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Brock, Aleah S., and Sandie M. Bass-Ringdahl. "Facilitative Language Techniques Used in the Home by Caregivers of Young Children Who Are Deaf or Hard of Hearing." Perspectives of the ASHA Special Interest Groups 6, no. 5 (October 20, 2021): 1137–45. http://dx.doi.org/10.1044/2021_persp-20-00297.
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Purpose This research note reports preliminary data from an investigation of facilitative language techniques (FLTs) used in the natural environment by caregivers of children who are deaf or hard of hearing (DHH). The investigation seeks to establish a new method to collect and analyze data on caregiver FLT use in the home. Method This pilot investigation included two children under the age of 36 months with moderate-to-profound sensorineural hearing loss. Both children were consistent users of hearing devices and were pursing oral communication. Data were collected via the Language ENvironment Analysis (LENA) system in the participants' homes. Thirty-six 5-min segments containing the highest adult word count were extracted from each participant's sample. Researchers coded segments for the presence or absence of 10 FLTs within 30-s intervals. Results The collection, coding, and analysis of caregiver FLTs using LENA was a feasible method to investigate caregiver linguistic input in the natural environment. Despite differences in age, sex, and hearing level, the distribution of caregiver FLTs was similar for both participants. Caregivers used high levels of narration, closed-ended questions, and directives throughout the day. Conclusions Results of this investigation provide information about the types of FLTs that are used in the home by caregivers of young children who are DHH. Furthermore, results indicate the feasibility of this method to investigate in-home use of caregiver FLTs.
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Lee, B. B., J. Laredo, and R. Neville. "Reconstructive surgery for chronic lymphedema: a viable option, but." Vascular 19, no. 4 (July 22, 2011): 195–205. http://dx.doi.org/10.1258/vasc.2010.oa0287.
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The aim of the paper is to assess the efficacy of reconstructive lymphatic surgery in the treatment of chronic lymphedema via retrospective analysis. Lymphovenous anastomotic surgery (LVAS) or free lymph node transplant surgery (FLTS) was performed on 32 patients who failed to respond to complex decongestive therapy (CDT) alone for a minimum of a one-year period. In LVAS, three patients with good compliance among 19 were able to maintain initial improvement through the four-year follow-up period. All three had secondary lymphedema in clinical stage II. In FLTS, among 13 patients, three compliant patients with the secondary lymphedema in clinical stage II kept initial improvement through the four-year follow-up. In conclusion, reconstructive lymphatic surgery (LVAS and FLTS) appears to be more effective in secondary lymphedema versus primary lymphedema when performed in the early stages. Patient compliance to maintain CDT postoperatively remains the most critical factor in maintaining durable long-term results. FLTS seems to have an additional risk involved to the donor lymph node harvest and a limited role compared to LVAS. Further extended study on FLTS is required to demonstrate its efficacy compared with LVAS.
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Kouah, Sofia, and Djamel-Eddine Saidouni. "Fuzzy Labeled Transition Refinement Tree." International Journal of Agent Technologies and Systems 6, no. 3 (July 2014): 1–31. http://dx.doi.org/10.4018/ijats.2014070101.
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This paper aims to provide a formal framework that supports an incremental development of dynamic systems such as multi agents systems (MAS). We propose a fuzzy labeled transition system model (FLTS for short). FLTS allows a concise action refinement representation and deals with incomplete information through its fuzziness representation. Afterward, based on FLTS model, we propose a refinement model called fuzzy labeled transition refinement tree (FLTRT for short). The FLTRT structure serves as a tree of potential concurrent design trajectories of the system. Also, we introduce bisimulation relations for both models in order to identify equivalent design trajectories, which could be assessed with respect to relevant design parameters.
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Dysli, Chantal, Muriel Dysli, Sebastian Wolf, and Martin Zinkernagel. "Fluorescence lifetime distribution in phakic and pseudophakic healthy eyes." PLOS ONE 18, no. 1 (January 6, 2023): e0279158. http://dx.doi.org/10.1371/journal.pone.0279158.
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Purpose To investigate the influence of the lens status and to describe fundus autofluorescence lifetimes (FLT) in a large cohort of healthy eyes across a wide age range. Materials and methods FLT data were acquired from healthy phakic and pseudophakic eyes using fluorescence lifetime imaging ophthalmoscopy (FLIO). Retinal autofluorescence was excited with a 473 nm laser and emitted autofluorescence was detected in a short and a long spectral channel (SSC: 498–560 nm; LSC: 560–720 nm). Results 141 healthy eyes from 141 participants (56 ± 18 years) were included. The shortest mean FLTs were measured within the macular center, followed by the temporal inner and outer ETDRS (Early Treatment Diabetic Retinopathy Study) grid segments, and the remaining areas of the inner and the outer ETDRS ring. In phakic participants (81%), mean, short and long FLTs correlated with the age (SSC: r2 = 0.54; LSC: r2 = 0.7; both p<0.0001) with an increase of about 33 ps in the SSC resp. 28 ps in the LSC per decade. In pseudophakic subjects (19%), mean FLTs only correlated with age in the long spectral channel (r2 = 0.44; p = 0.0002) but not in the short spectral channel (r2 = 0.066; p = 0.2). Conclusions Fundus autofluorescence lifetimes are age dependent. FLTs in the SSC are more susceptible to lens opacities but less dependent on age changes, whereas FLTs in the LSC are largely independent of the lens status but display a higher degree of age dependency. Study registry ClinicalTrials.gov NCT01981148.
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Lee, Youjin, Heesun Park, Hyun Sub Sim, and Youngmee Lee. "Parental Linguistic Inputs to Toddlers with Cochlear Implants during Parent-Toddler Interaction." Communication Sciences & Disorders 27, no. 3 (September 30, 2022): 689–702. http://dx.doi.org/10.12963/csd.22892.
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Objectives: Parental linguistic input is one of the most important factors in the early language environment of young children. This study aimed to investigate the characteristics of parental linguistic input in toddlers with cochlear implants (CIs), aged 12-36 months, compared to those with typical hearing (TH); and to explore the relationships between parental linguistic input variables and the language development of toddlers in each group. Methods: Parental linguistic input to 14 toddlers with CIs and 18 toddlers with TH was examined during a 20 minute free-play activities. This study compared the amounts of parental linguistic input and the proportion of facilitative language techniques (FLTs) between the CI and TH groups. Results: Parents of toddlers with CIs used more utterances and shorter mean length of utterance than parents of toddlers with TH. However, toddlers with CIs were exposed to a similar number of different words compared to toddlers with TH. Parents of toddlers with CIs used less FLTs than parents of toddlers with TH. In the TH group, high- and low-level FLTs were significantly correlated with language skills of toddlers. However, there was no significantly relationship between parental linguistic input variables and toddlers’ language skills in the CI group. Conclusion: These results suggested that toddlers with CIs were exposed to a different quantity and quality of parental linguistic input compared to toddlers with TH. These findings can be used to develop the parent education program in the early intervention for toddlers with CIs.
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Kouah, Sofia, Djamel Eddine Saïdouni, and Ilham Kitouni. "Open Fuzzy Synchronized Petri Net." International Journal of Intelligent Information Technologies 12, no. 1 (January 2016): 63–94. http://dx.doi.org/10.4018/ijiit.2016010104.
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Designing Multi agent systems needs a high-level specification model which supports abstraction, dynamicity, openness and enables fuzziness. Since the model of Synchronized Petri Nets supports dynamicity and abstraction, we extend it by fuzziness, openness and interaction with environment. The proposed model called Open Fuzzy Synchronized Petri Nets (OFSyPN for short) associates action name with transitions and enables openness feature and interaction with environment. Each action has an uncertainty degree and places are typed. The authors give an operational semantics for OFSyPN in terms of Fuzzy Labeled Transition System (FLTS for short). FLTS is a semantics model, which allows a concise action refinement representation and deals with incomplete information through its fuzziness representation. Furthermore the structure can be used to produce a tree of potential concurrent design trajectories, named fuzzy labeled transition refinement tree (FLTRT for short). We exemplify the OFSyPN model thought a case study.
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Liu, Xianjin, Fengjuan Wang, Jiuru Yang, Xudong Zhang, and Xiliang Du. "Fiber Ring Laser Directional Torsion Sensor with Ultra-Wide Linear Response." Sensors 19, no. 16 (August 20, 2019): 3613. http://dx.doi.org/10.3390/s19163613.
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In this paper, a comprehensive passive torsion measurement is performed firstly in a 40-cm-long polarization maintaining fiber-based Sagnac interferometer (PMF-SI), and the non-linear torsion response is found and investigated. Then, a fiber laser torsion sensor (FLTS) with a dual-ring-cavity structure is proposed and experimentally demonstrated, in which the PMF-SI is utilized as the optical filter as well as the sensing unit. In particular, the highly sensitive linear range is adjusted through fine phase modulation, and owing to the flat-top feature of fringes, an ~83.6% sensitivity difference is effectively compressed by the generated lasing. The experimental results show that, without any pre-twisting, the ultra-wide linear response from –175 to 175 rad/m is gained, and the torsion sensitivities are 2.46 and 1.55 nm/rad with high linearity (>0.99) in the clockwise and anti-clockwise directions, respectively. Additionally, a high extinction ratio (>42 dB) and small line-width (~0.14 nm) are obtained in the proposed FLTS, and the corresponding detection limit reaches 0.015 rad/m.
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Konstantinidis, P. A., G. C. Koltsakis, and A. M. Stamatelos. "Computer aided assessment and optimization of catalyst fast light-off techniques." Proceedings of the Institution of Mechanical Engineers, Part D: Journal of Automobile Engineering 211, no. 1 (January 1, 1997): 21–37. http://dx.doi.org/10.1243/0954407971526191.
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Strict future legislation standards are forcing the car industry to employ new techniques for reducing exhaust gas emissions. Most of these techniques focus on accelerating the appearance of catalyst light-off and are thus called fast light-off techniques (FLTs). Optimized exhaust systems comprising FLTs will be able to meet the forthcoming legislation standards for the United States [low emissions vehicle (LEV) and ultra-low emissions vehicle (ULEV)] and the European Union (Stage III). The most promising active and passive FLT systems are briefly reviewed. Computer aided optimization of such systems can be realized with the help of specific computational tools, which are briefly presented in this paper, and according to a concept optimization methodology, which is also discussed. The results indicate an increased sensitivity of FLT systems’ performance over the selected values of certain design and operating parameters that were featured in the examples presented. Moreover, by comparing the computational results with knowledge gained from experiments and testing, the paper indicates that, given the suitable computational tools, the optimization procedure can take place in a most cost-effective manner by substituting many experiments with computer test case runs.
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Lesinigo, E., L. Lodi, and F. Rocca. "2 OC The early trends of functional liver tests (FLTs) in choledocholithiasis: What it means?" Digestive and Liver Disease 34 (June 2002): A55. http://dx.doi.org/10.1016/s1590-8658(02)90210-0.
