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Kumar, S. Vijai, and S. Thanigaiarasu. "A new mathematical model for studying fully ionized plasma flows in MPD thrusters." International Journal of Modeling, Simulation, and Scientific Computing 07, no. 03 (August 23, 2016): 1650014. http://dx.doi.org/10.1142/s1793962316500148.
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The paper describes a novel mathematical model to study the physics of fully ionized plasma flow through MPD thrusters otherwise known as magnetoplasmadynamic thrusters. The developed model consists of a set of differential equations obtained by coupling the Navier–Stokes equations with Maxwell’s equations. The model developed was tested for various 1D and 1.5D cases. These simulations have been carried out for a special case of geometries called Tikhonov fitted geometries for alleviating the instability phenomenon commonly known as onset phenomenon in self-field MPD thrusters. The work was also extended to applied field MPD thrusters. A new equation for magnetic field was introduced to incorporate a virtual cathode. All the computations were carried out using a higher order integration scheme. The results obtained were found to be in good agreement with the previous work done on similar models.
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Xuefei, Xu, and Liao Guisheng. "MPD model for radar echo signal of hypersonic targets." Journal of Engineering 2014, no. 8 (August 1, 2014): 399–406. http://dx.doi.org/10.1049/joe.2014.0097.
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Albertoni, R., F. Paganucci, and M. Andrenucci. "A phenomenological performance model for applied-field MPD thrusters." Acta Astronautica 107 (February 2015): 177–86. http://dx.doi.org/10.1016/j.actaastro.2014.11.017.
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Hostetter, Margaret K. "Career development for physician-scientists: The model of the pediatric scientist development program." Journal of Pediatrics 140, no. 2 (February 2002): 143–44. http://dx.doi.org/10.1067/mpd.2002.121584.
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MIYASAKA, Takeshi, Noriyuki FUKUOKA, and Toshi FUJIWARA. "Numerical Analyses of MHD Flows Based on a Two-Fluid Model in MPD Thrusters." Journal of the Japan Society for Aeronautical and Space Sciences 48, no. 561 (2000): 350–56. http://dx.doi.org/10.2322/jjsass.48.350.
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Pollack, Harold A., and John G. Frohna. "A competing risk model of sudden infant death syndrome incidence in two US birth cohorts." Journal of Pediatrics 138, no. 5 (May 2001): 661–67. http://dx.doi.org/10.1067/mpd.2001.112248.
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Nada, T. R. "Performance characterisation of MPD thrusters." Aeronautical Journal 111, no. 1121 (July 2007): 443–52. http://dx.doi.org/10.1017/s000192400000470x.
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Abstract This paper introduces a characterisation of the performance indices and operating limits of the self field magnetoplasmadynamic thruster. The thrust, specific impulse, and efficiency are considered as the main performance indices, while the operating limits are the cathode lifetime, onset phenomenon, and the overfed state of the thruster. The effects of thruster parameters (current, mass flow rate, geometry, and propellant type) on the performance indices and operating limits are examined using one-dimensional model of cylindrical self-field thrusters. Design charts are presented to help the designers to choose the optimum and safe set of the thruster parameters that realise certain mission requirements.
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Gravdal, Jan Einar, Rolf J. Lorentzen, Kjell K. Fjelde, and Erlend H. Vefring. "Tuning of Computer Model Parameters in Managed-Pressure Drilling Applications Using an Unscented-Kalman-Filter Technique." SPE Journal 15, no. 03 (April 22, 2010): 856–66. http://dx.doi.org/10.2118/97028-pa.
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Summary To manage the annular pressure profile during managed-pressure drilling (MPD) operations, simulations performed with advanced computer models are needed. To obtain a high degree of accuracy in these simulations, it is crucial that all parameters describing the system are as correct as possible. A new methodology for real-time updating of key parameters in a well-flow model by taking into account real-time measurements, including measuring uncertainty, is presented. Key model parameters are tuned using a recently developed estimation technique based on the traditional Kalman filter. The presented methodology leads to a more-accurate prediction of well-flow scenarios. Although the present study is motivated by applications in MPD, the idea of tuning model parameters should be of great importance in a wide area of applications. The performance of the filter is studied, using both synthetic data and real measurements from a North Sea high-pressure/high-temperature (HP/HT) drilling operation. Benefits by this approach are seen in more-accurate downhole-pressure predictions, which are of major importance for safety and economic reasons during MPD operations.
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Chen, LianYu, Chien-shan Cheng, HuiFeng Gao, Ling Zhan, FengJiao Wang, Chao Qu, Ye Li, et al. "Natural Compound Methyl Protodioscin Suppresses Proliferation and Inhibits Glycolysis in Pancreatic Cancer." Evidence-Based Complementary and Alternative Medicine 2018 (2018): 1–9. http://dx.doi.org/10.1155/2018/7343090.
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Methyl protodioscin (MPD) is one of the main bioactive components in the plant of Dioscoreaceae. MPD has been demonstrated to possess antitumor activities. However, its role in pancreatic cancer and the underlying molecular mechanisms are poorly defined. In the present study, we demonstrated that MPD inhibited proliferation and promoted apoptosis of pancreatic cancer. Furthermore, our results demonstrated that MPD decreased oncogene c-Myc in protein level and resulted in concomitant reduction in glycolysis. In vivo assays with xenograft mouse model further confirmed the in vitro observations, which indicated that MPD inhibited 18FDG uptake in tumors formed by subcutaneously injection of MIA PaCa-2 cells. Collectively, our present study uncovered novel antitumor functions of MPD in pancreatic cancer and provided the possible molecular mechanism.
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Urbanetto, Janete de Souza, Maria Cristina Cademartori Magalhaes, Vanessa Oreda Maciel, Viviane Massena SantAnna, Andreia da Silva Gustavo, Carlos Eduardo Poli-de-Figueiredo, and Tania Solange Bosi de Souza Magnago. "Work-related stress according to the demand-control model and minor psychic disorders in nursing workers." Revista da Escola de Enfermagem da USP 47, no. 5 (October 2013): 1180–86. http://dx.doi.org/10.1590/s0080-623420130000500024.
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This was a cross-sectional study that aimed to assess the association between work-related stress according to the Demand-Control Model, and the occurrence of Minor Psychic Disorder (MPD) in nursing workers. The participants were 335 professionals, out of which 245 were nursing technicians, aged predominantly between 20 and 40 years. Data were collected using the Job Stress Scale and the Self-Reporting Questionnaire-20. The analysis was performed using descriptive and analytical statistics. The prevalence of suspected MPD was 20.6%. Workers classified in the quadrants active job and high strain of the Demand-Control Model presented higher potential for developing MPD compared with those classified in the quadrant low strain. In conclusion, stress affects the mental health of workers and the aspects related to high psychological demands and high control still require further insight in order to understand their influence on the disease processes of nursing workers.
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VALERO, A., E. CARRASCO, F. PÉREZ-RODRÍGUEZ, R. M. GARCÍA-GIMENO, and G. ZURERA. "Modeling the Growth of Listeria monocytogenes in Pasteurized White Asparagus." Journal of Food Protection 70, no. 3 (March 1, 2007): 753–57. http://dx.doi.org/10.4315/0362-028x-70.3.753.
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Growth of Listeria monocytogenes in pasteurized white asparagus was monitored at different storage temperatures (4, 10, 20, and 30°C). Among the main microbial kinetic parameters, growth rate (μ) per hour was calculated at each temperature using the Baranyi-Roberts model. L. monocytogenes was able to grow at all temperatures, although at 4°C only a slight increment of the microbial population was observed (∼1 log CFU/g) after 300 h of storage. Subsequently, two different secondary modeling approaches were proposed to study the relationship between μ and storage temperature: the Arrhenius and Ratkowsky models. Although both models properly described the data observed, smaller values of root mean square error (RMSE) and standard error of prediction (SEP) were obtained with the Ratkowsky model, providing a better goodness of fit (Ratkowsky model: RMSE = 0.010, SEP = 21.23%; Arrhenius model: RMSE = 0.026, SEP = 54.37%). The maximum population density (MPD) was calculated at each temperature studied. A clear dependence between MPD and temperature was found; lower temperatures produced lower values of MPD. This finding confirmed the Jameson effect, indicating that multiple hurdles in the food-processing chain plus lower temperatures reduced L. monocytogenes growth. Predicting the growth of L. monocytogenes along the food chain will help to reduce microbial risks associated with consumption of pasteurized white asparagus.
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Haibo, Liang, and Li Hongyan. "Control Model of Throttle Back Pressure of Managed Pressure Drilling." Journal of Computational and Theoretical Nanoscience 13, no. 10 (October 1, 2016): 7603–9. http://dx.doi.org/10.1166/jctn.2016.5759.
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This paper established a controlling model of Throttling Back Pressure system of Managed Pressure Drilling (MPD), and aim at its nonlinear characteristics of the model, a fuzzy-PID controlling method with a capability of parameter self-tuning was proposed. This method utilizes the idea of fuzzy controlling and designs a fuzzy inference theory to realize the function of online tuning PID control parameters. Through comparing this controlling algorithm with conventional controlling algorithms and analyzing, results showed that overshoot of this throttling back pressure controlling system using fuzzy-PID controlling method with a capability of parameter self-tuning reduced to 4.1%, and its dynamic response speed reduced to 1.4 s, which can effectively solve back pressure controlling model problems such as slow response and poor robustness during MPD using conventional controlling algorithms.
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Kabir, Umar Yusuf, Angela Askew, Yu Jiang, Soumitra S. Bhuyan, Emmanuel Ezekekwu, and Aram Dobalian. "Moderate psychological distress as a barrier to breast cancer screening among women." Journal of Hospital Administration 9, no. 4 (August 2, 2020): 1. http://dx.doi.org/10.5430/jha.v9n4p1.
