survival (p=0.02 at 10 weeks), compared to the control group (n=7). Summary: MM-206 is a novel naphthalene sulfonamide inhibitor of STAT3 activity, with potent anti-AML activity in preclinical models that incorporate the stromal environment, including a mouse xenograft model. Future work will evaluate the activity of this compound in combination with chemotherapy, as a strategy to overcome environment-mediated chemoresistance. Figure 1. MM-206 treatment slows disease progression in a xenograft model of AML. NSG mice were injected iv with 106 MV4-11.ffluc AML cells at day 0. After two weeks, mice began treatment with MM-206 30 mg/kg, or vehicle, ip daily 5 days per week for 2 weeks or 4 weeks (weeks 2 - 4 or 2 - 6). Representative luminescence images from mice one week after completion of two weeks of treatment. Figure 1. MM-206 treatment slows disease progression in a xenograft model of AML. NSG mice were injected iv with 106 MV4-11.ffluc AML cells at day 0. After two weeks, mice began treatment with MM-206 30 mg/kg, or vehicle, ip daily 5 days per week for 2 weeks or 4 weeks (weeks 2 - 4 or 2 - 6). Representative luminescence images from mice one week after completion of two weeks of treatment. Disclosures Tweardy: StemMed, Ltd.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: compounds including MM-206, Research Funding.
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Van Der Meer, Laurens T., Samantha YA Terry, Dorette van Ingen Schenau, Kiki Andree, Gerben M. Franssen, Debbie Roeleveld, Bart Metselaar, et al. "Cathepsin B Mediated Lysosomal Degradation in Macrophages Controls the Pharmacokinetics of the Therapeutic Protein Asparaginase." Blood 126, no. 23 (December 3, 2015): 3768. http://dx.doi.org/10.1182/blood.v126.23.3768.3768.
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Abstract Asparaginase (ASNase) is one of the cornerstones of the multi-drug treatment protocol that is used to treat acute lymphoblastic leukemia (ALL) in pediatric and adult patients. Despite the fact that ASNase has been used in ALL treatment protocols for decades, little is known about the biodistribution and the mechanism of ASNase turnover in vivo. A large inter-individual variation in ASNase pharmacokinetics is observed in patients. While elevated ASNase levels are associated with an increase in adverse events, underexposure, frequently caused by antibody mediated clearance, seriously reduces therapeutic efficacy. To date, it is not possible to predict pharmacokinetics of ASNase in individual patients and therefore current therapeutic protocols are supported by frequent monitoring of ASNase levels and adjustments of administration schemes. We used an in vivo imaging approach to study ASNase biodistribution and pharmacodynamics in a mouse model and provide in vitro and in vivo evidence that identifies the endo-lysosomal protease Cathepsin B in macrophages as a critical component of ASNase degradation. Results/Discussion Mice were injected with 111Indium-labeled ASNase and biodistribution was monitored by quantitative microSPECT/CT scans and ex vivo analysis of organs using a gamma counter. Over time, ASNase accumulated in the liver and particularly the spleen and the bone marrow. We hypothesized that macrophages in these organs, efficiently take up the ASNase, thereby rapidly clearing the active enzyme from the blood. Immunohistochemical analysis confirmed the presence of ASNase in cells positive for the murine macrophage marker F4/80. To confirm the importance of macrophage populations in ASNase clearance, we depleted mice from phagocytic cells by injection of clodronate liposomes, and studied ASNase biodistribution and kinetics. Indeed, clodronate pretreatment significantly diminished the accumulation of ASNase in the liver, spleen and the bone marrow while doubling the circulatory half-life of serum ASNase activity. We conclude from these experiments that macrophages determine the pharmacokinetics of asparaginase, which raises the question whether rapid clearance of the drug by bone marrow resident macrophages will negatively affect the depletion of asparagine in the bone marrow niche. We previously linked a germline mutation in the gene encoding endosomal protease Cathepsin B to strongly diminished asparaginase degradation in a pediatric ALL patient. To connect the macrophage mediated clearance to the proposed role of Cathepsin B in ASNase degradation, we studied the contribution of this protease in macrophage-mediated degradation of asparaginase. We used cell lines to show that Cathepsin B expression is induced during differentiation from monocytes towards macrophages. This is consistent with our finding that macrophages, but not monocytes, are capable of degrading ASNase. Furthermore, we used both chemical inhibition and RNAi mediated knockdown of Cathepsin B to show that this protease is required for ASNase degradation in these macrophages. Finally, by comparing Cathepsin B knockout mice with wildtype littermates, we demonstrated that loss of Cathepsin B activity significantly delayed clearance of serum asparaginase, consistent with a prominent role for this lysosomal protease in ASNase turnover. In conclusion, by using in vivo imaging we showed that asparaginase is efficiently cleared from the circulation by macrophages. In particular, bone marrow resident macrophages may provide a protective environment for leukemic cells by effectively removing the therapeutic protein from the bone marrow niche. However, both the prominent role of macrophages and the importance of the lysosomal protease Cathepsin B in asparaginase clearance, may allow the rational design of a next generation asparaginase. Disclosures Metselaar: Enceladus Pharmaceuticals: Employment, Equity Ownership.