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Vita, Leonardo, and Davide Gattamelata. "Analytical Method for Assessing Stability of a Counterbalanced Forklift Truck Assembled with Interchangeable Equipment." Applied Sciences 13, no. 2 (January 16, 2023): 1206. http://dx.doi.org/10.3390/app13021206.
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Counterbalanced forklift trucks (FLT) are frequently used in combination with interchangeable equipment in order to handle loads in different manners. The main risks which may arise after assembling interchangeable equipment to a FLT are related to the loss of stability of the assembly. Actually, the presence of interchangeable equipment and the associated payload may change in a significant way the overall centre of gravity with respect to the FLT in its basic configuration with forks. Therefore, the stability limits of the assembly, based on the same footprints on the ground of the FLT alone, are affected by the position of the overall centre of gravity. Thus, the presence of interchangeable equipment could reduce the functionality (e.g., lifting capability, lifting height, etc.) of the FLT in order to continue its stability during use. Often, interchangeable equipment is placed on the market by manufacturers other than the FLT manufacturer. In these cases, the correct and safe coupling of the interchangeable equipment with the FLT is the responsibility of the manufacturers of interchangeable equipment, including the stability risk assessment. Thus, the interchangeable equipment manufacturer should have access to the relevant information of the FLT concerning operative and structural features and its configuration as a procedure for assessing the correct and safe coupling. Otherwise, he should perform experimental stability tests for each model of FLT so that its interchangeable equipment can be fitted. Specific research activity is developed in order to define an analytical procedure to assess the stability of FLT when assembled with interchangeable equipment. Specific typologies of FLTs and interchangeable equipment have been selected in order to better characterise the case study. The analytical equations mimic the static stability tests. The results achieved have been compared to experimental data in order to optimise the procedure. The results attained by the application of the analytical procedure to all the combinations of main typologies of FLTs and the interchangeable equipment selected showed good agreement with experimental tests.
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Wen, Qiufang, and Hong Zhang. "Building professional learning communities of foreign language teachers in higher education." Círculo de Lingüística Aplicada a la Comunicación 84 (December 2, 2020): 1–12. http://dx.doi.org/10.5209/clac.72815.
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In recent decades there has been increasing interest in identifying the critical features of effective professional learning communities (PLCs). This identification is useful for evaluating the quality of a PLC, but not for building one. This study aims at describing a conceptual model for developing a new PLC, illustrating its application with an example. The model is explained in terms of four constitutive elements (PARTICIPANTS, OBJECTIVES, MEDIATORS, and MECHANISM), and their interactive relations. The development of a PLC of foreign language teachers (PLC-FLTs) at Beijing Foreign Studies University is used to illustrate how the model can function successfully. The illustration is coupled with a discussion of the PLC’s decades of experience in collective leadership, management of the four elements, and tips for tackling various challenges in keeping the PLC going.
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Lee, Hyewon, Seok-Ki Kim, Tae Sung Kim, Se Hun Kang, Weon Seo Park, and Hyeon Seok Eom. "Response Assessment Using Early and End-of-Treatment 18F-FLT PET Can Predict Outcome in Patients with Non-Hodgkin Lymphoma,." Blood 118, no. 21 (November 18, 2011): 3679. http://dx.doi.org/10.1182/blood.v118.21.3679.3679.
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Abstract Abstract 3679 Background Fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) scan has been known as a useful modality for response assessment in malignant lymphoma. However, FDG is not tumor-specific and can be false positive in inflammatory lesions. To overcome these limitations, a new PET tracer, thymidine analog 3'-deoxy-3'-18F-fluorothymidine (FLT), was introduced recently. Preliminary data showed close correlation between FLT uptake and tumor cell proliferation in lymphoma, suggesting the possibility of noninvasive tumor grading and early response assessment. Therefore, we performed a prospective trial to evaluate the feasibility of FLT-PET in risk stratification and prediction for treatment outcome, especially in early interim analysis, in patients with non-Hodgkin lymphoma (NHL). Methods Seventy-five patients newly diagnosed with NHL were prospectively enrolled at National Cancer Center, Korea, from Oct 2005 to Oct 2008. All received standard chemotherapy for their pathologic classifications. Patients were evaluated with FLT-PET at baseline (FLT0), after 1 cycle of chemotherapy (FLT1, early), and after completion of the 1st line chemotherapy (FLTE, end-of-treatment). FLT-PET results were assessed according to the International Workshop Criteria (IWC). Maximum standardized uptake values (SUVmax) of each FLT-PET were calculated to evaluate its correlation with the clinical characteristics and treatment outcome. Treatment outcome was estimated using 3-year progression-free survival (3yr-PFS) and overall survival (3yr-OS). Results Of the 75 enrolled patients, 63 (84%) had diffuse large B-cell lymphoma. Median age at diagnosis was 57 years (range, 29–87). Twenty-eight (37.3%) presented with stage III or IV diseases and 20 (26.7%) showed more than 3 IPI scores. Median follow up duration was 4.5 years (range, 3.5–5.8). Five (6.7%) patients underwent hematopoietic stem cell transplantation at last. Three-year PFS and OS rates for all enrolled patients were 68% and 78.7%. Seventy-three (97.3%) had their FLT-PET at baseline, 69 (92%) after 1 cycle of chemotherapy, and 66 (88%) at the end of the 1st line treatment. By IWC, 50 (66.7%) patients achieved complete remission (CR) on FLT1 and 56 (74.7%) had CR on FLTE. Positive predictive values (PPV) of residual uptake on FLT1 and FLTE for relapse or disease progression were 83.3% (95%CI 57.7–95.6) and 80% (95%CI 44.2–96.5), respectively. Negative predictive values (NPV) of them were 88% (95%CI 75.0–95.0) and 82.1% (95%CI 69.2–90.7). Sensitivity and specificity were 71.4% (47.7–87.8) and 93.6% (81.4–98.3) for FLT1 and 44.4% (22.4–67.8) and 95.8% (84.6–99.3) for FLTE, respectively. Complete disappearance of uptake on FLT1 was significantly associated with better PFS compared to residual uptake on FLT1 (3yr-PFS rates, 87.5% and 12.2%, p<0.001). Three-year OS rates according to CR achievement on FLT1 were 96.0% and 27.8%, significantly lower in patients with residual disease after 1 cycle of chemotherapy (p<0.001). SUVmax of FLT0 correlated with LDH level significantly (p=0.044), but not with age (p=0.214), Ki-67 index (p=0.073), IPI score (p=0.270), and Ann Arbor stage (p=0.089). SUVmax of FLT0 were not associated with survival outcomes, however, residual SUVmax of FLT1 reflecting early response to treatment was significantly associated with poor survival outcome (PFS, HR 1.29, 95%CI 1.14–1.47; OS, HR 1.27, 95%CI 1.08–1.49). In multivariate analysis, SUVmax of FLT1 remained as an independent predictive factor for PFS (HR 1.63, 95%CI 1.25–2.13) and for OS (HR 1.89, 95%CI 1.38–2.58). Residual SUVmax of FLTE also revealed to be significantly associated with PFS (HR 1.43, 95%CI 1.05–1.94) and OS (HR 1.59, 95%CI 1.12–2.26) in the same multivariate model. Conclusion Response assessment in cooperation with FLT-PET provided accurate prediction for clinical outcome including PFS and OS in patients with NHL. Especially, early FLT-PET result after 1 cycle of chemotherapy was an independent predictive factor for survival as well as relapse or disease progression, with comparable performance with end-of-treatment FLT-PET. Disclosures: No relevant conflicts of interest to declare.
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Cheng, Hao, Chen Lin, Liangjie Wang, Junfeng Xiong, Lingyun Peng, and Chenxi Zhu. "The Influence of Different Forest Characteristics on Non-point Source Pollution: A Case Study at Chaohu Basin, China." International Journal of Environmental Research and Public Health 17, no. 5 (March 10, 2020): 1790. http://dx.doi.org/10.3390/ijerph17051790.
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Forestland is a key land use/land cover (LULC) type that affects nonpoint source (NPS) pollution, and has great impacts on the spatiotemporal features of watershed NPS pollution. In this study, the forestland characteristics of the Chaohu Basin, China, were quantitatively represented using forestland types (FLTs), watershed forest coverage (WFC) and forest distance from the river (DFR). To clarify the impact of forests on NPS pollution, the relationship between forestland characteristics and watershed nutrient outputs (TN and TP) was explored on a monthly scale using SWAT (Soil and Water Assessment Tool) and the period simulation was 2008–2016. The results showed that: (1) the TN and TP showed similar output characteristics and the rainy season was the peak period of nitrogen and phosphorus output. (2) Among the forestland characteristics of forestland types, watershed forest coverage and forest distance from the river, watershed forest coverage and forest distance from the river had greater effects than forestland types on the control of watershed nutrient outputs (TN and TP). (3) In different forestland types, the watershed nutrient outputs intensity remained at the lowest level when the FLTs was mixed forest, with a TN output of 1244.73kg/km2 and TP output of 341.39 kg/km2. (4) The watershed nutrient outputs and watershed forest coverage were negatively correlated, with the highest watershed forest coverage (over 75%) reducing the TN outputs by 56.69% and the TP outputs by 53.46% compared to the lowest watershed forest coverage (below 25%), it showed that in areas with high forest land coverage, the non-point source pollution load in the watershed is smaller than in other areas. (5) forest distance from the river had an uncertain effect on the TN and TP output of the basin, the forestland itself is a source of pollution, but it also has the function of intercepting pollution movement; the forest distance from the river in the range of 500–1000 m had the lowest NPS pollution. Considering the different forest characteristics and topographical factors, an optimal allocation mode of differentiated forest land was proposed, these suggestions will provide a scheme for surface source pollution prevention and control in the basin. This research gap is the basis of real forestland optimization. We may optimize the forestland layout for NPS pollution prevention and control by clarifying the internal mechanism.
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Nguyen, Linh Anh. "Computing crisp simulations for fuzzy labeled transition systems." Journal of Intelligent & Fuzzy Systems 42, no. 4 (March 4, 2022): 3067–78. http://dx.doi.org/10.3233/jifs-210792.
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The problem of checking whether a state in a finite fuzzy labeled transition system (FLTS) crisply simulates another is one of the fundamental problems of the theory of FLTSs. This problem is of the same nature as computing the largest crisp simulation between two finite FLTSs. A naive approach to the latter problem is to crisp the given FLTSs and then apply one of the currently known best methods to the obtained crisp labeled transition systems. The complexity of the resulting algorithms is of order O (l (m + n) n), where l is the number of fuzzy values occurring in the specification of the input FLTSs, m is the number of transitions and n is the number of states of the input FLTSs. In the worst case, l can be m + n and O (l (m + n) n) is the same as O ((m + n) 2n). In this article, we design an efficient algorithm with the complexity O ((m + n) n) for computing the largest crisp simulation between two finite FLTSs. This gives a significant improvement. We also adapt our algorithm to computing the largest crisp simulation between two finite fuzzy automata.