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Objective: To examine the relationship between Breast Cancer Screening (BCS) and Moderate Psychological Distress (MPD). Also, to assess the effect of aggregating women with No Psychological Distress (NPD) and MPD into one group, as done in prior studies when evaluating the relationship between BCS and Psychological Distress (PD).Methods: The study population comprised of 34,565 women aged 50-74 years who participated in the National Health Interview Survey from 2013 to 2017. The Kessler-6 PD index score (0-24) was dichotomized (0-12: NPD; > 13: Severe Psychological Distress SPD) and trichotomized (0-5: NPD; 5-12: MPD; > 13 SPD). Two multivariate logistic regressions were conducted for the dichotomous and trichotomous PD categories. Andersen’s Behavioral Model of Health Services Use guided the choice of covariates. Data analysis was conducted using SAS version 9.4.Results: Our study showed 4.6% had SPD, and 17.9% had MPD. The latter group (MPD) was included in the NPD group in the dichotomous analysis. In the dichotomous analysis, women with SPD (adjusted Odds Ratio (aOR) = 0.71, 95% CI = 0.63, 0.81, p < .00001) were less likely to have received a mammogram than those with NPD. In the trichotomous model, women with SPD (aOR = 0.76, 95% CI = 0.67, 0.87, p = .0001) and MPD (aOR = 0.84, 95% CI = 0.78, 0.91, p <.00001) were both less likely to have had a mammogram than those with NPD.Conclusions: Prior studies that included individuals with MPD among those with NPD overestimated the effect of SPD on mammography and minimized the importance of targeting women with MPD along with those that have SPD to enhance the uptake of mammography.
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Lawrence, J. Josh, Heikki Haario, and Emily F. Stone. "Presynaptic cholinergic neuromodulation alters the temporal dynamics of short-term depression at parvalbumin-positive basket cell synapses from juvenile CA1 mouse hippocampus." Journal of Neurophysiology 113, no. 7 (April 2015): 2408–19. http://dx.doi.org/10.1152/jn.00167.2014.
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Parvalbumin-positive basket cells (PV BCs) of the CA1 hippocampus are active participants in theta (5–12 Hz) and gamma (20–80 Hz) oscillations in vivo. When PV BCs are driven at these frequencies in vitro, inhibitory postsynaptic currents (IPSCs) in synaptically connected CA1 pyramidal cells exhibit paired-pulse depression (PPD) and multiple-pulse depression (MPD). Moreover, PV BCs express presynaptic muscarinic acetylcholine receptors (mAChRs) that may be activated by synaptically released acetylcholine during learning behaviors in vivo. Using acute hippocampal slices from the CA1 hippocampus of juvenile PV-GFP mice, we performed whole cell recordings from synaptically connected PV BC-CA1 pyramidal cell pairs to investigate how bath application of 10 μM muscarine impacts PPD and MPD at CA1 PV BC-pyramidal cell synapses. In accordance with previous studies, PPD and MPD magnitude increased with stimulation frequency. mAChR activation reduced IPSC amplitude and transiently reduced PPD, but MPD was largely maintained. Consistent with a reduction in release probability ( pr), MPD and mAChR activation increased both the coefficient of variation of IPSC amplitudes and the fraction of failures. Using variance-mean analysis, we converted MPD trains to pr functions and developed a kinetic model that optimally fit six distinct pr conditions. The model revealed that vesicular depletion caused MPD and that recovery from depression was dependent on calcium. mAChR activation reduced the presynaptic calcium transient fourfold and initial pr twofold, thereby reducing PPD. However, mAChR activation slowed calcium-dependent recovery from depression during sustained repetitive activity, thereby preserving MPD. Thus the activation of presynaptic mAChRs optimally protects PV BCs from vesicular depletion during short bursts of high-frequency activity.
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Chien, Yu-Hung, Chun-Kai Yao, and Yu-Han Chao. "Effects of Multidisciplinary Participatory Design Method on Students’ Engineering Design Process." Eng 1, no. 2 (October 10, 2020): 112–21. http://dx.doi.org/10.3390/eng1020007.
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This study took the ergonomics design course as an example to propose a design teaching model of multidisciplinary participatory design (MPD), and investigated the effects of this teaching model on the engineering design behavior of college students. We used lag behavior sequential analysis to compare the design behaviors of three student groups: a participatory design (PD) experimental group, an MPD experimental group, and a control group. The results of the study show that (1) students in the PD experimental group had 13 significant sequential engineering design behaviors, students in the MPD experimental group had 10, and students in the control group had only seven. The engineering design behaviors of the experimental groups were more diversified than those of the control group. (2) The three groups of students had a small number of significant design behavior transfers in the engineering design process, indicating that the students’ sequential design behaviors between two different design activities were insufficient. We concluded by detailing the pros and cons of using the MPD teaching model based on the results of this study, and hopefully by providing a reference for teaching engineering design.
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Cain, Jennifer A., Jing Chen, Zhifu Xiang, Julie O’Neal, Benjamin H. Lee, Friederike Kreisel, Ifor Williams, AnnaLynn Colson, and Michael H. Tomasson. "Myeloproliferative Disease Induced by TEL-PDGFRB Displays Dynamic Range Sensitivity to Stat5 Gene Dosage in Mice." Blood 108, no. 11 (November 16, 2006): 3620. http://dx.doi.org/10.1182/blood.v108.11.3620.3620.
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Abstract Expression of the constitutively activated TEL/PDGFβR fusion protein is associated with the t(5;12)(q33;p13) chromosomal translocation found in a subset of patients with chronic myelomonocytic leukemia (CMML). TEL/PDGFβR activates multiple signal transduction pathways in cell culture systems and induces myeloproliferative disease (MPD) in a murine bone marrow transduction/transplantation model of disease. Two TEL-PDGFβR juxtamembrane tyrosines, corresponding to tyrosines activating Stat5 and Src signaling molecules in native PDGFβR, are required for TEL-PDGFRB mediated MPD in mice. We used gene-targeted mice as donors in bone marrow transduction/transplantation experiments to characterize the contribution of Stat and Src genes in the development of TEL-PDGFRB disease. Mice transplanted with cells harboring targeted deletions of both Stat5a and Stat5b genes (TPiGFP→Stat5ab−/−) were protected from rapidly fatal MPD (median survival >125 vs. 25 days in TPiGFP→Stat5ab+/+mice, P<0.0001). In contrast, TPiGFP→Lyn−/−Hck−/−Fgr−/− mice developed rapidly fatal MPD characterized by splenomegaly and leukocytosis. Similarly, TEL-PDGFRB induced MPD in TPiGFP→Stat1−/− mice and TPiGFP→Stat1+/+ strain-matched mice alike (median survival 45 vs. 53 days). These data suggest that Stat5, but not Src family kinases Lyn, Hck and Fgr nor Stat family member Stat1, is functionally relevant in the development of TEL-PDGFRB mediated disease. To assess the relative contribution of the Stat5a gene in TEL-PDGFRB mediated disease, we used mice harboring either homozygous (Stat5a−/−) or heterozygous (Stat5a+/−) deletion as donors in bone marrow transduction/transplantation experiments with TEL-PDGFRB. Surprisingly, survival was significantly prolonged in TPiGFP→Stat5a−/− mice (144 vs. TPiGFP→Stat5a+/+ 31 days, P <0.0001) and TPiGFP→Stat5a+/− mice (145 versus TPiGFP→Stat5a+/+ 31 days, P <0.001), demonstrating significant sensitivity of TEL-PDGFRB-induced MPD to loss of even a single Stat5a allele. TEL-PDGFRB induced severe leukocytosis in TPiGFP→Stat5a+/+ mice (median WBC 547K/μL), but disease was attenuated in TPiGFP→Stat5a+/− mice mice (median WBC 56K/μL) and undetectable in TPiGFP→Stat5a−/−mice (median WBC 5K/μL), suggesting that TEL-PDGFRB disease is exquisitely sensitive to Stat5a gene dosage. On the other hand, TPiGFP→Stat5b−/− mice developed robust MPD with similar latency to wild-type mice. However, 4 of 13 TPiGFP→Stat5b−/− mice failed to develop MPD and were longer-lived, suggesting a role for Stat5b in TEL-PDGFRB disease penetrance. To address the possibility that Stat5a and Stat5b were distinct in their ability to transmit myeloproliferative signals in TEL-PDGFRB mediated MPD, we designed add-back constructs to co-express TEL-PDGFRB with either Stat5a (TPiStat5a) or Stat5b (TPiStat5b). Addback Stat5 restored MPD with similar disease latency in TPiStat5a→Stat5a−/− and TPiStat5b→Stat5a−/− mice (median survival 96 and 97 days, respectively). TPiStat5a→Stat5a+/− mice developed MPD with shorter disease latency (28 days), again correlating with Stat5a gene dosage. These data provide functional evidence for the importance of the Stat5 pathway in a model of TEL-PDGFRB-induced CMML and suggest that Stat5a and Stat5b play unique roles in the development of disease in this model.
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Landgren, Ola, Lynn R. Goldin, Sigurdur Y. Kristinsson, Jan Samuelsson, and Magnus Bjorkholm. "Increased Risks of Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Myelofibrosis (MF) among 24577 First-Degree Relatives of 11039 Patients with Chronic Myeloproliferative Disorders (MPD) in Sweden." Blood 110, no. 11 (November 16, 2007): 680. http://dx.doi.org/10.1182/blood.v110.11.680.680.
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Abstract Background. Familial clustering of PV, ET, MF, and chronic myeloid leukemia (CML) has been reported through case reports and smaller case series. Recently, several studies reported that in families with multiple MPD patients, the JAK2 mutation is not an early germ line predisposing factor for MPD but rather a facilitator of proliferative advantages. However, the degree of familial clustering in the population has not been defined. We have conducted the first large population-based study to quantify risks of developing MPD and related malignancies in first-degree relatives of MPD patients. Methods. Using high-quality central population-based registries, we identified 6217 PV, 2838 ET, and 1984 MF patients diagnosed in Swedish hospitals 1958–2005 (Cancer and local hospital-based registries), with linkable relatives; 43550 frequency-matched controls (Population registry); and first-degree relatives of cases (n=24577) and controls (n=99542) (Multigenerational registry). Relatives of MPD patients and controls were linked with the Cancer and local hospital-based registries to define occurrence of MPD and other related neoplasms. We used a marginal survival model to calculate relative risks (RR) and 95% confidence intervals (CI) as measures of familial aggregation. Results. Compared with controls, relatives of MPD patients had significantly increased risks of PV (RR=5.70; 95% CI 3.55–9.14), ET (RR=7.37; 95% CI 3.67–14.81), and MF (RR=3.53; 95% CI 1.59–7.85). Risks were similar when we restricted the analyses to relatives of patients with the same MPD (PV-PV, ET-ET, and MF-MF) Also, risk-estimates were virtually the same for various types of first-degree relatives (parents, siblings, offspring); the same was true when we calculated risks by age at MPD of cases (above vs. below 65 yrs), and sex of relatives. Age at diagnosis of MPD was not different for case and control relatives. Furthermore, relatives of MPD patients (vs. controls) had a borderline increased risk of CML (RR=1.86; 95% CI 0.90–3.74; p=0.07). As expected, we found excess of subsequent acute myeloid leukemia (AML) (n=271; 2.5%) and myelodysplastic syndrome (MDS) (n=27; 0.2%) among MPD patients; however, there were no increased risks of AML or MDS among relatives of MPD patients. Conclusions. In this first large population-based study including more than 11000 MPD patients and their almost 25000 linkable first-degree relatives, we found 3- to 7-fold elevated risks of developing MPDs among first-degree relatives of MPD patients. Our results support the hypothesis that there are common, strong, shared susceptibility genes that predispose to PV, ET, MF, and possibly CML.