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Suryani, Santi, Keith CS Sia, Lauryn Bracken, Hernan Carol, Kathryn Evans, Raushan Kurmasheva, Peter J. Houghton, Malcolm A. Smith, and Richard B. Lock. "Dual Inhibition of JAK/STAT and MAPK Pathways Results in Synergistic Cell Killing of JAK-Mutated Pediatric Acute Lymphoblastic Leukemia." Blood 120, no. 21 (November 16, 2012): 3562. http://dx.doi.org/10.1182/blood.v120.21.3562.3562.
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Abstract Abstract 3562 Relapsed/refractory pediatric acute lymphoblastic leukemia (ALL) remains a continuing challenge to treat with currently available therapies, and new treatments are urgently required for the management of these high-risk cases. Activating mutations in the pseudokinase or kinase domains of Janus kinases (JAKs) 1, 2 and 3 are present in approximately 10% of high-risk pediatric ALL and are associated with high expression of cytokine receptor-like factor 2 (CRLF2) and poor outcome. These mutations can lead to continuous activation of JAKs, resulting in constitutive activation by phosphorylation of downstream signaling, including the signal transducer and activator of transcription (STAT), AKT, and mitogen-activated protein kinase (MAPK) pathways. The availability of specific JAK inhibitors, developed primarily for the treatment of JAK-mutated myeloproliferative diseases (MPDs), represents an opportunity to improve the treatment options for JAK-mutated pediatric ALL. AZD1480, a potent ATP-competitive small-molecule JAK2 inhibitor that also exhibits inhibitory activity against JAK1, is in solid tumor clinical trials. The purpose of this study was to gain a greater understanding of a potential role for AZD1480 in the treatment of JAK-mutated pediatric ALL either as a single agent or in rational drug combinations, using a preclinical model of xenografts established in immune-deficient mice from direct patient explants. As part of the Pediatric Preclinical Testing Program (PPTP) we previously showed that AZD1480 administered at 10 mg/kg twice daily × 5 then at 15mg/kg once daily × 2 via oral gavage for an intended three weeks significantly delayed the progression of only one in five JAK-mutated xenografts, with no tumor regressions observed. We now show that the relative insensitivity of JAK-mutated ALL xenografts to AZD1480 is a cell-intrinsic phenomenon, since 6/7 JAK1- or JAK2-mutated xenografts exhibited ex vivo IC50 values >2 μM following 72 h drug exposures, as assessed by mitochondrial function cell viability (MTT) assay. In order to gain a greater understanding of the underlying mechanisms for the lack of AZD1480 single-agent efficacy against JAK-mutated xenografts we analyzed intracellular signaling pathways and their responses to AZD1480 treatment. In contrast with “Typical” B-cell precursor (BCP)-ALL xenograft cells, JAK-mutated xenografts exhibited constitutive JAK pathway activation, as assessed by increased levels of phospho-JAK1 (pJAK1), pJAK2, pSTAT1/3/5, pAKT, pMAP2K1/2 (MEK1/2) and phospho-extracellular signal-regulated kinase 1/2 (pERK1/2). Ex vivo exposure of JAK-mutated xenografts to 1 μM AZD1480 caused rapid (within 1 h) and sustained (up to 24 h) decreases in pSTATs, but minimal reduction in pMEK1/2 and pERK1/2. These results indicate that AZD1480 alone selectively inhibits JAK downstream signaling pathways, which may be insufficient to delay leukemia