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Viezzer, Cristina, Roberto Revoltella, and Lucia Celotti. "The Capacity of Murine Epithelial Cell Lines with Different Degrees of Malignant Transformation to Metabolise Benzo[a]pyrene." Alternatives to Laboratory Animals 24, no. 4 (August 1996): 541–46. http://dx.doi.org/10.1177/026119299602400413.
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Cultures of three murine cell lines derived from fetal mouse liver (FL, FLT3 and FLT5) were treated with benzo[a]pyrene to evaluate their ability to activate promutagens. DNA adducts were detected in all three cell lines when they were treated with the major active metabolite of benzo[a]pyrene, benzo[a]pyrene diolepoxide. DNA adducts were also produced in FL and FLT3 cells when they were treated with the promutagen, benzo[a]pyrene, while treatment of FLT5 cells resulted in very few DNA adducts. In treated FL and FLT3 cells, the most evident adduct spot detected showed a chromatographic position similar to that of the main adduct formed in cells treated with (±)-r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydro-benzo[a]pyrene.
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Purnomo, Muhammad Ridwan Andi. "New Product Pricing Using Fuzzy Logic Type-2." Advanced Materials Research 1125 (October 2015): 630–34. http://dx.doi.org/10.4028/www.scientific.net/amr.1125.630.
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The process of pricing a new product is quite challenging since it involves several factors which are blended with uncertainties caused by dynamic condition. The decision of product pricing will effect to the competition ability in the market. However, since the factors are blended with uncertainties, it is necessary to develop a system that could model the uncertainties for obtaining reasonable price. This study focuses on modelling the uncertainties using Fuzzy Logic Type-2 (FLT2). The reason of the use of FLT2 instead of FLT1 is because of the ability of FLT2 to cope with uncertainties better compared to the FLT1. This study refers to a previous study that was conducted by Haji and Assadi in 2009 in determining the factors that affect to a new product pricing. A new important factor that has not been considered in such study has been added in this study, which is product warranty. The result shows that the proposed FLT2 able to model uncertainties in product pricing and resulting reasonable price for a new product.
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Zarrinkar, Patrick P., Robert C. Armstrong, Ruwanthi N. Gunawardane, Joyce James, Mazen W. Karaman, and Shripad S. Bhagwat. "AC220 Is a Uniquely Potent and Selective Second-Generation FLT3 Inhibitor." Blood 112, no. 11 (November 16, 2008): 859. http://dx.doi.org/10.1182/blood.v112.11.859.859.
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Abstract Activating mutations in the receptor tyrosine kinase FLT3 are present in up to approximately 30 % of acute myeloid leukemia (AML) patients, implicating FLT3 as a potential target for kinase inhibitor therapy. While several compounds have been evaluated in the clinic as FLT3 inhibitors, including CEP-701 (lestaurtinib), PKC-412 (midostaurin), MLN-518 (tandutinib) and most recently sorafenib, none of these was originally developed as a FLT3 inhibitor. We report here the characterization of AC220, a novel compound that has been expressly optimized as a selective FLT3 inhibitor. We demonstrate that this second generation FLT3 inhibitor has a unique combination of high potency, exceptional selectivity, bioavailability, and pharmacokinetic properties compatible with once a day oral dosing. In an in vitro binding assay AC220 interacted with FLT3 with high affinity (Kd = 1.6 nM). In the FLT3 dependent human leukemia cell line MV4-11, which harbors a homozygous activating FLT3 internal tandem duplication (ITD) mutation, AC220 inhibited FLT3 autophosphorylation and cellular proliferation with subnanomolar potency. Inhibition of proliferation of a FLT3 independent cell line was several hundred-fold less potent, demonstrating cellular selectivity for FLT3. A biochemical screen against a panel of 402 kinase assays representing almost 80 % of human protein kinases revealed a highly focused and selective interaction pattern. The only targets with affinity for AC220 within 10-fold that for FLT3 were closely related class III receptor tyrosine kinases (KIT, PDGFR, RET, CSF1R), and the only targets with affinity within 100-fold that for FLT3 were four additional receptor tyrosine kinases (FLT1, FLT4, DDR1, VEGFR2). When orally administered to mice at a dose of 10 mg/kg, AC220 achieved a peak plasma concentration (Cmax) of 3.8 μM (2,100 ng/mL) within two hours of dosing. When corrected for plasma protein binding, the concentration of AC220 in plasma remained above the cellular IC50 for FLT3 inhibition 24 hours after dosing. Total exposure (AUC0-24 h) as well as Cmax increased proportionally with the administered dose from 0.1 to approximately 30 mg/kg. At higher doses, both Cmax and AUC0-24 h continued to increase, approaching a plateau above 100 mg/kg. In a FLT3-ITD-dependent MV4-11 tumor xenograft model, AC220 showed substantial, dose dependent efficacy when dosed at 1, 3 and 10 mg/kg orally once a day for 28 days. Tumors regressed at 3 and 10 mg/kg, and remained static at 1 mg/kg. In a follow-on study at the 10 mg/kg oral dose, tumor size was monitored for an additional 60 days after dosing was discontinued. By the end of the study eight complete responses and two partial responses were observed in the ten animals treated with AC220. AC220 also had activity in a leukemia tumor model at doses as low as 1 mg/kg given orally once a day. A direct comparison of AC220 with the first generation FLT3 inhibitors CEP-701, MLN-518, PKC-412, sorafenib and sunitinib revealed that the combination of potency, selectivity and pharmacokinetic properties is unique to AC220. AC220 is a second generation FLT3 inhibitor that has been explicitly optimized for the combination of properties believed to be required for the successful treatment of FLT3-dependent AML, and specifically to test the hypothesis that selective FLT3 inhibition will result in clinical benefit. AC220 is currently being evaluated in a phase I clinical trial in relapsed or refractory AML patients.
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Kaipainen, A., J. Korhonen, K. Pajusola, O. Aprelikova, M. G. Persico, B. I. Terman, and K. Alitalo. "The related FLT4, FLT1, and KDR receptor tyrosine kinases show distinct expression patterns in human fetal endothelial cells." Journal of Experimental Medicine 178, no. 6 (December 1, 1993): 2077–88. http://dx.doi.org/10.1084/jem.178.6.2077.
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The growth factor receptors expressed on endothelial cells are of special interest because of their potential to program endothelial cell growth and differentiation during development and neovascularization in various pathological states, such as wound healing and angiogenesis associated with tumorigenesis. Vascular endothelial growth factor ([VEGF] also known as vascular permeability factor) is a potent mitogen and permeability factor, which has been suggested to play a role in embryonic and tumor angiogenesis. The newly cloned FLT4 receptor tyrosine kinase gene encodes a protein related to the VEGF receptors FLT1 and KDR/FLK-1. We have here studied the expression of FLT4 and the other two members of this receptor family in human fetal tissues by Northern and in situ hybridization. These results were also compared with the sites of expression of VEGF and the related placenta growth factor (PlGF). Our results reveal FLT4 mRNA expression in vascular endothelial cells in developing vessels of several organs. A comparison of FLT4, FLT1 and KDR/FLK-1 receptor mRNA signals shows overlapping, but distinct expression patterns in the tissues studied. Certain endothelia lack one or two of the three receptor mRNAs. These data suggest that the receptor tyrosine kinases encoded by the FLT gene family may have distinct functions in the regulation of the growth/differentiation of blood vessels.
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Aydin, Selami, and Ozgehan Ustuk. "The Foreign Language Teaching Anxiety Scale: Preliminary Tests of Validity and Reliability." Journal of Language and Education 6, no. 2 (June 30, 2020): 44–55. http://dx.doi.org/10.17323/jle.2020.10083.
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Although anxiety in the foreign language learning context has been studied extensively, the anxiety experienced by foreign language teachers, who are important stakeholders of classroom contexts and language learners themselves, seems to be overlooked. While research mainly focuses on foreign language anxiety in a learning context, there is not sufficient research to contextualize foreign language teaching anxiety (FLTA). In addition, in the current literature, few studies were performed to measure FLTA. In light of this, this study aims to present the preliminary results of the validity and reliability of the Foreign Language Teaching Anxiety Scale (FLTAS). A background questionnaire and the FLTAS were administered to 100 senior pre-service teachers of English as a foreign language (EFL), before performing Cronbach’s Alpha and exploratory factor analysis. The findings showed that the scale obtains a high reliability coefficient and internal consistency in a five-factor solution. The study ends with recommendations for further research.
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Н.А., Ашимова,, Уалиева, А.Е., Гайнутдин, А.Е., Майкенова, А.М., Абдыкадыров, М.К., Манарбекова, М.А., Ескендир, Д.Т., Ерланова, Е.Е., and Нерсесов, А.В. "LIVER DISORDERS IN PATIENT WITH SARS-COV-2 INFECTION." Farmaciâ Kazahstana, no. 6 (December 30, 2022): 48–53. http://dx.doi.org/10.53511/pharmkaz.2022.60.62.007.