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Wen, Lu, Gregory T. Wolf, Monil Shah, David B. Page, Lynn Sadowski-Mason, Mark Prince, Jeffrey Moyer, Alfred E. Chang, and Qiao Li. "IRX-2 therapy with PD-L1 blockade in immunocompetent animal model." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e14149-e14149. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14149.
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e14149 Background: Multiple therapeutic components in IRX-2 including IL-2, IL-1, IFN-γ, TNFα, IL-6, GM-CSF, and IL-8 work synergistically to activate various immune cells including T cells, dendritic cells, and natural killer cells to recognize and kill tumors. Previous Phase 1 and Phase 2a clinical trials in head and neck cancer with IRX-2 have shown a benign safety profile. Immunologically stimulating host immunity using IRX-2, while simultaneously blocking PD-1/PD-L1-mediated immune suppression, may have the potential to enhance the outcome of current immunotherapy using IRX-2 alone. Methods: Healthy C3H mice were inoculated with SCC7 murine head and neck cancer cells. Fourteen days after inoculation, the tumor-bearing mice were treated with subcutaneous injection of IRX-2 once a week for 3 weeks, followed with anti-mPD-L1(i.p.) injection after each IRX-2 administration. Tumor size and survival were monitored for the therapeutic efficacy evaluation. Two weeks after the last IRX-2 administration, all mice were sacrificed and spleen, blood and residual tumor samples were harvested for immune function assays. Results: High levels of PD-L1 were expressed on SCC7 cell line and fresh tumors. The FCM data suggested that PD-L1 was preferentially expressed on the ALDHhigh SCC7 cancer stem cells. IRX-2 alone significantly inhibited SCC7 tumor growth, and the anti-tumor efficacy of IRX-2 was significantly enhanced by anti-mPD-L1 injection in a dose dependent manner in the immunocompetent hosts. Serum IgG from animals subjected to IRX-2 plus anti-mPD-L1 treatment mediated significantly (p < 0.05) higher cytotoxicity on SCC7 cells via ADCC than the IgG from animals treated with IRX-2 alone. CD8+ lymphocytes isolated from purified, activated and expanded CD3+ splenic T cells harvested from the animals subjected to IRX-2+anti-mPD-L1 treatment mediated significantly (p < 0.05) higher cytotoxicity than those subjected to IRX-2 or anti-PD-L1 mono-therapy against SCC7 tumor cells. Conclusions: Co-administration of IRX-2 and anti-PD-L1 promoted more powerful antitumor immunity with both B cell and T cell modulation. The combination treatment increased the specific IgG production that could kill tumor cells via ADCC, and enhanced the T cell CTL activity. Therefore, IRX-2 therapy plus anti-PD-L1 administration may represent a promising novel strategy to treat cancer patients.
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Guo, Wang, Fan Honghai, and Liu Gang. "Design and calculation of a MPD model with constant bottom hole pressure." Petroleum Exploration and Development 38, no. 1 (February 2011): 103–8. http://dx.doi.org/10.1016/s1876-3804(11)60017-7.
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Zhang, Xiaowu, Ramesh Subrahmanyam, Ray Wong, Alec W. Gross, and Ruibao Ren. "The NH2-Terminal Coiled-Coil Domain and Tyrosine 177 Play Important Roles in Induction of a Myeloproliferative Disease in Mice by Bcr-Abl." Molecular and Cellular Biology 21, no. 3 (February 1, 2001): 840–53. http://dx.doi.org/10.1128/mcb.21.3.840-853.2001.
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ABSTRACT Bcr-Abl, a fusion protein generated by t(9;22)(q34;q11) translocation, plays a critical role in the pathogenesis of chronic myelogenous leukemia (CML). It has been shown that Bcr-Abl contains multiple functional domains and motifs and can disrupt regulation of many signaling pathways and cellular functions. However, the role of specific domains and motifs of Bcr-Abl or of specific signaling pathways in the complex in vivo pathogenesis of CML is not completely known. We have previously shown that expression of Bcr-Abl in bone marrow cells by retroviral transduction efficiently induces a myeloproliferative disorder (MPD) in mice resembling human CML. We have also shown that the Abl kinase activity within Bcr-Abl is essential for Bcr-Abl leukemogenesis, yet activation of the Abl kinase without Bcr sequences is not sufficient to induce MPD in mice. In this study we investigated the role of Bcr sequences within Bcr-Abl in inducing MPD using this murine model for CML. We found that the NH2-terminal coiled-coil (CC) domain was both essential and sufficient, even though not efficient, to activate Abl to induce an MPD in mice. Interestingly, deletion of the Src homology 3 domain complemented the deficiencies of the CC-deleted Bcr-Abl in inducing MPD in mice. We further demonstrated that the Grb2 binding site at Y177 played an important role in efficient induction of MPD. These studies directly demonstrated the important roles of Bcr sequences in induction of MPD by Bcr-Abl.
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Vinš, Václav, Miroslav Čenský, Jan Hrubý, and Jiří Hykl. "Investigation of droplet nucleation in CCS relevant systems: Progress in the design and testing of the mixture preparation device." EPJ Web of Conferences 213 (2019): 02092. http://dx.doi.org/10.1051/epjconf/201921302092.
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The study presents progress in the development of mixture preparation device (MPD) representing an important part of the larger experimental setup intended for investigation of homogeneous droplet nucleation in CO2-rich systems. MPD allows for accurate adjustment of flow parameters, i.e. temperature, pressure, and flow rate, of CO2 in either superheated vapor or supercritical fluid phases and of other gas components such as argon or nitrogen. Through accurate settings of flow rates of individual components, the mixture composition can continuously be defined. MPD is going to be connected to the expansion chamber, where the droplet nucleation will experimentally be observed. In this work, CO2-branch, i.e. the core part of MPD, was modified and tested. Several components, e.g., pressure transducers and safety valve, had to be calibrated and adjusted to assure well-defined and safe operation. Most attention was paid to the design and performance of throttling capillary tubes installed in thermostatic bath, which define final flow parameters of CO2 coming from the CO2 branch. The flow characteristics of two capillary tubes with lengths of 7.8 and 4.0 m and inner diameter 0.1 mm were measured and compared to the predictions of a numerical model. The 1-D model of isothermal capillary flow was found to provide quite good agreement with the measured data.
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Zaleskas, Virginia M., Wayne W. Chan, Peter Evangelista, Katherine Lazarides, Rajesh Chopra, Michael Zinda, Dennis Huszar, and Richard A. Van Etten. "A Selective and Potent Oral Inhibitor of the JAK2 Tyrosine Kinase Reverses Polycythemia and Leukocytosis Induced by JAK2 V617F in a Mouse Model." Blood 110, no. 11 (November 16, 2007): 557. http://dx.doi.org/10.1182/blood.v110.11.557.557.
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Abstract A somatic mutation (V617F) in the pseudokinase domain of the non-receptor tyrosine kinase JAK2 is found in virtually all patients with the myeloproliferative disease (MPD) polycythemia vera (PV), and about half of those with essential thrombocythemia and chronic idiopathic myelofibrosis. When expressed in mice by retroviral bone marrow transduction and transplantation, JAK2 V617F but not JAK2 wild-type induces leukocytosis with neutrophilia and recapitulates the entire erythroid phenotype of PV, with polycythemia, reticulocytosis, low plasma Epo, and endogenous erythroid colonies (Zaleskas et al., PLoS ONE2006;1:e18; Wernig et al., Blood2006;107:4274; Lacout et al., Blood2006;108:1652). By analogy to BCR-ABL in chronic myeloid leukemia, JAK2 V617F is therefore a rational target for therapy in PV and other JAK2 V617F+ MPDs. Previous studies with a nonselective and parenteral tyrphostin JAK2 inhibitor suggested that short-term inhibition of JAK2 could decrease reticulocytosis in recipients of JAK2 V617F-transduced marrow (Zaleskas et al., op cit.). Here, we studied one of a novel series of inhibitors of JAK2, AZ-01, which potently inhibited JAK2 kinase activity (IC50 < 1nM) and suppressed proliferation of cell lines carrying the JAK2 V617F mutation. We treated cohorts of Balb/c mice with JAK2 V617F-induced polycythemia and leukocytosis with AZ-01 at 10 mg/kg by oral gavage twice daily, or with vehicle alone. After 28 days of treatment, AZ-01-treated mice had significant reductions in hematocrit, hemoglobin, reticulocytes, and splenomegaly, as well as normalization of peripheral blood leukocyte counts (Figure 1). These results demonstrate that oral administration of a potent and selective JAK2 inhibitor can reverse the hematopoietic abnormalities of JAK2 V617F-induced MPD in mice, and validate JAK2 as a target for therapy of human JAK2 V617F+ MPD. Figure Figure An orally available JAK2 inhibitor decreases the leukocyte count, hematocrit, and reticulocyte count in mice with JAK2 V617F-induced MPD. Leukocyte count (left), hematocrit (center) and reticulocyte counts (right) of cohorts of mice with JAK2 V617F-induced MPD treated with vehicle or drug at 10 mg/kg BID. Blood counts were assessed at 15 and 28 days of treatment. Decreases in d28 hematocrit and retic count in the drug-treated cohorts were significant (p=0.008 and p<0.0001, respectively, t-tests).
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Chu, Nathan, Enrico Brambilla, Paul Yoo, and Tanner J. Ferguson. "Evaluation of negative pressure transfer through tissue in a benchtop cornea and eyelid model." Therapeutic Advances in Ophthalmology 12 (January 2020): 251584142097140. http://dx.doi.org/10.1177/2515841420971406.