progression in vivo or induce cell death ex vivo. Moreover, they provide a rationale for dual targeting of the JAK and MAPK pathways to elicit synergistic anti-leukemic cell killing in JAK-mutated ALL. Ex vivo exposure of two JAK2-mutated xenografts to 1 μM of the MEK1/2 inhibitor AZD6244 (selumetinib) caused a profound decrease in pERK1/2, and the combination of 1 μM each of AZD1480 and AZD6244 resulted in reductions of both pSTATs and pERK1/2. Moreover, fixed-ratio MTT cytotoxicity assays using these two JAK2-mutated xenografts demonstrated very strong synergy between AZD1480 and AZD6244, with Combination Indices for each xenograft of 0.36 and 0.098 at the ED50; 0.23 and 0.015 at the ED75; and 0.15 and 0.002 at the ED90. This strong synergistic effect was observed despite AZD1480 and AZD6244 exerting minimal cell killing activity against the xenograft cells when used as single agents. In conclusion, our data indicate that AZD1480 is unlikely to exert significant single-agent activity in the treatment of JAK-mutated pediatric ALL, and that future efforts focusing on dual targeting of the JAK/STAT and MAPK offer a potential pathway to achieving clinical efficacy. Disclosures: No relevant conflicts of interest to declare.
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Smyth, Mark J., Morgan E. Wallace, Stephen L. Nutt, Hideo Yagita, Dale I. Godfrey, and Yoshihiro Hayakawa. "Sequential activation of NKT cells and NK cells provides effective innate immunotherapy of cancer." Journal of Experimental Medicine 201, no. 12 (June 20, 2005): 1973–85. http://dx.doi.org/10.1084/jem.20042280.
Full textAbstract:
The CD1d reactive glycolipid, α-galactosylceramide (α-GalCer), potently activates T cell receptor-α type I invariant NKT cells that secondarily stimulate the proliferation and activation of other leukocytes, including NK cells. Here we report a rational approach to improving the antitumor activity of α-GalCer by using delayed interleukin (IL)-21 treatment to mature the α-GalCer–expanded pool of NK cells into highly cytotoxic effector cells. In a series of experimental and spontaneous metastases models in mice, we demonstrate far superior antitumor activity of the α-GalCer/IL-21 combination above either agent alone. Superior antitumor activity was critically dependent upon the increased perforin-mediated cytolytic activity of NK cells. Transfer of α-GalCer–pulsed dendritic cells (DCs) followed by systemic IL-21 caused an even more significant reduction in established (day 8) metastatic burden and prolonged survival. In addition, this combination prevented chemical carcinogenesis more effectively. Combinations of IL-21 with other NK cell–activating cytokines, such as IL-2 and IL-12, were much less effective in the same experimental metastases models, and these cytokines did not substitute effectively for IL-21 in combination with α-GalCer. Overall, the data suggest that NK cell antitumor function can be enhanced greatly by strategies that are designed to expand and differentiate NK cells via DC activation of NKT cells.
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Khudolii, Oleg, Sergii Iermakov, Olha Ivashchenko, and Mykola Nosko. "Strength Abilities: Modeling of Immediate and Delayed Training Effect of Strength Loads in Boys Aged 8 Years." Teorìâ ta Metodika Fìzičnogo Vihovannâ 20, no. 4 (December 25, 2020): 248–55. http://dx.doi.org/10.17309/tmfv.2020.4.08.
