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Durand de Gevigney, J., C. Changenet, F. Ville, and P. Velex. "Thermal modelling of a back-to-back gearbox test machine: Application to the FZG test rig." Proceedings of the Institution of Mechanical Engineers, Part J: Journal of Engineering Tribology 226, no. 6 (January 16, 2012): 501–15. http://dx.doi.org/10.1177/1350650111433243.
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A thermal model of a back-to-back gear test rig relying on a network approach is presented in which the predictions of temperatures and power losses are coupled. The numerical findings are in good agreement with the measurements for transient regimes on a FZG test rig and it is demonstrated that the proposed simulation is reliable. A number of results are presented which illustrate the influence of the pinion and gear immersion depths. It is found that, in certain conditions, the classic isothermal method for estimating integral temperatures is questionable because the actual bulk temperature can substantially deviate from that of the oil sump. The practical consequences in terms of scuffing capacity are emphasised.
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Navet, P., C. Changenet, F. Ville, D. Ghribi, and J. Cavoret. "Thermal Modeling of the FZG Test Rig: Application to Starved Lubrication Conditions." Tribology Transactions 63, no. 6 (August 24, 2020): 1135–46. http://dx.doi.org/10.1080/10402004.2020.1800155.
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Höhn, B. R., P. Oster, and U. Schedl. "Pitting load capacity test on the FZG gear test rig with load-spectra and one-stage investigations." Tribotest 5, no. 4 (June 1999): 417–30. http://dx.doi.org/10.1002/tt.3020050407.
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Spiegelberg, C., and M. Christie. "Torque loss in spur gears with interference." Proceedings of the Institution of Mechanical Engineers, Part J: Journal of Engineering Tribology 217, no. 5 (May 1, 2003): 385–95. http://dx.doi.org/10.1243/135065003322445304.
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Gears with interference (zero backlash) are used in robots and other precision equipment. The reason for using interference gearing is to improve positioning and motion control. It is then also desirable to compensate for the friction losses and therefore it is important to model the friction losses accurately. In this paper, results from a model for simulating spur gears with interference are compared with results from a test rig for spur gears with interference. FZG gears are used both in the test rig and in the simulations. Brief descriptions of the test rig and the simulation model are given in the paper; more thorough descriptions can be found in studies by Hedström and Kårhammar and by Spiegelberg, Andersson and Sellgren respectively. There is also a description of the measurements and the procedure of making them. The aim of this paper is to compare the results from the test rig with the results from the simulation model and to analyse the results from the test rig. The results show that the simulated torque loss corresponds well with the measured torque loss within the range of the test rig. The results from both the test rig and the simulation model show that there are large variations in the frictional torque during one mesh of a gear tooth. The loss increases with the number of contact points and the lowest loss is found when a driving gear flank passes the pitch point. The overall efficiency decreases when the mesh force increases and the lowest efficiency readings are found when a combination of high mesh force and low load is applied.
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Höhn, B. R., K. Michaelis, C. Eberspächer, and L. Schlenk. "A scuffing load capacity test with the FZG gear test rig for gear lubricants with high EP performance." Tribotest 5, no. 4 (June 1999): 383–90. http://dx.doi.org/10.1002/tt.3020050405.
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Bergstedt, Edwin, Jiachun Lin, and Ulf Olofsson. "Influence of gear surface roughness on the pitting and micropitting life." Proceedings of the Institution of Mechanical Engineers, Part C: Journal of Mechanical Engineering Science 234, no. 24 (June 9, 2020): 4953–61. http://dx.doi.org/10.1177/0954406220931541.
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Pitting and micropitting are the two main gear rolling contact fatigue modes. It is widely accepted that micropitting will lead to pitting; however, the relationship between pitting and micropitting life needs further investigation. In this work, micropitting and pitting tests were performed on an FZG back-to-back test rig using standard FZG PT-C and GF-C gears. The gear tooth profile change due to micropitting and pitting damage was measured in situ in the gearbox using a profilometer after each test. The gear surface roughness parameters were calculated from the measured tooth profile. A Gaussian low pass filter with cut off length [Formula: see text] mm was applied to the measured tooth profile to obtain the waviness. The calculated roughness parameters and the obtained tooth profile with waviness for each test were imported into the KISSsoft software to calculate the contact stress and specific film thickness at the corresponding load stage. Experimental results show that smooth gear surface can reduce or even avoid micropitting damage, but could lead to a reduction in pitting life.