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Факторы поражения печени при ассоциированной с SARS-COV-2 пневмонии. Цель: провести сравнительную характеристику пациентов с SARS-COV-2-ассоциированной пневмонией (SAP) с поражением печени и без него. Материалы и методы: Анализ данных 40 пациентов с SAP с измененными функциональными пробами печени (ФПП) (основная группа, ОГ) и 40 пациентов аналогичного пола и возраста с SAP без измененных ФПП (контрольная группа, КГ), находившихся на лечении в филиале ГКИБ г. Алматы, с августа месяца по ноябрь 2021 гг. Проанализированы лабораторные исследования: рутинные анализы, ФПП, компьютерная томография органов грудной клетки (КТ ОГК), УЗИ органов брюшной полости (ОБП), а также оценка сопутствующих заболеваний и применяемых лекарственных препаратов. Результаты: Обследованы 80 пациентов, из них 48 (60%) составляли мужчины, 32 (40%) женщины, средний возраст составил - 59,6±5 лет. В основной группе среднее значение АЛТ достигло до 93,7 МЕ/мл, АСТ - 74,4 МЕ/мл. По данным КТ ОГК в основной группе степени поражение: КТ2 выявлена у 17 , КТ3 - у 18, КТ4 - у 5 больных, в контрольной группе КТ2 - у 19, КТ3- у17, КТ4- у 2 больных. Среднее значение СРБ составило 67,6 в ОГ и 29,9 мг/л в КГ (р <0,05), СОЭ - 21,4 и 20,8 мм/час, уровень Д-димера - 3320 и 1650 нг/мл соответственно (р <0,05). Среди сопутствующих заболеваний выявленных в ОГ и КГ, были ишемическая болезнь сердца (ИБС) (15; 37,5% и 7; 17,5%), хроническая сердечная недостаточность (ХСН) (8; 20% и 6; 15%), артериальная гипертензия (АГ) (26; 65% и 10; 25%), сахарный диабет (СД) (8; 20% и 3; 7,5%), ожирение (10; 25% и 6; 15%) соответственно. Больные ОГ и КГ получали ибупрофен (1200 мг/сут; 35; 87,5% и 800 мг/сут; 26; 65,0%) (р <0,05) , гепарин (38; 95% и 10; 25 %) (р <0,05), итраканазол (26; 65% и 22; 55%), левофлоксацин (10; 25% и 2; 5%), меропенем (5; 12,5% и 0), ремдесивир (12; 37,5% и 2; 5,0%). Средняя продолжительность госпитализации составила 11 дней в ОГ и 6 дней - в КГ (р <0,05). Выводы: Цитолиз коррелировал с тяжестью SAP, наличием сопутствующей патологии такие как: ИБС, ХСН, АГ, СД, ожирения и более частым применением высоких дозах ибупрофена, гепарина, ремдесивира и антибиотиков. Factors of liver damage in SARS-COV-2 associated pneumonia. Objective: Comparative characteristics of patients with SARS-COV-2 associated pneumonia (SAP) with and without liver damage. Materials and methods: 40 patients with SAP with altered functional liver tests (FLTs) (main group, MG) and 40 patients of the same sex and age with SAP without altered FLT (control group, CG), treated in the COVID department of Almaty infectious diseases hospital, were examined. Chest CT, comprehensive metabolic panel, FLTs, abdominal ultrasound and medication lists were analyzed. Results: The median age was 59.6±5 years, 48 (60%) were men, 32 (40%) - women. The median ALT and AST in the MG were 93.7 and 74.4 IU/ml. Lung damage of CT2 degree was revealed in 17, CT3 - in 18, CT4 - in 5 patients in the MG, and in 19, 17 and 2 patients in the CG respectively. The median CRP was 67.6 in the MG and 29,9 mg/l in the CG (p <0.05), ESR - 21.4 and 20,8 mm/hour, D-dimer - 3320 and 1650 ng/ml respectively (p<0.05). Concomitant diseases revealed in the MG and CG were ischemic heart disease (15; 37.5% and 7; 17.5%), chronic heart failure (8; 20% and 6; 15%), arterial hypertension (26 ; 65% and 10; 25%), diabetes mellitus (8; 20% and 3; 7.5%), obesity (10; 25% and 6; 15%) respectively. Patients in the MG and CG received ibuprofen (1200 mg/day; 35; 87.5% and 800 mg/day; 35; 87.5%), heparin (38; 95% and 10; 25%), itracanazole (26; 65 % and 22; 55%), levofloxacin (10; 25% and 2; 5%), meropenem (5; 12,5% and 0), remdesivir (12; 37.5% and 2; 5.0%). The average duration of hospitalization was 11 days in the MG and 9 -in the CG (p <0.05). Conclusion: Cytolysis was correlated with SAP severity, presence of concomitant ischemic heart disease, chronic heart failure, diabetes mellitus, hypertension, obesity, and more often use of ibuprofen in higher doses as well as heparin, remdesivir and antibiotics.
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Gomez-Marin, Beatriz, Francisco Gomez-Delgado, Javier Lopez-Moreno, Juan F. Alcala-Diaz, Rosa Jimenez-Lucena, Jose D. Torres-Peña, Antonio Garcia-Rios, et al. "Long-term consumption of a Mediterranean diet improves postprandial lipemia in patients with type 2 diabetes: the Cordioprev randomized trial." American Journal of Clinical Nutrition 108, no. 5 (November 1, 2018): 963–70. http://dx.doi.org/10.1093/ajcn/nqy144.
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ABSTRACT Background Patients with type 2 diabetes (T2D) have an elevated postprandial lipemia (PPL) that has been associated with increased cardiovascular risk. Objective We aimed to analyze whether the long-term consumption of 2 healthy dietary patterns is associated with an improvement in PPL and remnant cholesterol (RC) concentrations in patients with T2D. Design We selected patients from the Cordioprev study who underwent oral fat load tests (FLTs) at baseline and the 3-y follow-up (241 patients with and 316 patients without T2D). Subjects were randomly assigned to receive either a Mediterranean diet rich in olive oil (MedDiet; 35% of calories from fat [22% monounsaturated fatty acids (MUFAs)] and 50% from carbohydrates) or a low-fat (LF) diet [<30% fat (12–14% MUFAs) and 55% of calories from carbohydrates]. Lipids were measured in serial bloods drawn at 0, 1, 2, 3, and 4 h after the FLT. Results After 3 y of dietary intervention, patients with T2D showed an improvement in their PPL measured as postprandial triglycerides (TGs) (P < 0.0001), TG area under the curve (AUC) (P = 0.001), and TG-rich lipoproteins (TRLs-TG; P = 0.001) compared with baseline. Subgroup analysis, based on the type of dietary intervention, showed that those T2D patients randomly assigned to the MedDiet presented a reduction in the TG AUC of 17.3% compared with baseline (P = 0.003). However, there were no differences for T2D patients randomly assigned to the LF diet (P > 0.05) or in patients without T2D (P > 0.05) regardless of the dietary intervention. In addition, the MedDiet induced a significant improvement in the RC AUC in patients with T2D (P = 0.04). However, there was no significant improvement in those following the LF diet. Conclusions Our findings show that the long-term consumption of a MedDiet rich in olive oil improves PPL and RC concentrations mainly in patients with T2D. This trial was registered at clinicaltrials.gov as NCT00924937.
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Li, Qi, Zhilong Xie, and Guofang Zeng. "The Influence of Teaching Practicum on Foreign Language Teaching Anxiety Among Pre-Service EFL Teachers." SAGE Open 13, no. 1 (January 2023): 215824402211490. http://dx.doi.org/10.1177/21582440221149005.
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Most previous studies focused on foreign language learning anxiety, whereas relatively few have ever examined the foreign language teaching anxiety (FLTA), particularly experienced by pre-service EFL (English as a Foreign Language) teachers. By administering the “Foreign Language Teaching Anxiety Scale” (FLTAS) and a semi-structured interview, the current study examined whether the EFL teaching practicum had an influence on FLTA by comparing the differences of FLTA between pre-service EFL teachers who had 4 months of practicum experience and those without the practicum, and explored the potential factors contributing to FLTA. Results of descriptive analyses showed that overall the pre-service teachers had a relatively high level of FLTA. Results of independent sample t-test analyses indicated that the practicum group had significantly higher FLTA compared to the non-practicum group. Furthermore, within the two groups, female teachers consistently showed higher FLTA than the male teachers. Results of the interview content analyses revealed that anxiety-provoking factors primarily originated from fear of negative evaluation, low self-perception of language proficiency, and teaching inexperience. The findings of the current study provide insights of anxiety research in EFL context and implications for teachers to better reduce anxiety in English teaching practice.
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Chen, Yun, Yao Guo, Wanting Ho, and Zhizhuang Joe. "Identification and Characterization Of a Potent FLT3 Inhibitor." Blood 122, no. 21 (November 15, 2013): 5027. http://dx.doi.org/10.1182/blood.v122.21.5027.5027.
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Abstract Acute myeloid leukemia (AML) is a malignant myeloid disorder for which there is no effective treatment. Gain-of-function mutations of tyrosine kinase FLT3 are frequently found in AML patients. This makes FLT3 an attractive therapeutic target. Currently, several potent FLT3 inhibitors have been developed. However, their clinical efficacy is limited largely due to their poor effectiveness toward the FLT3-D835 mutants which are often present in AML or acquired after treatment of FLT3-ITD-positive AML with tyrosine kinase inhibitors. Needless to say, more potent FLT3 inhibitors targeting both FLT-ITD and FLT3-D835 mutants are needed. In addition, combinations of tyrosine kinase inhibitors with drugs targeting other signaling pathways represent a new trend in anti-cancer drug development. To establish an effective kinase assay for FLT3 inhibitor screening, we generated a protein substrate designated GST-FLT3S which was expressed in E. coli cells as a glutathione S-transferase fusion protein. The protein substrate together with recombinant proteins containing the catalytic domain of wild type and mutant forms of FLT3 expressed in baculovirus was used in biochemical screening of inhibitors. Several potent inhibitors were obtained. Importantly, one of the inhibitors with an oxindole core structure inhibited FLT3 and D835 FLT3 mutants equally well with nanomolar IC50 values. We further analyzed the potency of the inhibitor by performing cell-based assays. The cells used included FLT3-ITD-positive cell line MV-4-11 and an EPO-dependent erythroleukemia cell line transformed by retrovirus mediated expressions of FLT3-ITD and FLT3-D835 mutants. At nanomolar concentrations, the inhibitor blocked growth factor signaling and effectively caused apoptosis and cell cycle arrest. It showed significant advantage over the current available FLT3 inhibitor, sorafenib. Loss-of-function mutations of tumor suppressor p53 are common in solid tumors but relatively rare in AML although its expression is often suppressed. This makes p53 a potential target for anti-AML drug development. We employed MDM2 inhibitor nutlin-3 which blocks the degradation of p53. Importantly, at sub-nanomolar concentrations, FLT3 inhibitors and nutlin-3 synergistically inhibited growth of cells containing FLT3-ITD or FLT3-D835 mutants. Altogether, we developed an effective substrate for screening of FLT3 inhibitors and identified one compound with high potency toward both FLT3-ITD and FLT3-D835. We further demonstrated that targeting FLT3 and p53 simultaneously greatly increases drug potency. Disclosures: No relevant conflicts of interest to declare.
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Lim, Sung Hee, Sun-Young Kim, Kyung Kim, Hyojin Jang, Soomin Ahn, Kyoung-Mee Kim, Nayoung K. D. Kim, et al. "The implication of FLT3 amplification for FLT targeted therapeutics in solid tumors." Oncotarget 8, no. 2 (November 29, 2016): 3237–45. http://dx.doi.org/10.18632/oncotarget.13700.
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De Alarcon, Pedro, Manu Gnanamony, and Jessica Garcia. "An in Vitro Study on the Role of Angiogenesis in Iron Deficiency Induced Reactive Thrombocytosis." Blood 132, Supplement 1 (November 29, 2018): 2450. http://dx.doi.org/10.1182/blood-2018-99-115378.