Full textAbstract:
Purpose: A new glaucoma treatment device, known as the multi-pressure dial (MPD), has been introduced, which offers a novel approach to IOP reduction by delivering negative pressure to the periocular region. Clinical studies have demonstrated the IOP-lowering effect of the MPD via direct measurements using pneumatonometry. It remains unclear whether the eyelids, when closed, affect the transmission of negative pressure and subsequently affect IOP reduction. This study aimed to evaluate whether the transfer of negative pressure and subsequent decrease in IOP are altered by the presence of synthetic eyelid tissue. Methods: A model with 13 different configurations controlling for eyelid material type, presence of slit/opening, and eyelid–cornea contact was employed. The slit modification was employed to mimic the physiologic separation that exists between the eyelids. Baseline IOP within an eye model was set at various levels ranging from 10 to 30 mmHg with applied negative pressure settings of 10, 15, and 20 mmHg utilized at each baseline IOP. The percentage of vacuum transfer was calculated by comparing baseline IOP to resultant IOP measurements following application of vacuum to the system. Results: In the open configuration (without eyelid tissue), the mean % vacuum transfer was 98.7%. The sealed, full-contact configurations exhibited values of 97.4%, 98.8%, and 97.2%. The slit configurations, which closely mimic the physiologic eyelid, demonstrated a mean % vacuum transfer of 98.7% across all settings. Conclusions: The impact of eyelid tissue on transfer of negative pressure can be isolated and evaluated. The presence of eyelid tissue has an insignificant impact on the transfer of negative pressure, and the IOP reduction achievable with the MPD would not be altered with the eyelids closed.
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Caliendo, Ciro, Maurizio Guida, and Emiliana Pepe. "Seemingly Unrelated Regression Equations for Developing a Pavement Performance Model." Modern Applied Science 9, no. 13 (November 30, 2015): 199. http://dx.doi.org/10.5539/mas.v9n13p199.
Full textAbstract:
<p>The paper presents a joint analysis of some pavement performance indicators based on a system of seemingly unrelated regression equations (SURE) which allows to handle correlated error terms. In particular, three major indicators such as the side friction coefficient (SFC20°C), mean-profile depth (MPD), and international roughness index (IRI), were measured in a case study and subsequently used in analysis. Regression parameters were estimated by the Maximum Likelihood Method and the t-statistic was considered to show the statistical significance of regression coefficients. The results show that estimation points have the signs expected: the SFC<sub>20°C</sub> decreases as the number of accumulated trucks (<em>N</em><sub>t</sub>) increases; whereas the MPD and IRI increase as the number of trucks increases. A likelihood ratio test was also carried out to determine whether the system model, which assumes correlation among error terms, was more appropriate than separate models. In this particular case, with three degrees of freedom, was found that the result corresponds to a p-value 0.150 and the null hypothesis cannot be rejected at any significance level less than this value.</p>
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Pérez-Castán, Javier A., Fernando Gómez Comendador, Álvaro Rodríguez-Sanz, Rosa M. Arnaldo Valdés, and Jaime Torrecilla. "Conflict-resolution algorithms for RPAS in non-segregated airspace." Aircraft Engineering and Aerospace Technology 91, no. 2 (February 4, 2019): 366–72. http://dx.doi.org/10.1108/aeat-01-2018-0024.
Full textAbstract:
Purpose The purpose of this paper is to focus on the development of conflict-resolution algorithms between Remotely Piloted Aircraft System (RPAS) and conventional aircraft. The goal of the conflict-resolution algorithm is to estimate the minimum protection distance (MPD) which is required to avoid a potential conflict. Design/methodology/approach The conflict-resolution algorithms calculate the last location at which an RPAS must start climbing to avoid a separation minima infringement. The RPAS maneuvers to prevent the conventional aircraft based on the kinematic equations. The approach selects two parameters to model the conflict-geometry: the path-intersection angle and the Rate of Climb (ROCD). Findings Results confirmed that the aircraft pair flying in opposition was the worst scenario because the MPD reached its maximum value. The best value of the MPD is about 12 Nautical Miles to ensure a safe resolution of a potential conflict. Besides, variations of the ROCD concluded that the relation between the ROCD and the MPD is not proportional. Research limitations/implications The primary limitation is that the conflict-resolution algorithms are designed in a theoretical framework without bearing in mind other factors such as communications, navigation capacity, wind and pilot errors among others. Further work should introduce these concepts to determine how the MPD varies and affects air traffic safety. Moreover, the relation between an ROCD requirement and the MPD will have an impact on regulations. Practical implications The non-linear relation between the MPD and the ROCD could be the pillar to define a standardized MPD in the future for RPAS systematic integration. To accomplish this standard, RPAS could have to fulfil a requirement of minimum ROCD until a specified flight level. Originality/value This paper is the first approach to quantify the Minimum Protection Distance between RPAS and conventional aircraft, and it can serve the aeronautical community to define new navigation requirements for RPAS.
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Jouyban, Abolghasem, Maryam Khoubnasabjafari, and William E. Acree, Jr. "Solubility prediction of anthracene in nonaqueous solvent mixtures using a combination of Jouyban-Acree and Abraham models." Canadian Journal of Chemistry 84, no. 6 (June 1, 2006): 874–85. http://dx.doi.org/10.1139/v06-082.
Full textAbstract:
The applicability of previously developed quantitative structure-property relationships was extended to predict the solubility of anthracene in nonaqueous binary and ternary solvent mixtures. The accuracy of the proposed methods was evaluated using 81 solubility data sets collected from the literature. The individual and mean percentage deviation (IPD and MPD) of experimental and computed solubilities were calculated as accuracy criteria. The computations were carried out using experimental and predicted mole fraction solubility of anthracene in monosolvent systems for binary and ternary solvent systems. The overall MPD of solubility prediction using experimental values in monosolvents varied from 5.2% to 4.2% and from 16.5% to 10.7% for binary and ternary solvents, using water to solvent and gas to solvent solvational parameters, respectively. The IPD distribution was better for the gas to solvent model. The corresponding ranges for the predicted solubility of anthracene in monosolvents were 47.9% to 28.1% and 23.9% to 22.5% for binary and ternary solvents, respectively, and IPD distribution was more favourable for the gas to solvent model. In general, the models derived from gas to solvent coefficients provided more accurate predictions and are recommended for practical applications.Key words: solubility, prediction, cosolvency, anthracene, Abraham model, Jouyban-Acree model.
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Reutovich, M. Yu, and O. V. Krasko. "Intraoperative risk assessment of carcinomatosis development after radical surgery for gastric cancer." Oncologia i radiologia Kazakhstana 56, no. 2 (March 30, 2020): 26–30. http://dx.doi.org/10.52532/2521-6414-2020-2-56-26-30.
Full textAbstract:
Relevance: Metachronous peritoneal dissemination
(MPD) is the most frequent pattern of gastric cancer (GC)
progression after radical surgery. It is necessary to take into
account the existing risk of MPD development to ensure a
substantiated administration of intraperitoneal chemotherapy for its timely prevention.
The purpose of the study was to raise the MPD prognostication efficacy.
Results: The treatment outcomes of 1,065 radically operated patients (males – 640, 60.1%; females – 425, 39.9%)
aged 23 to 89 years (median age – 63±12) showed that a high
risk of GC recurrence in the form of peritoneal dissemination
is associated with: (1) metastatic invasion of the regional
lymph node – pN2-3 – RR 2.0 (95% CI 1.5–2.7), р < 0.001; (2)
ulcero-infiltrative and diffuse infiltrative forms of primary
gastric cancer growth – RR 3.7 (95% CI 2.5–5.5), р < 0,001),
and RR 2.3 (95% CI 1.5–3.6), р<0,001; (3) serosa invasion by
primary GC (pT4) – RR 2.5 (95% CI 1.8–3.6), р<0,001; (4) combined surgical treatment vs. standard surgery – RR 1.8 (95% CI
1.2–2.7), р=0.005; and (5) performing gastrectomy vs. distal
resection – RR 1.6 (95% CI 1.2–2.2), р=0.004.
A multivariate analysis (Fine-Grey model) was done to
propose a prognostic model for an intraoperative estimate of
the MPD development probability to determine indications
for intraoperative intraperitoneal chemotherapy (concordance index of 0.75).
Conclusion: The proposed nomogram- or formula-based
prognostic model allows a differentiated approach to administering intraoperative intraperitoneal chemotherapy taking
into account the existing probability of peritoneal dissemination development.
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Lin, Jiusheng, Henry van den Bedem, Axel T. Brunger, and Mark A. Wilson. "Atomic resolution experimental phase information reveals extensive disorder and bound 2-methyl-2,4-pentanediol in Ca2+-calmodulin." Acta Crystallographica Section D Structural Biology 72, no. 1 (January 1, 2016): 83–92. http://dx.doi.org/10.1107/s2059798315021609.
Full textAbstract:
Calmodulin (CaM) is the primary calcium signaling protein in eukaryotes and has been extensively studied using various biophysical techniques. Prior crystal structures have noted the presence of ambiguous electron density in both hydrophobic binding pockets of Ca2+-CaM, but no assignment of these features has been made. In addition, Ca2+-CaM samples many conformational substates in the crystal and accurately modeling the full range of this functionally important disorder is challenging. In order to characterize these features in a minimally biased manner, a 1.0 Å resolution single-wavelength anomalous diffraction data set was measured for selenomethionine-substituted Ca2+-CaM. Density-modified electron-density maps enabled the accurate assignment of Ca2+-CaM main-chain and side-chain disorder. These experimental maps also substantiate complex disorder models that were automatically built using low-contour features of model-phased electron density. Furthermore, experimental electron-density maps reveal that 2-methyl-2,4-pentanediol (MPD) is present in the C-terminal domain, mediates a lattice contact between N-terminal domains and may occupy the N-terminal binding pocket. The majority of the crystal structures of target-free Ca2+-CaM have been derived from crystals grown using MPD as a precipitant, and thus MPD is likely to be bound in functionally critical regions of Ca2+-CaM in most of these structures. The adventitious binding of MPD helps to explain differences between the Ca2+-CaM crystal and solution structures and is likely to favor more open conformations of the EF-hands in the crystal.
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Kirsammer, Gina, Sarah Jilani, Hui Liu, Elizabeth Davis, Sandeep Gurbuxani, Michelle M. Le Beau, and John D. Crispino. "Highly penetrant myeloproliferative disease in the Ts65Dn mouse model of Down syndrome." Blood 111, no. 2 (January 15, 2008): 767–75. http://dx.doi.org/10.1182/blood-2007-04-085670.