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Neurouth, Adrien, Christophe Changenet, Fabrice Ville, and Michel Octrue. "Influence of Rolling Element Bearing Modeling on the Predicted Thermal Behavior of the FZG Test Rig." Tribology Transactions 60, no. 4 (July 15, 2016): 753–61. http://dx.doi.org/10.1080/10402004.2016.1208856.
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Fürstenzeller, Adam, František Tóth, Milan Kadnár, Juraj Rusnák, and Miroslav Bošanský. "Comparison of PVD Coatings Nacro4 and TIALN + DLC Deposited on High Contact Ratio Gearing Interacting With Conventional and Ecological Lubricants." Acta Technologica Agriculturae 22, no. 2 (June 1, 2019): 48–55. http://dx.doi.org/10.2478/ata-2019-0009.
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Abstract Proposed paper deals with experimental tests performed on the Nieman M01 FZG test rig. Experiments were carried out in accordance with STN 65 6280 standard for FZG scuffing tests, from which load values for each load level were obtained. HCR gears made of 16MnCr5 material were utilized during experimental tests. Gear surface was deposited by PVD coatings of nACRo4 and TiAlN + DLC. Conventional lubricant MADIT PP 90H and biological lubricant OMW Biogear S150 were selected for lubrication environments. Aim of the experimental tests lied in application and comparison of PVD coatings deposited on HCR gears. Values of the maximum height of the assessed profile Rz for tip and reference diameters were measured after each load level. Results of experimental tests were statistically processed and relations between the maximum height of assessed profile Rz and load levels for both utilized coatings in both environments were established on the basis of these results.
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Magalhães, Luís, Ramiro Martins, Ivo Oliveira, and Jorge Seabra. "Comparison of tooth profiles and oil formulation focusing lower power losses." Proceedings of the Institution of Mechanical Engineers, Part J: Journal of Engineering Tribology 226, no. 6 (March 7, 2012): 529–40. http://dx.doi.org/10.1177/1350650112439260.
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Environmental awareness, lower consumption of raw materials and longer life of equipment are main concerns nowadays and are leading to the research and development of lubricants and equipment to access those requirements. In this study, the power loss performance of three different tooth profile geometries, developed with the purpose of decreasing power losses while keeping the predicted life, were tested and evaluated in a FZG test rig. The path to reduce power losses was based on the decrease of the module, the increase of the helix angle and increase of the addendum modification coefficients in order to reduce the path of contact, i.e. the sliding velocity. The power loss behaviour of two different lubricants was also evaluated for each tooth profile geometry considered. The influence of the oil level in the gearbox was also evaluated. One of the lubricants has an ester base while the other has a polyalphaolefin base and both are fully formulated. An energetic model was developed for the FZG test gearbox and applied to these tests to improve the knowledge about the influence of tooth geometries as well as lubricant formulation in the power losses and coefficient of friction between gear teeth. The developed geometries showed that the path followed for the reduction of power losses produced the expected results and can be implemented with success on gear design.
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Michalczewski, Remigiusz, Witold Piekoszewski, Marian Szczerek, Waldemar Tuszynski, and Maksim Antonov. "The Rolling Contact Fatigue of PVD Coated Spur Gears." Key Engineering Materials 527 (November 2012): 77–82. http://dx.doi.org/10.4028/www.scientific.net/kem.527.77.
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The aim of the study was to investigate the resistance to rolling contact fatigue of a C:H:W and MoS2/Ti coated gears. The investigation of rolling contact fatigue was realised by means of a gear test rig using FZG PT C/10/90 pitting test. Four material combinations of gears were tested: wheel and pinion uncoated, wheel and pinion coated, wheel coated and pinion uncoated as well as wheel uncoated and pinion coated. The tests were performed using for lubrication mineral gear oil of API GL-5 performance level and 80W/90 viscosity grade. The results indicate that for the coated/coated pair (pinion and wheel coated) and coated pinion/steel wheel pair a significant decrease in the fatigue life compared to the uncoated gears was obtained. The best results were obtained in the case of the uncoated pinion / a-C:H:W coated wheel – even fourfold increase in the fatigue life was observed. This shows a very high potential of application of PVD coatings for gears.