Full textAbstract:
The purpose of the study was to obtain regression models of immediate and delayed training effect of strength loads in boys aged 8 years, based on a full factorial experiment. Materials and methods. The study participants were 48 boys aged 8 years. The experiment was performed using a 22 factorial design. The study materials were processed by the IBM SPSS 22 statistical analysis program. The study examined the impact of four variants of strength load on the immediate (ITE) and the delayed (DTE) training effect of orthogonal strength exercises modes and rest intervals in boys aged 8 years. Results. The study results show that in the proposed matrix of the 22 full factorial design, the chosen step of variation of factors is sufficient to study the influence of different modes of strength exercises on the dynamics of ITE in boys aged 8 years. Based on the data analysis, the study obtained regression models of load for calculating the ITE1, ITE2, and DTE. The obtained regression models make it possible to calculate the number of repetitions and rest interval to achieve the most rational load variant. Conclusions. The analysis of regression equations shows the interrelation between training effects: ITE1 —> ITE2 —> DTE. The value of ITE1, ITE2, and DTE at station I (exercises to strengthen arms and shoulders) and station II (exercises to strengthen abdominal muscles) depends on the increase in the number of repetitions in a set and the duration of the rest interval. The value of ITE1, ITE2 at station ІІІ (exercises to strengthen back muscles) depends on the increase in the number of repetitions in a set and the duration of the rest interval. The value of DTE – on the increase in the number of repetitions in a set and the reduction of the rest interval duration. The value of ITE1 at station IV (exercises to strengthen leg muscles) depends on the increase in the number of repetitions in a set and the reduction of the rest interval duration. To strengthen the DTE, it is necessary to reduce the number of repetitions in a set and the duration of the rest interval.
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Bernhardt, Miranda L., Paula Stein, Ingrid Carvacho, Christopher Krapp, Goli Ardestani, Aujan Mehregan, David M. Umbach, Marisa S. Bartolomei, Rafael A. Fissore, and Carmen J. Williams. "TRPM7 and CaV3.2 channels mediate Ca2+ influx required for egg activation at fertilization." Proceedings of the National Academy of Sciences 115, no. 44 (October 15, 2018): E10370—E10378. http://dx.doi.org/10.1073/pnas.1810422115.
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The success of mammalian development following fertilization depends on a series of transient increases in egg cytoplasmic Ca2+, referred to as Ca2+ oscillations. Maintenance of these oscillations requires Ca2+ influx across the plasma membrane, which is mediated in part by T-type, CaV3.2 channels. Here we show using genetic mouse models that TRPM7 channels are required to support this Ca2+ influx. Eggs lacking both TRPM7 and CaV3.2 stop oscillating prematurely, indicating that together they are responsible for the majority of Ca2+ influx immediately following fertilization. Fertilized eggs lacking both channels also frequently display delayed resumption of Ca2+ oscillations, which appears to require sperm–egg fusion. TRPM7 and CaV3.2 channels almost completely account for Ca2+ influx observed following store depletion, a process previously attributed to canonical store-operated Ca2+ entry mediated by STIM/ORAI interactions. TRPM7 serves as a membrane sensor of extracellular Mg2+ and Ca2+ concentrations and mediates the effects of these ions on Ca2+ oscillation frequency. When bred to wild-type males, female mice carrying eggs lacking TRPM7 and CaV3.2 are subfertile, and their offspring have increased variance in postnatal weight. These in vivo findings confirm previous observations linking in vitro experimental alterations in Ca2+ oscillatory patterns with developmental potential and offspring growth. The identification of TRPM7 and CaV3.2 as key mediators of Ca2+ influx following fertilization provides a mechanistic basis for the rational design of culture media that optimize developmental potential in research animals, domestic animals, and humans.
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Lingo, Joshua, Jordan Kohlmeyer, Courtney Kaemmer, Amanda Scherer, Ellen Voigt, Michael Chimenti, Munir Tanas, et al. "Abstract A02: MEK-CDK4/6 inhibition induces plasma cell tumor infiltration and sensitizes de novo MPNSTs to immune checkpoint blockade." Cancer Immunology Research 10, no. 12_Supplement (December 1, 2022): A02. http://dx.doi.org/10.1158/2326-6074.tumimm22-a02.