Full textAbstract:
Children with Down syndrome (DS) display macrocytosis, thrombocytosis, and a 500-fold increased risk of developing megakaryocytic leukemia; however, the specific effects of trisomy 21 on hematopoiesis remain poorly defined. To study this question, we analyzed blood cell development in the Ts65Dn mouse model of DS. Ts65Dn mice are trisomic for 104 orthologs of Hsa21 genes and are the most widely used mouse model for DS. We discovered that Ts65Dn mice display persistent macrocytosis and develop a myeloproliferative disease (MPD) characterized by profound thrombocytosis, megakaryocyte hyperplasia, dysplastic megakaryocyte morphology, and myelofibrosis. In addition, these animals bear distorted hematopoietic stem and myeloid progenitor cell compartments compared with euploid control littermates. Of the 104 trisomic genes in Ts65Dn mice, Aml1/Runx1 attracts considerable attention as a candidate oncogene in DS–acute megakaryoblastic leukemia (DS-AMKL). To determine whether trisomy for Aml1/Runx1 is essential for MPD, we restored disomy at the Aml1/Runx1 locus in the Ts65Dn strain. Surprisingly, trisomy for Aml1/Runx1 is not required for megakaryocyte hyperplasia and myelofibrosis, suggesting that trisomy for one or more of the remaining genes can promote this disease. Our studies demonstrate the potential of DS mouse models to improve our understanding of chromosome 21 gene dosage effects in human hematologic malignancies.
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Passegue, Emmanuelle, Erwin F. Wagner, and Irving L. Weissman. "Junb Regulates Hematopoietic Stem Cell Numbers in Normal and Leukemic Mice." Blood 104, no. 11 (November 16, 2004): 560. http://dx.doi.org/10.1182/blood.v104.11.560.560.
Full textAbstract:
Abstract JunB is expressed in hematopoietic stem cells (HSC) as a partner for Fos in the composition of the AP-1 transcription factor. Previously, we have shown that junB inactivation in postnatal mice results in the development of a myeloproliferative disorder (MPD) resembling early human chronic myelogenous leukemia (CML) (Passegue et al., 2001, Cell, 104, 21-32). Here, we demonstrate that JunB is a critical transcriptional regulator of HSC numbers both in normal and leukemic mice. Overexpression of junB in long-term HSC (LT-HSC) dramatically decreases the frequency of LT-HSC, while inactivation of junB specifically expands the numbers of LT-HSC, and of granulocyte/macrophage progenitors (GMP), resulting in the development of a chronic MPD with many features of human CML, including progression to blast crisis, and death. JunB effects are mediated, at least in part, via the regulation of effectors genes such as the cell cycle inhibitor p16/INK4a, which is a direct junB-target gene and a key regulator of stem cell proliferation/senescence, as well as the anti-apoptotic proteins bcl2 and bcl-xl, two critical regulators of stem cell death. Using several models of conditional deletion of junB in hematopoietic cells, we demonstrate that junB inactivation must take place in LT-HSC, and not at later stages of myelopoiesis, to induce MPD. Most importantly, we show that only junB-deficient LT-HSC, and no other myeloid progenitor populations, are capable of transplanting the MPD to recipient mice. These results indicate a stem cell-specific role for JunB in normal and leukemic hematopoiesis, and provide an experimental demonstration that leukemia stem cells (LSC) can reside at the LT-HSC stage of development in a mouse model of chronic MPD.
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Freitag, Stefanie, Isolde Le Trong, Lisa A. Klumb, Patrick S. Stayton, and Ronald E. Stenkamp. "Atomic resolution structure of biotin-free Tyr43Phe streptavidin: what is in the binding site?" Acta Crystallographica Section D Biological Crystallography 55, no. 6 (June 1, 1999): 1118–26. http://dx.doi.org/10.1107/s0907444999002322.
Full textAbstract:
The streptavidin–biotin system is an example of a high-affinity protein–ligand pair (Ka ≃ 1013 mol−1). The thermodynamic and structural properties have been extensively studied as a model system for protein–ligand interactions. Here, the X-ray crystal structure of a streptavidin mutant of a residue hydrogen bonding to biotin [Tyr43Phe (Y43F)] is reported at atomic resolution (1.14 Å). The biotin-free structure was refined with anisotropic displacement parameters (using the SHELXL97 program package). The high-resolution data also allowed interpretation of side-chain and residue disorder in 41 residues where alternate conformations were refined. The Y43F mutation is unambiguously observed in difference maps, although only a single O atom per monomer is altered. The atomic resolution enabled the identification of 2-methyl-2,4-pentanediol (MPD) molecules in the biotin-binding pocket for the first time. Electron density for MPD was observed in all four subunit binding sites of the tetrameric protein. This was not possible with data at lower resolution (1.8–2.3 Å) for wild-type streptavidin or mutants in the same crystal form using MPD in the crystallization. The impact of MPD binding on these studies is discussed.
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Le, Xiuning, David M. Langenau, Matthew D. Keefe, Jeffery L. Kutok, and Leonard I. Zon. "Inducible hkRASG12D Expression in Zebrafish Hematopoietic Cells Leads to Myeloproliferative Disease." Blood 108, no. 11 (November 16, 2006): 2691. http://dx.doi.org/10.1182/blood.v108.11.2691.2691.
Full textAbstract:
Abstract Activating mutations in RAS family members are common in myeloproliferative disease (MPD) and acute myeloid leukemia (AML). Because the zebrafish has proven to be an excellent leukemia model and can be used in forward genetic and chemical screens to identify modulators of disease pathways, we developed a transgenic zebrafish model of RAS-induced myeloproliferative disease. Stable transgenic zebrafish lines were created in which the ubiquitous B-actin promoter drives expression of a loxed GFP transgene. Upon CRE-mediated recombination, the loxed GFP cassette is excised and the human kRASG12D transgene is expressed. When mated to hsp70-CRE transgenic zebrafish that express CRE recombinase when the animals are heated to 37C for 1 hour, a cohort of 300 double transgenic embryos was generated. In the heat-shocked group, the medial survival time was 25 days, suggesting that oncogenic RAS expression is lethal in developing zebrafish larvae. Of those animals that survived past this time window, most developed sarcomatous muscle tumors. In contrast, most of the double transgenic zebrafish that did not receive heatshock survived to adulthood. Because the hsp70 promoter is active in development and can be induced by stress, the hsp70-CRE transgenic zebrafish line exhibits low levels of CRE expression even in the absence of heatshock. In the non-heat shocked cohort, 10 of 120 double transgenic zebrafish developed MPD by 66 days of life. Histological examination and fluorescence cytometry analysis revealed an expansion of myeloid cell populations within the kidney, comprising granulocytic and monocytic cells in various stages of differentiation, mimicking myeloproliferative diseases seen in both human and mouse. To specifically induce kRASG12D expression in hematopoietic cells, kidneys were dissected from healthy double transgenic animals; heat shocked ex vivo, and then transplanted into sub-lethally irradiated recipient fish. Upon analysis of transplant animals at three months of age, flow cytometry confirmed that MPD had developed in the recipient fish, however other tumor subtypes were not observed. When kidney marrow from transplant animals having MPD were introduced into sub-lethally irradiated secondary recipients, transplant efficiency was greatly reduced. Taken together these results suggest that, as is seen in MPD in mammals, myeloid cells are not fully transformed in our model. In summary, we show that inducible hkRASG12D expression in zebrafish hematopoietic cells leads to myeloproliferative disease and suggest that this model will allow for the identification of novel pathways responsible for full transformation leading to AML.
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Deniz Gálvez, Nery Alejandro, Osval A. Montesinos-López, Emeterio Franco-Pérez, and J. Jesús García-Martínez. "Predicción de variables económicas del sector servicios de México con modelos estadísticos clásicos y Bayesianos / Prediction of economic variables of the service sector in Mexico using classical and Bayesian statistical models." RICEA Revista Iberoamericana de Contaduría, Economía y Administración 7, no. 14 (September 10, 2018): 107–32. http://dx.doi.org/10.23913/ricea.v7i14.120.
Full textAbstract:
La Encuesta Mensual de Servicios (EMS) es una actividad que realiza el Instituto Nacional de Estadística y Geografía (Inegi) con el objetivo de generar información estadística básica sobre el sector económico de los servicios en México. Considerando que se aplica mensualmente y su costo es relevante, en esta investigación se proponen modelos estadísticos (Bayesianos y clásicos) para poder predecir los indicadores de las cuatro variables agregadas que se generan a partir de los resultados de la encuesta. Se estudiaron 42 métodos resultantes de combinar 7 modelos (tres modelos multivariados y cuatro univariados), con 6 métodos de estimación (cuatro bayesianos, uno por mínimos cuadrados y otro por máxima verosimilitud restringida). Los modelos Bayesianos permiten introducir información a priori con el objetivo de obtener un ajuste más preciso de los parámetros.De los siete modelos estadísticos utilizados, el que tuvo mejor capacidad predictiva es el MP1 univariado, seguido por los modelos MP2, MP4 y MP3 multivariados; al final estuvieron los MP5, MP6 y MP7 univariados autoregresivos. De los seis métodos utilizados, el que tuvo mejor capacidad predictiva fue el BayesA, seguido por BayesB, BRR, máxima verosimilitud restringida, BayesC y mínimos cuadrados. En el caso en que predecimos para 3, 6, 12 y 18 meses, los modelos MP1 univariado, MP2, MP3 y MP4 multivariados obtuvieron la mejor capacidad predictiva utilizando los métodos BayesA, BayesB y mínimos cuadrados. De acuerdo con los resultados obtenidos, es razonable predecir con los modelos propuestos para aquellos indicadores con una correlación de 0.4 o mayor. Con los modelos implementados se encontró que es factible predecir los resultados de la encuesta hasta para tres meses, lo que ayudaría a reducir los costos actuales en forma considerablemente.
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NAKANE, Masakatsu, Masao NAGAO, Yoshio ISHIKAWA, Kenichi KUBOTA, and Ikkou FUNAKI. "Nozzle Shape Optimization for an MPD Thruster Using a Two-Dimensional Axisymmetric Flow Model." JOURNAL OF THE JAPAN SOCIETY FOR AERONAUTICAL AND SPACE SCIENCES 59, no. 687 (2011): 90–96. http://dx.doi.org/10.2322/jjsass.59.90.
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KOBAYASHI, Osamu, Kimiya KOMURASAKI, and Toshi FUJIWARA. "One-Dimensional Theory Based on a Two-Fluid Nonequilibrium Plasma Model in MPD Thrusters." Journal of the Japan Society for Aeronautical and Space Sciences 43, no. 492 (1995): 32–38. http://dx.doi.org/10.2322/jjsass1969.43.32.
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Shide, Kotaro, Takuro Kameda, Vadim Markovtsov, Takuya Matsunaga, Haruko Shimoda, Tomonori Hidaka, Keiko Katayose, et al. "Efficacy of R723, a Potent and Selective JAK2 Inhibitor, in JAK2V617F-Induced Murine MPD Model." Blood 114, no. 22 (November 20, 2009): 3897. http://dx.doi.org/10.1182/blood.v114.22.3897.3897.