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Abstract Introduction: Iron deficiency (ID) is one of the recognized causes of reactive thrombocytosis in children. Factors that are commonly associated with megakaryopoiesis such as thrombopoietin (TPO), interleukin 6 (IL-6) and IL-11 are not altered in patients with iron deficiency and thrombocytosis suggesting the role of alternate mechanisms in controlling this process. We have previously shown using an ID rat model that ID increased the number of megakaryocytes in the bone marrow. We have also shown an increase in VEGFR (FLT1) and CXCR4 staining in bone marrow slides of ID rats. This data suggests that angiogenesis plays a vital role in the development of reactive thrombocytosis in response to ID. In this report, we have expanded our study to identify specific angiogenic signaling molecules associated with ID and used functional assays to validate it. Methods: For this study, we used the megakaryoblast cell line MEG-01 as an in vitro model of megakaryopoiesis. MEG-01 cells were adapted to grow in chemically defined serum free medium containing iron (iron replete media). For iron deficiency, serum free iron free media was mixed with iron replete media at a 1% v/v concentration (iron deplete media). For our experiments, MEG-01 cells were grown in both iron replete and depleted media for 7 days. Cell viability was measured using the trypan blue exclusion assay. Messenger-RNA expression of iron-related markers (TFR1, TFR2, FLT1, FLT3, FTL, FTH1, TF, HMOX1 and HMOX2) and angiogenic markers (VEGFA, VEGFB, VEGFC, PDGF, ANGPTL1, ANGPTL2, FGF2) was studied using real time PCR. We performed functional validation of angiogenesis with an in vitro tube formation assay using human umbilical vein endothelial (HUVEC) cells. For statistical analysis of the data we performed the t test using graph pad prism software and we considered p<0.05 as statistically significant. Results: In low iron conditions, MEG-01 cells showed a significant increase in FLT1 (4 fold) and FLT3 (3 fold) expression using real time PCR (p<0.001). Iron deficiency also induced a 2 fold increase in the mRNA expression of angiogenic molecules VEGFB, VEGFC, FGF2 and PDGFA (p<0.001). Using the tube formation assay, we also show that conditioned media collected from iron deficient MEG-01 cells induced increased vessel formation in endothelial cells. Conclusion: In this study, we were able to validate our earlier in vivo findings on iron deficiency induced reactive thrombocytosis. We show that cells adapt to low iron conditions by upregulating FLT1, FLT3 and FTL. We also show that several markers in the angiogenesis pathway like VEGFB, VEGFC, FGF2 and PDGFA are upregulated in response to iron deficiency. We were also able to show that an increase in these angiogenic molecules induced increased vessel formation in endothelial cells. This report, along with our previous findings, points to the importance of the angiogenic pathway in reactive thrombocytosis induced by iron deficiency. Disclosures No relevant conflicts of interest to declare.
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Shuwen, Han, Yang Xi, Da Miao, Xu Jiamin, Zhuang Jing, and Gao Weili. "Nine Genes Mediate the Therapeutic Effects of Iodine-131 Radiotherapy in Thyroid Carcinoma Patients." Disease Markers 2020 (June 17, 2020): 1–13. http://dx.doi.org/10.1155/2020/9369341.
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Background. Thyroid carcinoma (THCA) is one of the most common malignancies of the endocrine system, which is usually treated by surgery combined with iodine-131 (I131) radiotherapy. Aims. This study is aimed at exploring the potential targets of I131 radiotherapy in THCA. Methods. The RNA-sequencing data of THCA in The Cancer Genome Atlas database (including 568 THCA samples) was downloaded. The differentially expressed genes (DEGs) between the tumour samples whether or not subjected to I131 radiotherapy were identified using edgeR package. Using the WGCNA package, the module that was relevant with I131 radiotherapy was selected. The intersection genes of the hub module nodes and the DEGs were obtained as hub genes, followed by the function and pathway enrichment analyses using the clusterProfiler package. Moreover, the protein-protein interaction (PPI) network for the hub genes was constructed using Cytoscape software. In addition, more important hub genes were analysed with function mining using the GenCLiP2 online tool. The qPCR analysis was used to verify the mRNA expression of more important hub genes in THCA tissues. Results. There were 500 DEGs (167 upregulated and 333 downregulated) between the two groups. WGCNA analysis showed that the green module (428 nodes) exhibited the most significant correlation with I131 radiotherapy. A PPI network was built after the identification of 53 hub genes. In the PPI network, CDH5, KDR, CD34, FLT4, EMCN, FLT1, ROBO4, PTPRB, and CD93 exhibited higher degrees, which were mainly implicated in the vascular function. The relative expression of nine mRNAs in the THCA tissues treated with I131 was lower. Conclusion. I131 radiotherapy might exert therapeutic effects by targeting CDH5, KDR, CD34, FLT4, EMCN, FLT1, ROBO4, PTPRB, and CD93 in THCA patients.
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Ryu, Hwani, Hyun-Kyung Choi, Hyo Jeong Kim, Ah-Young Kim, Jie-Young Song, Sang-Gu Hwang, Jae-Sung Kim, et al. "Antitumor Activity of a Novel Tyrosine Kinase Inhibitor AIU2001 Due to Abrogation of the DNA Damage Repair in Non-Small Cell Lung Cancer Cells." International Journal of Molecular Sciences 20, no. 19 (September 24, 2019): 4728. http://dx.doi.org/10.3390/ijms20194728.
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Class III receptor tyrosine kinase (RTK) inhibitors targeting mainly FLT3 or c-KIT have not been well studied in lung cancer. To identify a small molecule potentially targeting class III RTK, we synthesized novel small molecule compounds and identified 5-(4-bromophenyl)-N-(naphthalen-1-yl) oxazol-2-amine (AIU2001) as a novel class III RKT inhibitor. In an in vitro kinase profiling assay, AIU2001 inhibited the activities of FLT3, mutated FLT3, FLT4, and c-KIT of class III RTK, and the proliferation of NSCLC cells in vitro and in vivo. AIU2001 induced DNA damage, reactive oxygen species (ROS) generation, and cell cycle arrest in the G2/M phase. Furthermore, AIU2001 suppressed the DNA damage repair genes, resulting in the ‘BRCAness’/‘DNA-PKness’ phenotype. The mRNA expression level of STAT5 was downregulated by AIU2001 treatment and knockdown of STAT5 inhibited the DNA repair genes. Our results show that compared to either drug alone, the combination of AIU2001 with a poly (ADP-ribose) polymerase (PARP) inhibitor olaparib or irradiation showed synergistic efficacy in H1299 and A549 cells. Hence, our findings demonstrate that AIU2001 is a candidate therapeutic agent for NSCLC and combination therapies with AIU2001 and a PARP inhibitor or radiotherapy may be used to increase the therapeutic efficacy of AIU2001 due to inhibition of DNA damage repair.
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Willén, Torbjörn, and Eva Willén. "Byssus flos-aquae L." Algological Studies/Archiv für Hydrobiologie, Supplement Volumes 94 (September 16, 1999): 377–82. http://dx.doi.org/10.1127/algol_stud/94/1999/377.
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Dicker, Frank, Claudia Schoch, Torsten Haferlach, Wolfgang Kern, and Susanne Schnittger. "Trisomy 13 Defines a Subgroup of Myeloid Malignancies with an Extremely High Frequency of AML1 Gene Mutations and Newly Defined VEGFR-1 Mutations." Blood 108, no. 11 (November 16, 2006): 562. http://dx.doi.org/10.1182/blood.v108.11.562.562.
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Abstract Somatic mutations in the DNA-binding domain, the socalled Runt domain, of the AML1 gene have been identified to occur in AML with the highest incidence in the AML M0 subgroup as well as in myeloid malignancies displaying acquired trisomy 21. To characterize our own cohort of AML M0 patients (n = 83) for AML1 mutations, we analyzed AML1 transcripts by a combination of denaturing high performance liquid chromatography (dHPLC) and direct sequencing. In this cohort 37 cases (45%) carried an AML1 mutation. The AML1 mutated cases showed a remarkable high incidence of trisomy 13 (14/37 pts; 38%). In contrast to previous data only one case had a trisomy 21 (3%). The group without AML1 mutations (n = 46) included only one case with trisomy 13 (2%) and no trisomy 21. To extent this observation beyond the AML M0 subtype, we analyzed 14 additional trisomy 13 cases from other FAB subtypes. 79% (11/14) of the non-AML M0 trisomy 13 cases displayed an AML1 mutation. To evaluate the role of trisomy 13 in the context of AML1 mutations we looked for tyrosine kinase receptors on chromosome 13, which might play a cooperative role in concert with mutated AML1. The fms-related tyrosine kinase 3 (FLT3) and the fms-related tyrosine kinase 1 (FLT1, VEGFR-1) were identified as candidates on chromosome 13. In the AML M0 group 70 of 83 cases were analyzed for activating FLT3 length mutations (FLT3-LM) and/or activating point mutations in the tyrosine kinase domain (FLT3-TKD). 12 cases (18%) were positive for such activating mutations (9 FLT3-LM, 2 FLT3-TKD, 1 FLT3-LM+TKD) with 4 of these cases having an AML1 mutation in parallel. However, none of the 14 analyzed M0 cases with trisomy 13 were affected. FLT3 overexpression has also been suspected as a mechanism for constitutive FLT3 activation. Therefore, we hypothesized that trisomy 13 by means of a gene dosage effect might contribute to an increase in FLT3 expression. When we compared FLT3 RNA expression levels as determined by Affymetrix U133 Plus 2.0 gene expression arrays between AML M0 trisomy 13 samples (n = 9) versus other AML M0 samples (n = 19), we observed a significantly higher FLT3 expression in the trisomy 13 cases (p = 0.048, t-test). In the group of non M0 cases with trisomy 13 (n = 14) 3 cases (21%) had activating FLT3 mutations (2 FLT3-LM, 1 FLT3-TKD). Only 1 of these cases carried an AML1 mutation in parallel. In the trisomy 13 group we detected novel mutations in VEGFR-1 in 3 of 21 cases (14.2%). All three cases had an M0 phenotype as well as an AML1 mutation. Thus, 3 of 5 M0/trisomy 13 cases were positive for this new kind of mutation. In conclusion we confirm the high incidence of AML1 somatic mutations in the AML M0 subgroup (45%). We identified a new entity of AML characterized by trisomy 13 with an incidence of AML1 mutations of about 80%. We suggest that trisomy 13 might be a mechanism for the amplification of FLT3 transcript levels for the activation of FLT3 signaling which collaborates with AML1 somatic mutations in leukemogenesis. We identified a new kind of mutation in the tyrosine kinase domain of VEGFR-1 which might be a specific cooperating mutation for AML1 mutation.
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Paiola, Matthieu, Sobhan Roy, Siyuan Ma, Charkira Patrick, Marin Pavelka, Erin J. Adams, and Jacques Robert. "Flt3 and its ligand as an ancient regulators of dendritic cells: evidence in the amphibian Xenopus laevis." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 124.11. http://dx.doi.org/10.4049/jimmunol.208.supp.124.11.