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Abstract Malignant peripheral nerve sheath tumors (MPNSTs) are deadly, Ras-driven sarcomas that lack effective therapies. Many tumors are unresectable and toxic chemotherapies are ineffectual. The sensitivity of MPNSTs to immune checkpoint blockade (ICB) therapies is not known, although sarcomas are generally unresponsive. Patient tumor analyses comparing MPNSTs to benign precursors identified Ras effectors, MEK and CDK4/6 kinases, as rational targets for therapy. We tested the efficacy of dual MEK-CDK4/6 inhibition versus single drug therapy using preclinical MPNST models. In MPNST cells, low-dose drug combinations synergistically reactivated the retinoblastoma (RB1) tumor suppressor, induced cell death and decreased clonogenic survival. In de novo MPNSTs in immune competent mice, combination therapy caused tumors to shrink, substantially delayed resistant tumor outgrowth and improved survival relative to monotherapies. Tumor regression was associated with an immune activation gene expression profile featuring plasma cell infiltration, an event not previously observed with MEK-CDK4/6 inhibitor therapy. In other human tumor types, intratumoral plasma cells prognose better overall survival and improved response to ICB therapies. Excitingly, MEK-CDK4/6 therapy sensitized de novo MPNSTs to anti-programmed death ligand 1 (PD-L1) therapy with the combination achieving complete tumor ablation and apparent cure in 10% of mice. These findings implicate a critical role for plasma cells in mediating MPNST regression in response to kinase inhibitor therapy and sensitizing tumors to PD-L1 targeting. This novel therapeutic combination is a promising option for MPNST therapy that could improve ICB efficacy in other solid tumors. Citation Format: Joshua Lingo, Jordan Kohlmeyer, Courtney Kaemmer, Amanda Scherer, Ellen Voigt, Michael Chimenti, Munir Tanas, Varun Monga, Ben Darbro, David Meyerholz, Rebecca Dodd, Dawn Quelle. MEK-CDK4/6 inhibition induces plasma cell tumor infiltration and sensitizes de novo MPNSTs to immune checkpoint blockade [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A02.
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Proulx, Pierre-Paul. "Manpower Coefficients and the Forecasting of Manpower Requirements in Nova Scotia." Commentaires 22, no. 4 (April 12, 2005): 565–68. http://dx.doi.org/10.7202/027839ar.
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«... Devising a workable manpower plan... at best is an art, still in its infancy. Many assumptions and informed judgment are necessary to compensate for gaps in data. But if planning of any sort were delayed until our data were complete and a fool-proof methodology were developed, no forecasts of educational needs would ever be made. The enormous outlays on education today and in the future demand that we at least make an attempt to determine how we can best allocate these expenditures to meet our needs efficiently. As additional data become available and greater experience is gained in the techniques of manpower planning, many of the difficulties facing us will be overcome. Manpower forecasting although not an ideal approach to rational development of our educational resources at least provides a framework of additional required data that no other currently-known method offers ». 1 We are attempting to calculate « manpower coefficients » or if you wish, a fraction whose numerator is man-years of experienced labour by occupation group, and whose denominator is output by industry group. In other words, we shall estimate the number of man-years of labour of different occupation groups required to produce $1,000.00 of output in selected industries in Nova Scotia, in 1960-61. The fraction is no more and no less than an estimate of labour productivity. We have asked the Dominion Bureau of Statistics to provide a tabulation containing the experienced labour force in 1961, cross-classified, 1) by sex, 2) by class of worker (wage and salary earners, unpaid family workers, own business operators), 3) by industry group (54), 4) by occupation group (64), 5) by earnings group, 6) by years of schooling, 7) by weeks worked, 8) by hours per week, 9) by age group. We shall prepare a 64 (row) by 54 (column) matrix, one column for each industry group and one row for each occupation group. Each cell will contain a fraction which when applied to a forecast of gross value of output by industry will provide an estimate of the number of man-years of labour required to produce that output. If we sum across the rows we obtain the total demand for man-years of labour for each of occupation groups. I shall dispense with a discussion of the majority of the assumptions, limitations and peculiarities of the method, for these may be found in the report mentioned above. To obtain the numerator of our fraction (man-years of experienced labour force), we weighted bodies (the experienced labour force) by two fractions; one for weeks worked and one for hours worked. This is particularly important in Nova Scotia because of seasonal operations. If we found a person who had worked 26 out of the 52 weeks proceeding the 1961 levels, and