Full textAbstract:
Abstract Abstract 3897 Poster Board III-833 The V617F mutation of JAK2 (JAK2-V617F) occurs at a high frequency in Philadelphia chromosome-negative myeloproliferative diseases (MPDs). JAK2-V617F leads to constitutive activation of the JAK2 kinase, causing cytokine independent growth in cell lines and development of MPD in mice. These data suggest that aberrant activation of JAK2 plays a pivotal role in the pathophysiology of MPDs and targeting JAK2-V617F may be therapeutically useful. Some orally bioavailable inhibitors of JAK2 are already in clinical trials. R723 is a potent and highly selective (in vitro kinase assay: JAK2 IC50=2nM, JAK1 IC50 >1μM, JAK3 IC50 =24nM) small molecule inhibitor of JAK2. We tested R723 in a murine model of MPD induced by JAK2-V617F. H2Kb promoter-controlled JAK2-V617F expressing mice (V617F-TG) show extreme leukocytosis, thrombocytosis and progressive anemia. They also show hepato-splenomegaly with extramedullary hematopoiesis. Megakaryocytes are predominant in bone marrow and new formation of bony trabeculae and accumulation of fibers are seen. In vitro analysis of bone marrow cells shows constitutive activation of STAT5 and formation of cytokine-independent growth of erythroid colony-forming units (CFU-E). They exhibit high mortality compared to wild-type controls. At first, we assessed the effect of R723 on wild-type (WT) and V617F-TG bone marrow cells in vitro. R723 inhibited cytokine-independent CFU-E growth and constitutive activation of STAT5 of V617F-TG cells. R723 also inhibited cytokine-dependent colony growth and cytokine-induced STAT5 activation in both WT and V617F-TG cells at the same level. Next, we assessed the effect of R723 in vivo. On development of MPD, V617F-TG mice were divided into treatment or vehicle control groups. R723 was administered by oral gavage at 35mg/kg or 70mg/kg bid for 16 weeks, whereas the control groups received vehicle only. Mice were followed by blood counts and a subset of mice was euthanized for detailed histopathology and FACS analysis. In treated mice, there was a significant reduction in leukocyte count in both groups, and a reduction in platelet count in the high dose group. There was no improvement in anemia. They showed a dose-dependent-reduction of hepato-splenomegaly. Histopathology and FACS analysis revealed a reduction of myeloid cells, with partially restored architecture in spleen. In bone marrow, R723 had little effect on progression of fibrosis and megakaryocyte hyperplasia. During the time course of study, 6 out of 23 mice died in the vehicle group, whereas 1 out of 26 mice died in the 70mg/kg group. There was a statistically significant prolongation of survival in the 70mg/kg group (p<0.05). R723 shows therapeutic efficacy in a murine model of MPD induced by JAK2-V617F, and could become the basis for a next generation of potent and selective compounds targeting JAK2-dependent MPDs. Disclosures: Markovtsov: Rigel Pharmaceuticals,Inc.: Employment. Bhamidipati:Rigel Pharmaceuticals,Inc.: Employment. Park:Rigel Pharmaceuticals,Inc.: Employment. Torneros:Rigel Pharmaceuticals,Inc.: Employment. Duan:Rigel Pharmaceuticals,Inc.: Employment. Hitoshi:Rigel Pharmaceuticals,Inc.: Employment. Shimoda:Rigel Pharmaceuticals,Inc.: Research Funding.
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Engström, K. Gunnar, and Eva Löfvenberg. "Treatment of Myeloproliferative Disorders With Hydroxyurea: Effects on Red Blood Cell Geometry and Deformability." Blood 91, no. 10 (May 15, 1998): 3986–91. http://dx.doi.org/10.1182/blood.v91.10.3986.
Full textAbstract:
Abstract Hydroxyurea (HU) is used in suppressing the bone marrow and producing fetal-like red blood cells (RBCs). These RBCs are large in size and may theoretically disturb the microcirculation. In five patients with myeloproliferative disorders (MPD), the RBC geometry and deformability were analyzed before and after 6 to 8 months of HU treatment. In untreated MPD, the RBC geometry and filterability was normal. After HU, the RBC membrane area increased 24% and the cell volume increased 39% (P < .005). This change resulted in a 12% increase in the minimum cylindrical diameter (MCD). From a static bending model of initial deformation, the RBC diametrical cross-section had a significantly increased section modulus. However, this increase in profile stiffness was compensated for by its larger projected cell area and, thus, pressure load on the RBC corpuscle. The resulting resistance to initial deformation therefore remained unchanged after HU. These findings were tested experimentally; with 3-μm filter membranes, HU treatment caused a significant increase in flow resistance (P < .02), in accordance with MCD. However, with 5-μm pores, no difference was seen, again in consonance with the theoretical findings of initial deformation. Because most capillaries are larger than 3 μm, we suggest that HU is acceptable from a perspective of cellular microrheology.
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Engström, K. Gunnar, and Eva Löfvenberg. "Treatment of Myeloproliferative Disorders With Hydroxyurea: Effects on Red Blood Cell Geometry and Deformability." Blood 91, no. 10 (May 15, 1998): 3986–91. http://dx.doi.org/10.1182/blood.v91.10.3986.3986_3986_3991.
Full textAbstract:
Hydroxyurea (HU) is used in suppressing the bone marrow and producing fetal-like red blood cells (RBCs). These RBCs are large in size and may theoretically disturb the microcirculation. In five patients with myeloproliferative disorders (MPD), the RBC geometry and deformability were analyzed before and after 6 to 8 months of HU treatment. In untreated MPD, the RBC geometry and filterability was normal. After HU, the RBC membrane area increased 24% and the cell volume increased 39% (P < .005). This change resulted in a 12% increase in the minimum cylindrical diameter (MCD). From a static bending model of initial deformation, the RBC diametrical cross-section had a significantly increased section modulus. However, this increase in profile stiffness was compensated for by its larger projected cell area and, thus, pressure load on the RBC corpuscle. The resulting resistance to initial deformation therefore remained unchanged after HU. These findings were tested experimentally; with 3-μm filter membranes, HU treatment caused a significant increase in flow resistance (P < .02), in accordance with MCD. However, with 5-μm pores, no difference was seen, again in consonance with the theoretical findings of initial deformation. Because most capillaries are larger than 3 μm, we suggest that HU is acceptable from a perspective of cellular microrheology.
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James, Chloé. "The JAK2V617F Mutation in Polycythemia Vera and Other Myeloproliferative Disorders: One Mutation for Three Diseases?" Hematology 2008, no. 1 (January 1, 2008): 69–75. http://dx.doi.org/10.1182/asheducation-2008.1.69.
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Abstract The discovery of the JAK2V617F mutation has made the diagnosis of polycythemia vera (PV) much easier, but the pathogenesis of PV is still incompletely understood. In particular, it is not yet elucidated how a single mutation can be found in multiple myeloproliferative disorders (MPD) and myelodysplastic syndromes with ring sideroblasts and whether the sole JAK2V617F is sufficient to induce a MPD in humans. Several hypotheses are under investigation such as differences in the targeted hematopoietic stem cells (HSC), host modifier polymorphisms, intensity of JAK2V617F signaling, presence of other somatic mutations, or the presence of a pre-JAK2 event that may vary according to the MPD phenotype. Multiple studies have provided some evidence for and against each hypothesis, but it now seems possible to reconcile these hypotheses into a model that will need to be tested using newly developed tools. Recent investigations have also led to new treatment modalities that could benefit patients with PV.
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Ye, Zhaohui, Huichun Zhan, Prashant Mali, Sarah Dowey, Donna M. Williams, Yoon-Young Jang, Chi V. Dang, Jerry L. Spivak, Alison R. Moliterno, and Linzhao Cheng. "Human-induced pluripotent stem cells from blood cells of healthy donors and patients with acquired blood disorders." Blood 114, no. 27 (December 24, 2009): 5473–80. http://dx.doi.org/10.1182/blood-2009-04-217406.
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Abstract Human induced pluripotent stem (iPS) cells derived from somatic cells hold promise to develop novel patient-specific cell therapies and research models for inherited and acquired diseases. We and others previously reprogrammed human adherent cells, such as postnatal fibroblasts to iPS cells, which resemble adherent embryonic stem cells. Here we report derivation of iPS cells from postnatal human blood cells and the potential of these pluripotent cells for disease modeling. Multiple human iPS cell lines were generated from previously frozen cord blood or adult CD34+ cells of healthy donors, and could be redirected to hematopoietic differentiation. Multiple iPS cell lines were also generated from peripheral blood CD34+ cells of 2 patients with myeloproliferative disorders (MPDs) who acquired the JAK2-V617F somatic mutation in their blood cells. The MPD-derived iPS cells containing the mutation appeared normal in phenotypes, karyotype, and pluripotency. After directed hematopoietic differentiation, the MPD-iPS cell-derived hematopoietic progenitor (CD34+CD45+) cells showed the increased erythropoiesis and gene expression of specific genes, recapitulating features of the primary CD34+ cells of the corresponding patient from whom the iPS cells were derived. These iPS cells provide a renewable cell source and a prospective hematopoiesis model for investigating MPD pathogenesis.
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Li, Geqiang, Zhengqi Wang, Kristy L. Miskimen, Xiu Yan Xie, William Tse, Fabrice Gouilleux, Richard Moriggl, and Kevin D. Bunting. "Genetic and Pharmacologic Targeting of STAT5/Gab2/PI3K/mTOR Signaling in a Mouse Myeloproliferative Disease Model." Blood 114, no. 22 (November 20, 2009): 3902. http://dx.doi.org/10.1182/blood.v114.22.3902.3902.