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Abstract The evolution of hematopoietic-derived dendritic cells that are so critical for T cell activation is still poorely understood. In mammals, fms related tyrosine kinase 3 (Flt3) and its ligand (Flt3lg) are important regulator of dendritic cell homeostasis. Flt3 and Flt3lg co-evolution was investigated in all jawed vertebrates with special focus in an ancient allotetraploid tetrapod Xenopus laevis. flt3 synteny and predicted amino-acid structure are conserved in all jawed vertebrate including in the duplicated S and L homeologous chromosomes of X. laevis. Flt3lg gene is conserved among X. laevis homeologous chromosomes and most jaw vertebrates with the exception of ray-finned fish. Amino acid comparison, 3D structure modelling and tissue distribution suggest a subfunctionalization of Flt3 and Flt3lg homeologs. Tagged recombinant Flt3lg.S and Flt3lg.L were produced to investigate cell surface expression of Flt3s. Both Flt3lg.S and L specifically stain a splenic population of leukocyte MHC class IIhigh+ and CD8+ phenotypically similar to the recently described X. laevis dual follicular/dendritic-like XL cells. Our results indicate that Flt3lg.S and L are both involved in XL cell homeostasis and that XL cells have hematopoietic origin. In X. laevis, the non-polymorphic MHC class I-like XNC4 restricting innate-like T cells is critical for tadpoles’ resistance against the non-TB mycobacteria M.marinum. Preliminary experiments indicate that XL cells are XNC4+ and are being recruited to the infection site together with XNC4-restricted T cells. This suggests that XL cells are involved in T cell activation, which is consistent with the an ancestral dual follicular/dendritic cell function of XL cells. Supported by NIH (R24-AI059830 – R21-AI139718), NSF (1754274) and 2021 Rochester Vaccine Fellowship
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Fiskus, Warren, Catherine C. Smith, Jacqueline Smith, Scott C. Wise, Elisabeth Lasater, Lauren E. Damon, Sara Salerno, et al. "Activity of Allosteric, Switch-Pocket, ABL/FLT3 Kinase Inhibitor DCC2036 Against Cultured and Primary AML Progenitors with FLT-ITD or FLT3 Kinase Domain Mutations." Blood 118, no. 21 (November 18, 2011): 2611. http://dx.doi.org/10.1182/blood.v118.21.2611.2611.
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Abstract Abstract 2611 Approximately 30% of acute myeloid leukemia (AML) patients have activating mutations in FLT3, commonly internal tandem duplication (ITD) mutations, which are associated with poor survival. Although FLT3 tyrosine kinase inhibitors (TKI) such as AC220 can induce remissions, resistance-causing mutations in FLT3-ITD are known to impair the in vitro activity of first and second generation FLT3 TKIs. DCC2036 is a unique switch-pocket, non-ATP competitive (allosteric) inhibitor with low nanomolar inhibitory concentration 50 (IC50) activity against a number of tyrosine kinases including FLT3 (1.7 nM), TRKA (7.0 nM), TIE-2 (2.7 nM) and BCR-ABL (2.0 nM). DCC2036 has shown promising activity in a phase I/II clinical trial in chronic myeloid leukemia (CML), where plasma concentrations of 350 nM of DCC2036 have been safely achieved. DCC-2036 has induced clinical and molecular remissions in patients with TKI-resistant CML expressing the ‘gate-keeper’ T315I BCR-ABL mutation, as well as demonstrated activity against mutations that cause BCR-ABL conformational escape resistant (Cancer Cell. 2011;19:556). Here, we evaluated the in vitro activity of DCC2036 against FLT3-ITD in cell line model systems. In the FLT3-ITD expressing human leukemia MV4-11 and MOLM-13 cells, treatment with DCC2036 (20 to 500 nM for 24 hours) dose-dependently induced cell cycle G1-phase accumulation with decline in the S and G2/M phases. Exposure to 50 to 500 nM DCC2036 for 48 to 72 hours also dose-dependently induced apoptosis of 30 to 80 % of MV4-11 and MOLM-13, as well as induced 30 to 50% apoptosis of patient-derived primary AML cells with FLT3-ITD (n =4). This was associated with dose-dependent decline in the levels of p-FLT3, p-STAT5, p-AKT, p-ERK1/2 and Bcl-xL levels but increase in the levels of BIM and p27. In contrast, treatment with DCC2036 induced significantly lower level of apoptosis (<15%) in either normal CD34+ progenitor cells or AML cells without FLT3-ITD. We next evaluated the in vitro activity of DCC2036 against AC220-resistant mutations in FLT3-ITD (F691L, D835V/Y and Y842C/H) that we identified in a pre-clinical screen and in patients with loss of response to AC220 (Smith et al, ASH 2011, submitted), as well as against FLT3-ITD/F691I, analogous to the BCR-ABL/T315I mutation. DCC2036 potently inhibited proliferation of FLT3-ITD transduced Ba/F3 cells with an IC50 of 14.5 nM (IC50 of parental Ba/F3 cells in the presence of IL-3 >1000nM). DCC2036 retained some activity against the clinically relevant FLT3-ITD gatekeeper mutation F691L and F691I (IC50 49 nM and 34 nM), and was similarly active against the activation loop mutations Y842C and Y842H (IC50 26–28 nM). The activation loop mutations D835V and D835Y, which are commonly detected in patients with loss of response to AC220 and are hypothesized to destabilize the kinase inactive “DFG-out” conformation, were substantially less sensitive to DCC2036 (IC50 233 nM and 196 nM, respectively). Based on our previous findings (Blood. 2005;105:1768) that FLT3-ITD is a heat shock protein (hsp) 90 client oncoprotein, we also determined the effect of co-treatment with the non-geldanamycin hsp90 inhibitor AUY922 (5 to 10 nM) (Novartis Pharmaceuticals) against the cultured and primary FLT3-ITD expressing AML cells. Co-treatment with AUY922 significantly improved the activity of DCC2036 against primary AML cells (p < .05). These findings demonstrate that DCC2036 exhibits potent activity against cultured and primary AML cells with FLT-3-ITD, as well as against cellular models of FLT3-ITD with AC220-resistant gatekeeper and select activation loop mutations. The molecular basis of resistance to DCC2036 conferred by activation loop mutations at D835 is under investigation. Co-treatment with DCC-2036 and the hsp90 inhibitor AUY922 exerted higher lethal activity against cultured and primary AML cells with FLT3-ITD. Disclosures: Wise: Deciphera Pharmaceuticals LLC: Employment. Reyes:Millennium, Sanofi Aventis: Consultancy. Berger:Deciphera Pharmaceuticals: Employment. Rutkoski:Deciphera Pharmaceuticals: Employment.
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Rullkötter, Jürgen. "Of Mud Flats, Mixed Mud Flats and Sand Flats." German Research 26, no. 2-3 (December 2004): 8–12. http://dx.doi.org/10.1002/germ.200490024.
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Fiskus, Warren, Sunil Sharma, Jun Qi, Bhavin Shah, Santhana G. T. Devaraj, Christopher Leveque, Bryce P. Portier, Swaminathan Iyer, James E. Bradner, and Kapil N. Bhalla. "BET Protein Antagonist JQ1 Is Synergistically Lethal with FLT3 Tyrosine Kinase Inhibitor (TKI) and Overcomes Resistance to FLT3-TKI in AML Cells Expressing FLT-ITD." Molecular Cancer Therapeutics 13, no. 10 (July 22, 2014): 2315–27. http://dx.doi.org/10.1158/1535-7163.mct-14-0258.
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Capdevila, Silvia, Francisco M. Martínez-Granero, María Sánchez-Contreras, Rafael Rivilla, and Marta Martín. "Analysis of Pseudomonas fluorescens F113 genes implicated in flagellar filament synthesis and their role in competitive root colonization." Microbiology 150, no. 11 (November 1, 2004): 3889–97. http://dx.doi.org/10.1099/mic.0.27362-0.
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The ability of plant-associated micro-organisms to colonize and compete in the rhizosphere is specially relevant for the biotechnological application of micro-organisms as inoculants. Pseudomonads are one of the best root colonizers and they are widely used in plant-pathogen biocontrol and in soil bioremediation. This study analyses the motility mechanism of the well-known biocontrol strain Pseudomonas fluorescens F113. A 6·5 kb region involved in the flagellar filament synthesis, containing the fliC, flaG, fliD, fliS, fliT and fleQ genes and part of the fleS gene, was sequenced and mutants in this region were made. Several non-motile mutants affected in the fliC, fliS and fleQ genes, and a fliT mutant with reduced motility properties, were obtained. These mutants were completely displaced from the root tip when competing with the wild-type F113 strain, indicating that the wild-type motility properties are necessary for competitive root colonization. A mutant affected in the flaG gene had longer flagella, but the same motility and colonization properties as the wild-type. However, in rich medium or in the absence of iron limitation, it showed a higher motility, suggesting the possibility of improving competitive root colonization by manipulating the motility processes.
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Kremers, Marian. "Flets." Maatwerk 14, no. 2 (April 2013): 1. http://dx.doi.org/10.1007/s12459-013-0021-4.
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Le Jan, Yves, and Olivier Raimond. "Flots de noyaux et flots coalescents." Comptes Rendus Mathematique 336, no. 2 (January 2003): 181–84. http://dx.doi.org/10.1016/s1631-073x(03)00004-9.
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Kohli, M., V. Kaushal, and C. Y. Fan. "Vascular endothelial growth factor A & D and flt1/flk1/flt4 receptor expression in metastatic lesions from prostate cancer." Journal of Clinical Oncology 23, no. 16_suppl (June 2005): 4723. http://dx.doi.org/10.1200/jco.2005.23.16_suppl.4723.
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Kang, Hui, Chen Lijuan, Yubing Xu, Fanxiang Zeng, Huan Tong, Lihua Sun, Jinwei Hu, Yongqi Yue, Gung-wei Chirn, and Kai Wang. "Comprehensive Genomic Profiling of Chinese Acute Myeloid Leukemia (AML) with FLT3 ITD Using Ultra Deep Sequencing." Blood 132, Supplement 1 (November 29, 2018): 5262. http://dx.doi.org/10.1182/blood-2018-99-115631.