when he worked, worked the model hours in his occupation groups, we counted him as 1/2 a man-year of labour. One facet of the study which may interest individuals involved in training, retraining and education concerns the occupation groups we formed. We have grouped the 273 Census occupations of the 1961 Census into 64 occupation groups. We formed broad groups of occupations within which we believe workers are substitutable, transferable and interchangeable. This was done among other reasons because it is quite common to find workers with the same type of training in different occupations, or to put it differently because workers with one type of preparation often go into different kinds of jobs. This approach also reflects a belief that it is more effective to train workers in families of related skills rather than in specific skills in preparation for the labour market. Another reason is that Census occupation definitions often leave much to be desired. We have therefore formed 64 occupation groups which are in many respects similar to Dunlop's « job clusters » and Scoville « job families » which are defined as groups of job classifications limited by technology, administration and social custom or « jobs linked by materials used, equipment used and functions performed ». We have in effect formed 44 groups of occupations on the basis of affinity in functions and another 19 (one group, the 64th is for unpaid family workers) which segregate superior from intermediate from unskilled workers in many of these groups of occupations. We arrived at the latter by using earnings and education criteria. The reason for doing so is that workers with very different levels of skill were placed together in one Census occupation group (for example, many « engineers » in Nova Scotia have no secondary school training and very low incomes according to the 1961 Census; apparently many were promoted by their wives when the Census enumerator came). In many cases, we required that the worker meet either the earnings criterion or the education criterion depending upon the occupation group, and this among other reasons because we did not use age in the process. We neglected the use of an education criterion in most occupation groups except those in managerial, technical, professional and clerical categories. Let me also mention that we transformed reported earnings to annual rate earnings to match to our criteria because we know that many workers worked part-time, or were away from work for various reasons during the 12 months which proceeded the 1961 Census. This allowed us to exclude from superior categories individuals with little qualifications who held multiple jobs and worked an abnormal number of hours. We have also asked the Dominion Bureau of Statistics to provide information on the educational attainment of the workers in our different occupation groups by sex. This will allow users to draw implications concerning the formal educational requirements needed to produce the forecasted output. In conclusion, please allow me to mention what I believe to be some of the work required to improve our knowledge in this area. Care should be taken in preparing forecasts of the gross value of production (including inventories), in 1960 constant dollars, for the industry groups chosen in our study. These output forecasts should not be obtained from employment forecasts for the application of man-power coefficients to output forecasts thus derived would be tautological. Many specific studies of industry productivity trends would be helpful to narrow the zone of ignorance of the forecasts obtained through the use of our manpower coefficients. Much remains to be done to dynamize the manpower coefficients. We know that labour productivity (and hence the manpower coefficients) varies cyclically and all we have estimated is a fixed coefficient for 1960-1961. We also know that more frequent estimates of these manpower coefficients would allow us to determine how technological changes have altered them, although the robustness of manpower coefficients is improved by the fact that we have grouped industries and occupations. Our coefficients are based on ex post data of employment and output rather than ex ante data on the demand for labour (employment plus vacancies) and for output. They are therefore influenced by labour supply as well as by labour demand, i.e. they are the result of the interaction of manpower requirements and supplies. Much remains to be done to arrive at an interacting supply and demand model, and the new vacancies data soon to be published by the Dominion Bureau of Statistics should help us to refine those models we can think up now. Much remains to be done on the appropriateness of grouping occupations for training and retraining purposes, and on the criteria for doing so. Much analysis of the functional and employment requirements by occupation remains to be done for the use of sex, earnings and education, in this paper is certainly not fully satisfactory. (1) B.M. WILKINSON, Studies in the Economics of Education, Occasional Paper number 4, Economics and Research Branch, Department of Labour, Canada July 1965, pp. 37-38.