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Accorsi Gans, Luiz Henrique, Wilson Luiz Guesser, Marco Antonio Luersen, and Carlos Henrique da Silva. "Numerical Analysis of the Influence of Graphite Nodule Size on the Pitting Resistance of Austepered Ductile Iron Gears." Advanced Materials Research 1120-1121 (July 2015): 763–72. http://dx.doi.org/10.4028/www.scientific.net/amr.1120-1121.763.
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In this work, an experimental study of wear evaluation in combination with a finite element analysis (FEA) was carried out for austempered ductile iron (ADI) used in gears. Two different ADI materials were used to produce gears which were tested in a FZG back-to-back test rig. The experimental results were compared to those of carburized AISI 8620 steel and induction hardened AISI 4140 steel gears. The wear resistance for pitting and spalling on the gears surfaces were measured using image analysis. Comparing the two types of ADI, the one with smaller nodules showed a higher pitting resistance. In contact fatigue tests with severe load, the carburized AISI 8620 steel proved to be superior to ADI. However, ADI with smaller nodule size presented wear resistance similar to that of induction hardened AISI 4140 steel. The FEA was conducted using the commercial code ANSYS 11.0 and aimed to provide a better understanding of the microstructural effect on the stress state of subsurface regions. From the numerical results in ADIs, it was concluded that the nodule size affects the gears life independently of the mechanical properties of the matrix. The size and number of nodules affects both the nucleation and the propagation stages of cracks. ADIs with higher amount of nodules have a superior wear resistance by pitting. Also, compared to the Hertz contact theory (valid for isotropic materials), the presence of graphite nodules induced the maximum shear stress point moves toward the surface.
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Engelhardt, Christian, Jochen Witzig, Thomas Tobie, and Karsten Stahl. "Influence of water contamination in gear lubricants on wear and micro-pitting performance of case carburized gears." Industrial Lubrication and Tribology 69, no. 4 (July 10, 2017): 612–19. http://dx.doi.org/10.1108/ilt-07-2016-0152.
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Purpose Water can alter the performance of modern gear lubricants by influencing the flank load carrying capacity of gears significantly. The purpose of this paper is to investigate the influence of water contaminations in different kinds of base oils on the micro-pitting and wear performance of case carburized gears. Design/methodology/approach Concerning micro-pitting and wear, tests, based mostly on the following standardized tests, are performed on a Forschungsstelle fuer zahnraeder und getriebebau (FZG)-back-to-back gear test rig: micro-pitting short test Graufleckenkurztest (GFKT) according to DGMK 575 (screening test), micro-pitting test Graufleckentest (GT) according to FVA 54/7 (load stage test and endurance test) and Slow-speed wear test according to DGMK 377. To investigate the effect of water on the gear load carrying capacity dependent on different types of base oils, two polyglycol oils (PG1 and PG2), a polyalphaolefin oil, a mineral oil and an ester oil E are used. Each of these oils are common wind turbine gear oils with a viscosity ISO VG-220. Additionally, a manual transmission fluid with a viscosity of society of automotive engineers (SAE) 75W-85 is tested. Findings Considering the micro-pitting and wear performance, a significant decrease caused by water contaminations could not be detected. Regarding pitting damages, a generally negative influence was observed. This influence was differently distinctive for different base oil types. Especially non-polar lubricants seem to be affected negatively. The documented damages of the tooth flanks confirm this observation. While typical pitting damages appeared in test runs with polar lubricants, the disruption in test runs with non-polar lubricants was more extensive. Based on the experimental investigations, a general model of the damaging mechanisms of water contaminations in lubricants was derived. It is split into three partitions: interaction lubricant–water (effect of water on the molecular structure of base oils and additives), chemical-material-technological (especially corrosive reactions) and tribological influence (effect of water droplets in the contact zone). It has to be considered that the additive package of lubricants affects the influence of water contaminations on the flank load carrying capacity distinctively. An influence of water on the micro-pitting and wear performance in other than the given lubricants cannot be excluded. Originality/value While former research work was focused more on the effects of water in mineral oils, investigations concerning different types of base oils as well as different types of damages were carried out within this research project.
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Agbozo, Faith, Abdulai Abubakari, Clement Narh, and Albrecht Jahn. "Accuracy of glycosuria, random blood glucose and risk factors as selective screening tools for gestational diabetes mellitus in comparison with universal diagnosing." BMJ Open Diabetes Research & Care 6, no. 1 (June 2018): e000493. http://dx.doi.org/10.1136/bmjdrc-2017-000493.