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Abstract Introduction: The FMS-like tyrosine (FLT3) gene encodes a class III receptor tyrosine kinase, belonging family members, including c-kit, c-FMS, FLT1, and PDGF-𝛽R. FLT3 plays a key role in the hematopoiesis. It was discovered that in acute myeloid leukemia (AML) FLT3 is frequently mutated. Furthermore, constitutive activation of FLT3 by internal tandem duplication (ITD) mutation is one of the most common molecular variants in AML, occurring in approximately 20% to 30% of AML patients who have a comparatively poor clinical outcome and increased relapse rate. In the last years, next generation sequencing technology has allowed a high- throughput, comprehensive profiling of cancer genomes that can aid in making clinical decisions in the process of diagnosis and treatment. A few reports included somatic genomic profiling in AML with FLT3-ITD. However, none comprehensive genomic profiling data shows in chinese population. In this study, we sequenced 26 FLT3-ITD AML samples to show genomic profiling with multiple mutations types and discover the mutations associated with FLT3-ITD based on in-house bioinformatics mutation calling pipelines. Methods: DNA was extracted from blood or bone marrow of AML FLT3-ITD positive samples. Those DNA samples were subjected to comprehensive genomic profiling (CGP) assay consisting of whole exon coding region in 450 tumor actionable or cancer driver genes as well as selected introns (N=244) from 39 genes frequently involved in gene rearrangement using hybridization target capture and next generation sequencing (NGS) technologies and in house established bioinformatics pipelines. Somatic genomic alterations including SNV, short/long Indel, CNV and gene rearrangement were analyzed. Libraries were constructed with KAPA Hyper Prep kit( KAPA Biosystems), and hybridized to customized capture probes( Integrated DNA Technologies)and then sequenced on NovaSeq 6500 (Illumina). The mutation is detected with VAF of no less than 1% of point mutation, insertion and deletion, including long insertion and deletion( long indel). Long indel variants from 10bp-2kb were called with OriLindel algorithm, which is in silicon developed for structure variation calling, especially for FLT3-ITD variants calling. Results: In this study, we sequenced 26 FLT3-ITD AML samples to show genomic profiling with multiple mutations types. The average sequencing depth of 26 samples is above 700X(720-2300X). The mutation is detected with VAF of no less than 1% of point mutation, insertion and deletion, including long insertion and deletion( long indel). Long indel variants from 10bp-2kb were called with OriLindel algorithm, which is in silicon developed for structure variation calling, especially for FLT3-ITD variants calling. We discovered the previous reported high rate of mutations of NPM1(34.6%,9/26), DNMT3A(38.5%,10/26), IDH2(11.5%,3/26), NRAS(19.2%,5/26),RUNX1 (15.4%,4/26), WT1 (31%,8/26) and MLL3(KMT2C, 11.5%,3/26) which have consistent percentage with previous genomic profiling report of FLT3-ITD AML. A total of 42 mutations were detected on the FLT3 gene of 26 samples (162%, 42/26). All 36 ITD sequences of 26 samples were distributed in the protein kinase domain with lengths ranging from 18 to 207bp. 5 samples have more than two ITD variants (19.2%,5/26)). 6 point mutation of FLT3 were detected, 5 of which were located in the 835th amino acid residue of tyrosine kinase domain and 1 in the protein kinase catalytic domain. One of the samples contained two mutations, D835H and V592G. Using NGS technology and in silico bioinformatics pipeline could call multiple type mutations including point mutation, insertion and deletion of FLT3 simultaneously. We also found recurrent mutations found not often in AML, such as AXIN1 (7.7%,2/26) ,RIT1 (7.7%,2/26). AXIN1 belongs to Wnt signaling pathway. Wnt extracellular signaling pathway is one of the evolutionarily conserved pathways that regulate proliferation, polarity and cell migration. RIT1 belongs to Ras gene family. Somatic mutations of the Ras gene family are present in 20-30% of all human cancers,including15-20% of acute myeloid leukemia (AML). Ras-like-without-CAAX-1 (RIT1) gene is a new member of the family and has been found to be critical in noonan syndrome. One report shows the discovery of novel somatic mutations in the RIT1 gene in patients with myeloproliferative. Disclosures No relevant conflicts of interest to declare.
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Bayat, Hamid, Sayantan Sarkar, Bharath Anantharamaiah, Francesco Italiano, Aleksandar Bach, Shashidharan Tharani, Stephan Wulfinghoff, and Stefanie Reese. "Modeling of Forming Limit Bands for Strain-Based Failure-Analysis of Ultra-High-Strength Steels." Metals 8, no. 8 (August 10, 2018): 631. http://dx.doi.org/10.3390/met8080631.
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Increased passenger safety and emission control are two of the main driving forces in the automotive industry for the development of light weight constructions. For increased strength to weight ratio, ultra-high-strength steels (UHSSs) are used in car body structures. Prediction of failure in such sheet metals is of high significance in the simulation of car crashes to avoid additional costs and fatalities. However, a disadvantage of this class of metals is a pronounced scatter in their material properties due to e.g., the manufacturing processes. In this work, a robust numerical model is developed in order to take the scatter into account in the prediction of the failure in manganese boron steel (22MnB5). To this end, the underlying material properties which determine the shapes of forming limit curves (FLCs) are obtained from experiments. A modified Marciniak–Kuczynski model is applied to determine the failure limits. By using a statistical approach, the material scatter is quantified in terms of two limiting hardening relations. Finally, the numerical solution obtained from simulations is verified experimentally. By generation of the so called forming limit bands (FLBs), the dispersion of limit strains is captured within the bounds of forming limits instead of a single FLC. In this way, the FLBs separate the whole region into safe, necking and failed zones.
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Götze, Katharina S., Matthias Schiemann, Stefanie Marz, Christian Peschel, and Robert A. J. Oostendorp. "Acquisition of CD34 Correlates with Increased Hematopoietic and Self Renewal Activity of CD34−CD133+ Cord Blood Cells." Blood 104, no. 11 (November 16, 2004): 4143. http://dx.doi.org/10.1182/blood.v104.11.4143.4143.
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Abstract CD34 is a sialomucin expressed on hematopoietic cells, endothelial cells and muscle satellite cells. Within the hematopoietic system, CD34 expression has been associated with very immature progenitor cells as well as hematopoietic stem cells (HSC), and it is widely used to assess stem cell activity in clinical protocols. In the past, HSC activity was thought to be retained exclusively in the subset of cells expressing CD34. This view has been challenged by recent observations in mice in which HSC activity was also found in the CD34-negative fraction. These findings have since been reproduced using human marrow and cord blood cells. However, the exact relationship between CD34+ and CD34− stem cells remains unclear. We investigated the regulation of CD34 expression as dependent on cell division history. To follow cell division, human cord blood cells were labeled with the fluorescent dye CFSE. Lin-CD34−CD133+CFSE+ (CD34−) and CD34+ populations were almost indistinguishable in their ability to produce CAFCweek6 content. After three days of serum-free culture with stem cell factor, Flt3 ligand and thrombopoietin, almost all initially CD34− cells had acquired expression of CD34, including all undivided cells. We found that, in cultures initiated from CD34− cells, virtually all CAFCweek6 were produced from the divided, now CD34+ cells, indicating these cells had self-renewed. In contrast, similar cultures from initially CD34+ cells demonstrated that hematopoietic activity associated with the undivided cell fraction. We did not find any hematopoietic activity in the cell fraction that remained CD34− or the fraction that lost CD34 after division. Analysis of mRNA expression showed that CD34− and CD34+ cells expressed almost equal levels of CD34, AC133, Flt1, Flk1 and Flt4, while CD34− cells expressed significantly lower levels of Tie1 and Tie2 than CD34+ cells. The expression of CD34 message in CD34− cells was explained by our observation that these cells contained intracellular CD34, indicating that they are “primed” to express the antigen on their cell surface. In conclusion, Lin−CD34−CD133+ cells acquire expression of CD34, even in the absence of cell divisions. These CD34− cells self-renew more rapidly in vitro than cells initially expressing CD34, and self-renewal is preceded by acquisition of CD34 antigen.
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Jetani, Hardikkumar, Irene García-Cadenas, Thomas Nerreter, Ralph Goetz, Jorge Sierra, Halvard Bonig, Markus Sauer, Hermann Einsele, and Michael Hudecek. "FLT3 Inhibitor Treatment Increases FLT3 Expression That Exposes FLT3-ITD+ AML Blasts to Elimination By FLT3 CAR-T Cells." Blood 132, Supplement 1 (November 29, 2018): 903. http://dx.doi.org/10.1182/blood-2018-99-118171.
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Abstract Background: FMS-like tyrosine kinase 3 (FLT3) is a transmembrane protein uniformly expressed on leukemic blasts in acute myeloid leukemia (AML), and driver of leukemia-genesis in FLT3-ITD+ (Internal tandem duplication) AML. There is an increasing body of pre-clinical and clinical data suggesting that FLT3-ITD+ AML blasts respond to FLT3 inhibitor treatment by augmenting FLT3 expression in order to sustain the survival signal provided by this mutation. Here, we analyzed FLT3 expression on FLT3 wild type and FLT3-ITD+ AML cells after treatment with the FLT3 inhibitors midostaurin, quizartinib and crenolanib, and determined the antileukemia efficacy of combination treatment with FLT3 inhibitors and FLT3 CAR T cells in vitro and in vivo. Methods: MOLM-13 and MV4;11 AML cells (both FLT3-ITD+) were cultured in the presence of IC50 doses of midostaurin, quizartinib and crenolanib, respectively to induce resistance (MOLM-13R/MV4;11R). A FLT3-CAR comprised of BV10 scFv binding domain, CD28-CD3ζ signal module and EGFRt marker was encoded in a lentiviral vector and expressed in CD8+ and CD4+ T cells of healthy donors and patients (n=6). T cell mediated cytolytic activity was evaluated in luminescence-based assay, cytokine production analyzed by ELISA and proliferation assessed by CFSE dye dilution. NSG mice (n= 4-6 per group) were engrafted with MOLM-13/ffLuc AML cells and treated with 5x106 CAR T cells alone or in combination with FLT3 inhibitors. Results: We detected a significant increase in FLT3 expression on both MV4;11 and MOLM-13 AML cells after treatment with each of the inhibitors as assessed by mean fluorescence intensity (quizartinib > crenolanib > midostaurin). The increase in FLT3 expression occurred specifically on these FLT3-ITD+ AML cell lines and was not observed on FLT3 wt AML (THP-1), acute lymphoblastic leukemia (NALM-16), mixed lineage leukemia (KOPN-8 and SEM) cell lines and normal hematopoietic stem cells. We applied single molecule sensitive super-resolution microscopy to demonstrate that the average number of FLT3 molecules (per micrometer sq.) on MV4;11 AML cells had increased from 0.80 (untreated) to 10.7 (quizartinib), 4.7 (crenolanib), and 3.3 (midostaurin) (p<.05). Of interest, midostaurin induced clustering of FLT3, while FLT3 was still present as monomers after quizartinib and crenolanib treatment. Intriguingly, the higher FLT3 density after FLT3 inhibitor treatment translated into superior antileukemia reactivity of FLT3 CAR T cells against AML cell lines and primary AML cells in vitro and in vivo. We observed the strongest increase in cytolytic activity, cytokine production and proliferation by CD8+ and CD4+ FLT3 CAR T cells after treatment with crenolanib and quizartinib, followed by midostaurin (p<.05). We confirmed that upregulation of FLT3 occurred on MOLM-13 cells during FLT3 inhibitor therapy in NSG mice in vivo, and observed synergistic antileukemia efficacy of FLT3 CAR T cells in combination with each of the compounds. The mean frequency of FLT3 CAR T cells in mice that received FLT3 CAR T cells and an FLT3 inhibitor was 2-4 fold higher compared to mice had received FLT3 CAR T cells alone (p<.05) and was the highest in the cohort of mice that had received FLT3 CAR T cells in combination with crenolanib. FLT3 CAR T cells alone and each of the combination treatments of FLT3 CAR T & FLT3 inhibitor achieved 100% response rate which compares favorably to untreated or FLT3 inhibitor alone (0%). However, the mean fold reduction in leukemia burden (b/w day 7 and 10) was greater in all three combination treatment compare to only CAR treatment (p<.05). The most potent combination was FLT3 CAR T cells & crenolanib that accomplished the strongest reduction in leukemia burden as assessed by bioluminescence imaging and flow cytometry. Conclusion: Collectively, the data show that FLT3 inhibitors augment cell surface expression of FLT3 in FLT3-ITD+ AML cells which leads to enhanced recognition and elimination by FLT3 CAR T cells. This is, to our knowledge, the first demonstration that small molecule inhibitors and CAR T cell immunotherapy can be used synergistically to treat a hematologic malignancy. We confirmed this principle with each of the FLT3 inhibitors in our panel, and observed the strongest antileukemia activity of FLT3 CAR T cells in combination with crenolanib. Our data encourage the clinical evaluation of this combination treatment in high risk patients with FLT3-ITD+ AML. Disclosures Jetani: University hospital wuerzburg: Employment, Patents & Royalties: H.J. and M.H are co-inventors on a patent related to the use of FLT3-CAR T-cells to treat AML filed by the University of Wuerzburg, Wuerzburg, Germany. Bonig:Kiadis Pharma: Consultancy.