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Hsieh, Y. T., C. Hubeau, V. Massa, W. LI, S. Frei, B. Capraro, A. Umana, et al. "OP0316 EMERGING BEST-IN-CLASS IL-2 VARIANT HIGHLIGHTS TREG-DIRECTED THERAPY FOR AUTOIMMUNE DISEASE." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 195.1–195. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1999.
Full textAbstract:
Background:Impairment or deficiency of regulatory T cells (Treg) is associated with chronic inflammation and autoimmune diseases. Interleukin 2 (IL-2) is a cytokine indispensable for Treg expansion and immunosuppressive function. However, expansion of cytotoxic effector T (Teff) and NK cells and the associated vascular leakage side effect limit the use of IL-2 in autoimmune diseases [1].Objectives:Cugene developed a long-acting IL-2 variant with high Treg specificity and low toxicity to restore immune homeostasis and self-tolerance, and potentially cure autoimmune and inflammatory diseases.Methods:IL-2 variants were generated based on the quaternary structure of IL-2 and IL-2Rαβγ (alpha, beta, gamma) complex. Biological activity was determined by examining differential signaling activity in induction of STAT5 phosphorylation in defined lymphocyte populations of human PBMC using flow cytometry. Binding activity was evaluated by ELISA. Pharmacokinetics, pharmacodynamics, safety and tolerability were assessed in mice and cynomolgus monkeys. Treg suppressive function was determinedin vivo/ex vivo,and anti-inflammatory and anti-antibody production efficacy were determined in delayed-type hypersensitivity (DTH) and T-cell-dependent antibody response (TDAR) models.Results:Structure-based rational design and activity-guided fine-tuning generated an optimized IL-2 variant, CUG252. It demonstrated a strong and near wild-type IL-2 ability to stimulate STAT5 phosphorylation in IL-2Rαβγ dominant Treg cells but abolished activities in IL-2Rβγ dominant effector CD4, CD8 and NK cells. This was a result of biased binding activity to IL-2Rα while dramatically attenuated binding to IL-2Rβγ complex. In mice and monkeys, administration of CUG252 resulted in dose-dependent increases in Treg proliferation and expansion by more than 10- and 30-fold, respectively, with largely abolished activities in CD4+ T conventional, cytotoxic CD8+ Teff and NK cells. The ratio of Treg/Teff cells achieved was as high as 0.4 in mice and 1.2 in monkeys. Both CD4+ and CD8+ Tregs were expanded with preferential increases in memory over naïve subsets. A substantial increase in Treg-suppressive capacity over T effector cells was corroborated by enhanced expression of functional and inhibitory markers, including CD25, Foxp3, PD-1, CTLA-4, Tim3 and ICOS. In DTH and TDAR models, CUG252 strongly inhibited antigen-driven inflammation, B cell maturation, and antibody production. The sustained PK/PD profile supports monthly dosing or better in humans. CUG252 was well-tolerated and no changes in body weight, body temperature, clinical pathology or signs of vascular leakage were observed. Moreover, CUG252 demonstrated superior manufacturability.Conclusion:CUG252 demonstrates an emerging best-in-class profile among IL-2 variants. It displayed exquisite Treg-selectivity while retaining potency comparable to wild-type IL-2. It showed strong anti-inflammatory and anti-antibody production efficacy with significantly improved therapeutic index and manufacturability. Its favorable drug-like property and robust preclinical efficacy warrant further evaluation in patients with a variety of inflammation and autoimmune diseases.References:[1]Tahvildari M. et al. Low-Dose IL-2 Therapy in Transplantation, Autoimmunity, and Inflammatory Diseases. J Immunol. 2019; 203: 2749-2755Disclosure of Interests:Yao-te Hsieh Employee of: Cugene INC., CEDRIC HUBEAU Employee of: Cugene INC., Virginia MASSA Employee of: Cugene INC., WEN Li Employee of: Cugene INC., SANDRA FREI Employee of: Cugene INC., BEN CAPRARO Employee of: Cugene INC., ANDREA UMANA Employee of: Cugene INC., ANDREW AHERRERA Employee of: Cugene INC., YUESHENG LI Employee of: Cugene INC., JING XU Employee of: Cugene INC., LINGYUN RUI Employee of: Cugene INC.