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Abstract Abstract 3902 Poster Board III-838 Signal transducer and activator of transcription-5 (STAT5) is a latent transcription factor that can be activated by phosphorylation by Janus kinases (JAKs) in the cytoplasm, leading to dimerization, DNA binding, and retention within the nucleus. Phosphorylated STAT5 as determined at the single cell level by flow cytometry is a biomarker associated with poor prognosis in certain types of myeloid malignancies including juvenile myelomonocytic leukemia and M4/M5 leukemias. However, targeting of phosphorylated STAT5 or its aberrant signaling might be difficult since direct inhibition of STAT5 transcriptional activity in its entirety may present significant side effects including immune suppression, hematopoietic stem cell dysfunction, or liver problems. Understanding aberrant STAT5 signaling in normal vs. leukemic cells may allow development of novel strategies for leukemia therapy. Our recent demonstrations of cytoplasmic localization of phosphorylated STAT5 in chronic myeloid leukemia and acute myeloid leukemia have lead us to explore to the efficacy of molecularly defining and targeting cooperating signaling pathways. Persistently active STAT5 (STAT5aS711F) has close encounters with Grb2-associated binding protein (Gab2) in the cytoplasm which is associated with increased activation of Akt. Enhanced sensitivity to inhibition of STAT5, SHP-2, and Gab2 has also been described in Bcr/Abl induced oncogenic activities. We have shown that STAT5aS711F expression induces myeloid expansion and promotes growth through a Gab2-dependent mechanism as determined in vitro using Gab2 decoy molecules. However, the potential efficacy of targeting Gab2 in vivo in a live animal disease model has not been explored. Here we have retrovirally transduced wild-type or Gab2-/- mouse bone marrow cells with a murine stem cell virus (MSCV)-based retroviral vector expressing STAT5aS711F upstream of an internal ribosomal entry sequence and the enhanced green fluorescent protein (GFP). Transplanted bone marrow cells caused the expected myeloproliferative disease (MPD) phenotypes that were quantified along with mouse survival. Mice reconstituted with transduced bone marrow cells lacking Gab2 had a significantly attenuated accumulation of myeloid Gr-1+/Mac-1+ cells in the peripheral blood (3.4-fold; P=0.014), liver, and spleen and showed improved survival (control 30 days vs. >90 days without Gab2). However, phosphorylation of Akt activated by STAT5aS711F also occurred in mice lacking Gab2, indicating that Gab2-independent activation of Akt also occurs. Like reported by others in Jak2 and Bcr/Abl mouse MPD models we observed cell extrinsic MPD suggesting that STAT5 activates a paracrine signaling pathway that does not depend on direct Gab2 interaction. This lead us to consider alternative approaches for targeting the PI3K/Akt pathway and to begin defining Akt target genes of importance in STAT5 provoked MPD. Rapamycin is an effective inhibitor of mTORC1 and has been previously shown to synergize with protein tyrosine kinase inhibitors. Therefore, we utilized rapamycin to test whether targeting PI3K/Akt/mTOR signaling would be sufficient to impair cytokine-independent growth provoked by STAT5aS711F. First, BaF3 cells expressing STAT5aS711F were tested for their responsiveness to rapamycin (0.01 – 1 nM). Treatment with rapamycin effectively stopped the cells from growing but was not cytotoxic. Due to the effects of rapamycin on hematopoietic engraftment, it was necessary to optimize transplant and disease burden for rapamycin treatment in vivo. Strikingly, daily treatment of transplanted mice (vehicle N=9; rapamycin N=10) with 4 mg/kg of rapamycin at the early stage of MPD provided a 3.3-fold reduction in Gr-1+/Mac-1+ cells (P=0.002) and prolonged survival of treated mice (>90 days with rapamycin compared with 60 days for control). This effect was cytostatic but did not prevent the subsequent recurrence of MPD once the treatment was stopped. The use of additional drugs and/or optimized transplant/treatment protocols will be required for future studies Overall, these data provide in vivo evidence for clinically significant cooperative signaling by STAT5 and AKT-mTOR pathway in leukemic hematopoiesis and support targeting of the Akt-mTOR axis as therapy for MPDs with Jak2 or Mpl mutations and phosphorylated STAT5. Disclosures: No relevant conflicts of interest to declare.
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Maponya, Thabiso Carol, Kabelo Edmond Ramohlola, Nazia Hassan Kera, Kwena Desmond Modibane, Arjun Maity, Lebogang Maureen Katata-Seru, and Mpitloane Joseph Hato. "Influence of Magnetic Nanoparticles on Modified Polypyrrole/m-Phenylediamine for Adsorption of Cr(VI) from Aqueous Solution." Polymers 12, no. 3 (March 19, 2020): 679. http://dx.doi.org/10.3390/polym12030679.
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A novel, modified polypyrrole/m-phenylediamine (PPy–mPD) composite, decorated with magnetite (Fe3O4) nanoparticles, and prepared via an in-situ oxidative polymerisation, was investigated. The PPy–mPD/Fe3O4 nanocomposite was employed for the removal of highly toxic oxyanion hexavalent chromium Cr(VI) from an aqueous solution. The structure and successful formation of the PPy–mPD/Fe3O4 nanocomposite was confirmed and investigated using various techniques. The presence of Fe3O4 was confirmed by high resolution transmission electron microscopy, with an appearance of Fe lattice fringes. The estimation of the saturation magnetisation of the nanocomposite, using a vibrating sample magnetometer, was observed to be 6.6 emu/g. In batch adsorption experiments, PPy–mPD/Fe3O4 nanocomposite (25 mg) was able to remove 99.6% of 100 mg/L of Cr(VI) at pH 2 and 25 °C. Adsorption isotherms were investigated at different Cr(VI) concentration (100–600 mg/L) and temperature (15–45 °C). It was deduced that adsorption follows the Langmuir model, with a maximum adsorption capacity of 555.6 mg/g for Cr(VI) removal. Furthermore, isotherm data were used to calculate thermodynamic values for Gibbs free energy, enthalpy change and entropy change, which indicated that Cr(VI) adsorption was spontaneous and endothermic in nature. Adsorption–desorption experiments revealed that the nanocomposite was usable for two consecutive cycles with no significant loss of adsorption capacity. This research demonstrates the application potential for the fascinating properties of PPy–mPD/Fe3O4 nanocomposite as a highly efficient adsorbent for the removal of heavy metal ions from industrial wastewater.
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William, Basem M., Dan Feng, Wei An, Scott Nadeau, Bhopal Mohapatra, Matt Storck, and Hamid Band. "Fasudil, a Rho-Associated Protein Kinase (ROCK) Inhibitor, Decreases Disease Burden in a Cbl/Cbl-b Deficiency-Driven Murine Model for Myeloproliferative Disorders." Blood 124, no. 21 (December 6, 2014): 4569. http://dx.doi.org/10.1182/blood.v124.21.4569.4569.
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Abstract Myeloproliferative disorders (MPDs) are heterogeneous clonal diseases with variable clinical courses. Mutations in the Cbl family genes have been reported in multiple independent studies to be present in about 10% of patients with MPDs and these patients tend of have a poorer prognosis. We have previously demonstrated that Cbl-flox/flox, Cbl-b-null mice rendered Cbl/Cbl-b double knockout (DKO) in the hematopoietic compartment with MMTV-Cre develop a disease phenotypically similar to human MPDs. An in vitro kinase inhibitor screen identified fasudil, a ROCK inhibitor, with relatively selective anti-proliferative activity against Cbl/Cbl-b DKO vs. control murine bone marrow cells. We established a mouse model with a uniform time of MPD onset by transplanting Cbl/Cbl-b DKO bone marrow cells (2x106 per recipient) into 21 busulfan-conditioned NOD/SCID/gamma chain-deficient (NSG) mice. All recipients showed donor cell engraftment. Four weeks post-transplant, we treated 13 mice with 100 mg/kg fasudil daily by gavage. By two weeks of treatment, total white cell and monocyte counts were significantly lower in mice treated with fasudil (p=0.02 and 0.04 respectively). For the entire group, we observed a trend towards improved survival in fasudil-treated mice that didn't reach statistical significance (p=0.07). However, analysis of male recipients only (n=12) revealed a significant survival advantage in fasudil-treated group (p=0.04). The gender difference may stem from a currently unexplained more severe disease phenotype we observed in female recipients. Notably, while all untreated mice succumbed to MPD, prolonged survival was observed in 2 mice beyond 27 weeks, nearly twice the average life-span in the Cbl/Cbl-b DKO MPD model (16 weeks). The 2 long-term survivors had undetectable levels of myosin light chain (MLC), a downstream target of ROCK phosphorylation (figure) suggesting that inhibition of downstream signaling of ROCK is associated with improved disease control and survival. Taken together, our data suggest a therapeutic potential for fasudil in the treatment of MPDs or other mutant Cbl-driven myeloid disorders. Figure: Fasudil activity in mouse model of Cbl/Cbl-b DKO MPD. Total WBC (A) and monocyte (B) counts over time in untreated and fasudil-treated mice (mean+/-SEM), C: MLC levels by Western Blot in peripheral blood of control vs. fasudil-treated mice; those surviving longer than 27 weeks are indicated. Figure:. Fasudil activity in mouse model of Cbl/Cbl-b DKO MPD. Total WBC (A) and monocyte (B) counts over time in untreated and fasudil-treated mice (mean+/-SEM), C: MLC levels by Western Blot in peripheral blood of control vs. fasudil-treated mice; those surviving longer than 27 weeks are indicated. Disclosures No relevant conflicts of interest to declare.
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Jindal, Megha, and Sangeeta Gupta. "Placental biometry for prediction of small for gestational age fetuses in low resource setting." International Journal of Reproduction, Contraception, Obstetrics and Gynecology 6, no. 12 (November 23, 2017): 5266. http://dx.doi.org/10.18203/2320-1770.ijrcog20175069.
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Background: Small for gestational age refers to foetuses with birth weight less than tenth centile for gestational age. Such foetuses are at increased risk of intrauterine fatal demise in comparison to others. Placenta plays a central role in supporting foetal growth. Researchers have emphasized on three dimensional sonographic placental volumetry as a predictor of SGA. This study focussed on role of two dimensional Ultrasonographic placental measurement in predicting SGA foetuses.Methods: Prospective study was conducted at Department of Obstetrics and Gynecology, Maulana Azad Medical College from November 2013 to February 2015. In singleton pregnancies at 18-22 weeks of gestation, placental biometry (in two dimensions) was performed. Maximal Placental Diameter (MaxPD) and Maximal Placental Thickness (MaxPT) in two orthogonal planes was recorded. Mean Placental Diameter (MPD) and Mean Placental Thickness (MPT) were calculated. At the time of delivery, as per the birth weight the neonate was classified into appropriate for gestational age (AGA)/ SGA/ large for gestational age (LGA). MPD and MPT were analyzed as predictors of SGA.Results: Both the MaxPDs and MPD were significantly smaller in SGA pregnancies (all with p ≤ 0.001). Similarly, both the MaxPTs (p = 0.006 and p = 0.001) and MPT (p = 0.000) were significantly smaller in SGA pregnancies. The ROC curve for combined placental biometry had the maximum area under the curve (0.805).Conclusions: Placental measurements taken in mid-gestation are a valuable predictor of SGA. Measurement of placental diameter and thickness is quick and simple. This approach should be explored in future to develop a predictive model for growth restricted foetuses.