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Laude, Eugineus Rivado Victor, and Satriya Wahyu Firmandhani. "A Study of Energy Efficiency in Flats, Case Study: The A-B-C Tower of Tambora Flats in Jakarta, Indonesia." Journal of Architectural Design and Urbanism 3, no. 2 (April 30, 2021): 97–106. http://dx.doi.org/10.14710/jadu.v3i2.10915.
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Flats are one of the government's solution to provide decent housing for low-income people. However, as mostly flats overlook energy efficiency aspects, residents must pay high rental and operational costs. Therefore, this paper aims to study the principles of green buildings, especially in the building envelope that can bear the operating costs of flats with the case study on the A-B-C Tower of Tambora Flats. The A-B-C Tower of Tambora Flats is one of the flats building in Jakarta that has rental cost issues. This study employed the EDGE application that provided energy saving values in the application of green building principles, such as building mass and orientation, wall and roof finishing materials, natural shading and ventilation elements. From these values, it was only the application of green building principles that was significant for the Tambora flats. The results of this study revealed that the optimization of natural ventilation for flats was still important and having a significant impact on energy savings
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Hower, Mary. "Salt Flats." Iowa Review 20, no. 1 (January 1990): 103. http://dx.doi.org/10.17077/0021-065x.3854.
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Briesewitz, Roger. "Fathoming Flt3." Blood 113, no. 17 (April 23, 2009): 3889–90. http://dx.doi.org/10.1182/blood-2009-02-205435.
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Vroom, Marike. "Fles champagne." Management Kinderopvang 24, no. 3 (May 2018): 2–3. http://dx.doi.org/10.1007/s41190-018-0069-4.
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Brown, P., and D. Small. "FLT3 Inhibitors." European Journal of Cancer 40, no. 5 (March 2004): 707–21. http://dx.doi.org/10.1016/j.ejca.2003.08.030.
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Zheng, R., E. Bailey, B. Nguyen, X. Yang, O. Piloto, M. Levis, and D. Small. "Further activation of FLT3 mutants by FLT3 ligand." Oncogene 30, no. 38 (April 25, 2011): 4004–14. http://dx.doi.org/10.1038/onc.2011.110.
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Imbert, A., O. Rosnet, S. Marchetto, V. Ollendorff, D. Birnbaum, and M. J. Pébusque. "Characterization of a yeast artificial chromosome from human chromosome band 13q12 containing the FLT1 and fLT3 receptor-type tyrosine kinase genes." Cytogenetic and Genome Research 67, no. 3 (1994): 175–77. http://dx.doi.org/10.1159/000133817.
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Zheng, Rui, Obdulio Piloto, and Donald Small. "FLT3 Mutant Activation Is Still Dependent on FLT3 Ligand." Blood 106, no. 11 (November 16, 2005): 2294. http://dx.doi.org/10.1182/blood.v106.11.2294.2294.
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Abstract FLT3 is a member of the class III receptor tyrosine kinase family and is primarily expressed on hematopoietic stem/progenitor cells. FLT3 ligand (FL) interacts with wild-type FLT3 (wtFLT3) receptors leading to the activation of FLT3 signaling. Constitutive activation of wt FLT3 through autocrine activation by FL is also observed in a number of cell lines and primary AML samples. Incubation of leukemic blasts expressing FLT3 with FL results in enhanced proliferation and decreased spontaneous apoptosis in many cases of acute leukemia. Somatic mutations of FLT3 involving internal tandem duplication (ITD) of the juxtamembrane domain or point mutations in the tyrosine kinase domain (TKD) have been identified in approximately 17–34% and 7–9% of acute myeloid leukemia (AML) patients, respectively. The ITD and TKD mutations appear to activate the tyrosine kinase domain of FLT3 in a FL-independent manner. However, these data were all obtained in human and murine cell lines that express FL. Thus, it is not clear whether FL also plays a role in the activation of FLT3 mutants. In order to determine whether or not FLT3 mutants are completely or somewhat dependent on FL, a FL deficient murine embryo fibroblast cell line (MEF) was derived from FL deficient (FL−/−) mice by SV40 large T antigen transformation. This eliminates the possibility of autocrine stimulation of transfected FLT3 receptor by FL. Expression of FLT3/ITD and FLT3/TKD mutations in FL−/−MEF cells resulted in some constitutive phosphorylation of FLT3 receptor. However, a more than 4 fold increase of FLT3 activation was induced by addition of FL. Retroviral introduction of FL in FL−/− MEF cells expressing FLT3 mutants led to more than 3 fold and 2 fold increase of tyrosine phosphorylation of FLT3 and AKT, respectively. In addition, FL expression resulted in a 3 fold increase of phosphorylation of STAT5 in FL−/−MEF cells expressing FLT3/ITD. In these FL expressing cells, addition of exogenous FL showed no further stimulation of FLT3, AKT and STAT5. These data strongly suggest that the level of FLT3 activation mediated by FLT3 mutants is still largely dependent on FL.
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Chen, Fangli, Yuichi Ishikawa, Hitoshi Kiyoi, and Tomoki Naoe. "Mechanism of FLT3 Ligand Dependent Resistance to FLT3 Inhibitors." Blood 124, no. 21 (December 6, 2014): 908. http://dx.doi.org/10.1182/blood.v124.21.908.908.
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Abstract Background: FLT3mutation, which is found in about 30% of acute myeloid leukemia (AML) patients, is involved in the signaling pathway of autonomous proliferation and differentiation block in leukemia cells. Since FLT3 mutation is associated with a poor prognosis in AML patients, mutated FLT3 serves as an important molecular target in the treatment of leukemia. To date, several FLT3 inhibitors are undergoing investigation, but their clinical efficacies were lower than expected. The inhibitory effects of FLT3 inhibitors were mainly evaluated using the sole mutant FLT3-expressing cells in pre-clinical studies, while clinicallymost AML cells harboring FLT3 mutation co-express wild-type (Wt) FLT3, suggesting that FLT3 ligand (FL)-dependent Wt-FLT3 signal might cause the lower clinical efficacies of FLT3 inhibitors. Recently, it was reported that administration of FLT3 inhibitors induced increased concentration of FL in plasma. Thus, here we analyzed how FL-dependent signal affects the inhibitory effect of FLT3 inhibitors and proliferation on Wt- and ITD-FLT3-coexpressing cells. Methods: 5 kinds of FLT3-expressing 32D cells were established: Wt-FLT3, FLT3-ITD, extra cellular domain-lacking FLT3-ITD (cyFLT3-ITD), Wt- and FLT3-ITD co-expressing and Wt- and cyFLT3-ITD co-expressing 32D cells. The growth inhibitory effects of 6 FLT3 inhibitors (AC220, CEP701, FI-700, KW2449, PKC412 and Sorafenib) with and without FL stimulation were evaluated by MTT assay. Furthermore, cell cycle analysis was performed to evaluate cell proliferation, and inhibitory effects on FLT3 kinase and its downstream molecules were also evaluated by western-blot. In vivo, cells were inoculated into C3H/Hej mice intravenously to follow survival rate and NOD/SCID mice subcutaneously to compare tumor volume between sole ITD-FLT3-expressing 32D cells and Wt and ITD-FLT3-coexpressing 32D cells. Results: The FL-stimulation reduced growth inhibitory effects by FLT3 inhibitors on Wt- and ITD-FLT3-co-expressing 32D cells, while those reducing effects were little on the sole extracellular domain lacked ITD-FLT3 (cyITD-FLT3)-expressing 32D cells. Of note, FL-stimulation induced cell cycle arrest dose-dependently, resulting reduced proliferation in Wt- and ITD-FLT3-co-expressing cells. In vivo, all syngeneic C3H mice inoculated with sole cyITD-FLT3-expressing 32D cells and sole ITD-FLT3-expressing 32D cells developed leukemia within 16 days and 72 days respectively, but mice inoculated with Wt- and ITD-FLT3-co-expressing cells survived more than 100 days (P<0.0001). Furthermore, the growth of tumors driven by sole ITD- and cyITD- FLT3-expressing 32D cells was significantly faster than tumors driven by Wt- and ITD-FLT3-co-expressing cells in NOD/SCID subcutaneous model. Western blot shows AKT and ERK are activated in Wt- and ITD-FLT3-co-expressing cells by FL stimulation. STAT3 is highly phosphorylated in Wt- and ITD-FLT3-co-expressing cells and can be further activated by FL stimulation, while the phosphorylation is weak in sole ITD expressing cells. Immunopricipitation demonstrated that FLT3 ligand activated only Wt-FLT3 but not ITD-FLT3 in co-expressing cells. Furthermore, p21 (CIP1/WAF1) can be up-regulated by FL and induce cell cycle arrest in Wt- and ITD-FLT3-co-expressing cells. FL impeded the inhibitory effect of FLT3 inhibitors by persistent activation of ERK and AKT through Wt-FLT3. Also, down-regulation of p21 and Mcl-1induced by FLT3 inhibitor can be suppressed by FL. Conclusions: These results suggested that FLT3 Ligand dependent resistance to FLT3 inhibitors were associated with reduced proliferation ability caused by up-regulation of P21 and persistent ERK and AKT activation through Wt-FLT3 signal. Disclosures Kiyoi: Bristol-Myers Squibb: Research Funding; Chugai Pharmaceutical Co. LTD: Research Funding; Kyowa Hakko Kirin Co. LTD.: Research Funding; Dainippon Sumitomo Pharma: Research Funding; Zenyaku Kogyo: Research Funding; FUJIFILM Corporation: Research Funding. Naoe:Otsuka Pharmaceutical Co. LTD: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis Pharma: Research Funding; Chugai Pharmaceutical Co. LTD: Research Funding; Kyowa Hakko Kirin Co. LTD: Research Funding; Dainippon Sumitomo Pharma: Research Funding; Zenyaku Kogyo: Research Funding; FUJIFILM Corporation: Research Funding.