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Gong, Jibing, Li Cui, Kejiang Xiao, and Rui Wang. "MPD-Model: A Distributed Multipreference-Driven Data Fusion Model and Its Application in a WSNs-Based Healthcare Monitoring System." International Journal of Distributed Sensor Networks 8, no. 12 (December 6, 2012): 602358. http://dx.doi.org/10.1155/2012/602358.
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Middleton, Melissa Kristine, Alicia Marie Zukas, Tanya Rubinstein, Michele Jacob, Peijuan Zhu, Liang Zhao, Ian Blair, and Ellen Puré. "Identification of 12/15-lipoxygenase as a suppressor of myeloproliferative disease." Journal of Experimental Medicine 203, no. 11 (October 16, 2006): 2529–40. http://dx.doi.org/10.1084/jem.20061444.
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Though Abl inhibitors are often successful therapies for the initial stages of chronic myelogenous leukemia (CML), refractory cases highlight the need for novel molecular insights. We demonstrate that mice deficient in the enzyme 12/15-lipoxygenase (12/15-LO) develop a myeloproliferative disorder (MPD) that progresses to transplantable leukemia. Although not associated with dysregulation of Abl, cells isolated from chronic stage 12/15-LO–deficient (Alox15) mice exhibit increased activation of the phosphatidylinositol 3–kinase (PI3-K) pathway, as indicated by enhanced phosphorylation of Akt. Furthermore, the transcription factor interferon consensus sequence binding protein (ICSBP) is hyperphosphorylated and displays decreased nuclear accumulation, translating into increased levels of expression of the oncoprotein Bcl-2. The ICSBP defect, exaggerated levels of Bcl-2, and prolonged leukemic cell survival associated with chronic stage Alox15 MPD are all reversible upon treatment with a PI3-K inhibitor. Remarkably, the evolution of Alox15 MPD to leukemia is associated with additional regulation of ICSBP on an RNA level, highlighting the potential usefulness of the Alox15 model for understanding the transition of CML to crisis. Finally, 12/15-LO expression suppresses the growth of a human CML–derived cell line. These data identify 12/15-LO as an important suppressor of MPD via its role as a critical upstream effector in the regulation of PI3-K–dependent ICSBP phosphorylation.
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Melnikov, Grigory Yu, Tatyana P. Denisova, Alexander P. Safronov, Oleg M. Samatov, Roman T. Khandukhanov, Nikita A. Kulesh, Ricardo Andrade, and Galina V. Kurlyandskaya. "Methodological aspects of small iron concentrations determination in black yeasts grown in the presence of iron oxide nanoparticles." EPJ Web of Conferences 185 (2018): 10007. http://dx.doi.org/10.1051/epjconf/201818510007.
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Nonpathogenic Exophiala nigrum (black yeasts) unicelular organisms of the Baikal Lake were used as a model system for determination of small iron concentrations in the samples grown without or with controlled amount of maghemite nanoparticles (MNPs) in nutrient. MNPs were produced by the electrophysical laser target evaporation technique. Electrostatically stabilized suspensions were prepared using sodium citrate solutions in distilled water. We assumed that one maximum permissive dose of ionic iron in water 1 MPD is equal to 0.3 mg/L. For biological experiments Saburo liquid nutrient medium was prepared with iron concentrations of 0, 102, 103 and 104 MPD. One ml of E. Nigrum cell suspension was added to Saburo liquid nutrient for 24 hours exposure. Followed by sowing onto a solid agar Saburo for 30 days colonies grows. Biosamples for electron microscopy, magnetic and total reflection X-ray fluorescence spectroscopy measurements were collected simultaneously. We were able to comparatively analyze the trace concentrations of iron in the yeast of the order of 10 ppm for control group and 600 ppm for the group grown in the presence of 104 MPD of iron.
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Chan, Gordon, Demetrios Kalaitzidis, Tatiana Usenko, Jeffery L. Kutok, Wentian Yang, M. Golam Mohi, and Benjamin G. Neel. "Leukemogenic Ptpn11 causes fatal myeloproliferative disorder via cell-autonomous effects on multiple stages of hematopoiesis." Blood 113, no. 18 (April 30, 2009): 4414–24. http://dx.doi.org/10.1182/blood-2008-10-182626.
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Abstract PTPN11, which encodes the tyrosine phosphatase SHP2, is mutated in approximately 35% of patients with juvenile myelomonocytic leukemia (JMML) and at a lower incidence in other neoplasms. To model JMML pathogenesis, we generated knockin mice that conditionally express the leukemia-associated mutant Ptpn11D61Y. Expression of Ptpn11D61Y in all hematopoietic cells evokes a fatal myeloproliferative disorder (MPD), featuring leukocytosis, anemia, hepatosplenomegaly, and factor-independent colony formation by bone marrow (BM) and spleen cells. The Lin−Sca1+cKit+ (LSK) compartment is expanded and “right-shifted,” accompanied by increased stem cell factor (SCF)–evoked colony formation and Erk and Akt activation. However, repopulating activity is decreased in diseased mice, and mice that do engraft with Ptpn11D61Y stem cells fail to develop MPD. Ptpn11D61Y common myeloid progenitors (CMPs) and granulocyte-monocyte progenitors (GMPs) produce cytokine-independent colonies in a cell-autonomous manner and demonstrate elevated Erk and Stat5 activation in response to granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation. Ptpn11D61Y megakaryocyte-erythrocyte progenitors (MEPs) yield increased numbers of erythrocyte burst-forming units (BFU-Es), but MEPs and erythrocyte-committed progenitors (EPs) produce fewer erythrocyte colony-forming units (CFU-Es), indicating defective erythroid differentiation. Our studies provide a mouse model for Ptpn11-evoked MPD and show that this disease results from cell-autonomous and distinct lineage-specific effects of mutant Ptpn11 on multiple stages of hematopoiesis.
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Ma, Xiaomei, K. Gary J. Vanasse, H. Andrew Selinger, Yun Wang, and Brenda Cartmel. "Prevalence of Polycythemia Vera and Essential Thrombocythemia." Blood 110, no. 11 (November 16, 2007): 4667. http://dx.doi.org/10.1182/blood.v110.11.4667.4667.
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Abstract Polycythemia vera (PV) and essential thrombocythemia (ET) are two common types of myeloproliferative disorders (MPD). The prevalence of PV and ET in the United States (US) has not been well documented. Recent breakthroughs in the molecular etiology of these disorders and the accelerated development of targeted pharmacotherapeutics to treat the MPD have significantly increased the need to accurately define the affected population. In the present study, we obtained detailed demographic and health claims data from major commercial insurance payers in Connecticut and the Center for Medicare and Medicaid Services to estimate the prevalence of PV and ET. Health claims data from one payer and the actual diagnoses made by physicians who submitted claims with MPD-related ICD-9 codes were utilized to develop claim-based statistical algorithms to predict the probability that an individual with claims suggestive of MPD truly has PV or ET. Specifically, logistic regression was used to develop the algorithms, and area under the receiver operating characteristics curve (AUC) was used as the measure of goodness-of-fit for each model. Different models were fit, and the model with the highest AUC was selected. For PV, the best-fitting model included age as a continuous variable and the frequency of two PV-related ICD-9 codes (238.4 and 289.6 combined) as a continuous variable, and the AUC was 0.95. For ET, the best-fitting model included age as a continuous variable and the frequency of code 289.9 as a categorical variable (=0, =1, or ≥2), and the AUC was 0.72. For both models, the addition of gender or the frequency of the non-specific code 238.7 did not improve AUC. Subsequently, the algorithms were applied to health claims from multiple payers to estimate the number of PV and ET patients in Connecticut. The total number of Connecticut residents included in the study was close to 2,900,000, which represented about 83.2% of the estimated population of the entire state in July 2003. As of 2003, the age-standardized prevalence of PV and ET in Connecticut was 22 per 100,000 and 24 per 100,000, respectively. Applying the age-specific prevalence of PV and ET to the entire US population resulted in an estimated total of 65,243 patients with PV and 71,078 patients with ET in the US in 2003. This study is the first to assess the prevalence of PV and ET in a very large US population. Given the large number of individuals afflicted with these diseases and the fact that demographic changes alone will further increase the burden of these diseases in the foreseeable future, it is imperative to conduct more systematic research into the etiology and treatment of PV and ET.
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Grimes, H. Leighton, and Shane R. Horman. "A Gene Dosage Requirement for Transcription Factor Gfi1 in the Regulation of Myelopoiesis and Myeloproliferative Disorders." Blood 108, no. 11 (November 16, 2006): 4180. http://dx.doi.org/10.1182/blood.v108.11.4180.4180.
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Abstract The generation of mature myeloid lineage cells from hematopoietic stem cells (HSCs) requires a precise synergy between cytokine signaling and lineage-specific transcription factors. Gfi1 (Growth Factor Independence 1) is a zinc finger transcription factor that is necessary for normal myelopoiesis. Gfi1 knockout mice display an abnormal ratio of phenotypic common myeloid progenitors (CMP) and granulocyte/monocyte progenitors (GMP), and such mice completely lack mature neutrophils. In contrast, the Gfi1 heterozygote mouse presents no obvious phenotype. Here we show a gene dosage requirement for Gfi1 in the differentiation of mature myeloid cells. While bone marrow from wild type littermates generates granulocytic, monocytic and mixed methylcellulose colonies, Gfi1 knockout bone marrow cells yield mainly monocytic colonies. In comparison to wild type littermates, Gfi1+/− bone marrow cells generate lower numbers of granulocytic colonies and higher numbers of monocytic colonies. Interestingly, methylcellulose colonies from both Gfi1 knockout mice and heterozygotes display increased serial replating capacity in comparison to wild type littermates. These data suggest that Gfi1 gene dosage may control self renewal and may relate to oncogenic transformation. Activating mutations in K-Ras are common genetic abnormalities in human acute myeloid leukemia and myeloproliferative disease (MPD). However, expression of activated Ras from endogenous regulatory sequences (knock-in) results in an MPD of varying lethality. The severity of the K-Ras-induced MPD depends on unknown genetic modifiers, as lethality is increased in a Balb/c genetic background. Given the effect of Gfi1 gene dosage on serial replating, we have analyzed the effect of Gfi1 gene dosage on the activated Ras knock-in mouse model of MPD. Preliminary data indicate that lowering Gfi1 gene dosage modifies the phenotype of activated Ras MPD by dramatically increasing the number of immature circulating myeloid progenitors. These results reveal that Gfi1 is a modifier of Ras induced disease pathogenesis.