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ObjectiveDespite the short-term and long-term health implications of gestational diabetes mellitus (GDM), opinions are divided on selective vis-à-vis universal screening. We validated the accuracy of screening tests for GDM.Research design and methodsPregnant women (n=491) were recruited to this prospective, blind comparison with a gold standard study. We did selective screening between 13 and 20 weeks using reagent-strip glycosuria, random capillary blood glucose (RBG) and the presence of ≥1 risk factor(s). Between 20 and 34 weeks, we did universal screening following the ‘one-step’ approach using glycated hemoglobin (HbA1c), fasting venous plasma glucose (FPG), and the 1-hour and the ‘gold standard’ 2-hour oral glucose tolerance test (OGTT). Tests accuracy was estimated following the WHO and the National Institute for Health and Care Excellence (NICE) diagnostic criteria. Overall test performance was determined from the area under the receiver operating characteristic curve (AUC).ResultsGDM prevalence per 2-hour OGTT was 9.0% for the WHO criteria and 14.3% for the NICE criteria. Selective screening using glycosuria, RBG and risk factors missed 97.4%, 87.2% and 45.7% of cases, respectively. FPG threshold ≥5.1 mmol/L had the highest clinically relevant sensitivity (68%) and specificity (81%), but FPG threshold ≥5.6 mmol/L had higher positive predictive value. Although sensitivity of 1-hour OGTT was 39.5%, it had the highest accuracy and diagnostic OR. Regarding test performance, 1-hour OGTT and FPG were very good (AUC>0.8), RBG was poor (AUC≈0.60), whereas HbA1c was invaluable (AUC<0.5).ConclusionsSelective screening using glycosuria and random blood glucose is unnecessary due to its low sensitivity. Fasting glucose ≥5.1 mmol/L could be applicable for screening at the population level. Where 2-hour OGTT is not available, FPG ≥5.6 mmol/L, complemented by the presence of risk factors, could be useful in making therapeutic decision.
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Gillett, Mike, Alan Brennan, Penny Watson, Kamlesh Khunti, Melanie Davies, Samiul Mostafa, and Laura J. Gray. "The cost-effectiveness of testing strategies for type 2 diabetes: a modelling study." Health Technology Assessment 19, no. 33 (May 2015): 1–80. http://dx.doi.org/10.3310/hta19330.
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BackgroundAn estimated 850,000 people have diabetes without knowing it and as many as 7 million more are at high risk of developing it. Within the NHS Health Checks programme, blood glucose testing can be undertaken using a fasting plasma glucose (FPG) or a glycated haemoglobin (HbA1c) test but the relative cost-effectiveness of these is unknown.ObjectivesTo estimate and compare the cost-effectiveness of screening for type 2 diabetes using a HbA1ctest versus a FPG test. In addition, to compare the use of a random capillary glucose (RCG) test versus a non-invasive risk score to prioritise individuals who should undertake a HbA1cor FPG test.DesignCost-effectiveness analysis using the Sheffield Type 2 Diabetes Model to model lifetime incidence of complications, costs and health benefits of screening.SettingEngland; population in the 40–74-years age range eligible for a NHS health check.Data sourcesThe Leicester Ethnic Atherosclerosis and Diabetes Risk (LEADER) data set was used to analyse prevalence and screening outcomes for a multiethnic population. Alternative prevalence rates were obtained from the literature or through personal communication.Methods(1) Modelling of screening pathways to determine the cost per case detected followed by long-term modelling of glucose progression and complications associated with hyperglycaemia; and (2) calculation of the costs and health-related quality of life arising from complications and calculation of overall cost per quality-adjusted life-year (QALY), net monetary benefit and the likelihood of cost-effectiveness.ResultsBased on the LEADER data set from a multiethnic population, the results indicate that screening using a HbA1ctest is more cost-effective than using a FPG. For National Institute for Health and Care Excellence (NICE)-recommended screening strategies, HbA1cleads to a cost saving of £12 and a QALY gain of 0.0220 per person when a risk score is used as a prescreen. With no prescreen, the cost saving is £30 with a QALY gain of 0.0224. Probabilistic sensitivity analysis indicates that the likelihood of HbA1cbeing more cost-effective than FPG is 98% and 95% with and without a risk score, respectively. One-way sensitivity analyses indicate that the results based on prevalence in the LEADER data set are insensitive to a variety of alternative assumptions. However, where a region of the country has a very different joint HbA1cand FPG distribution from the LEADER data set such that a FPG test yields a much higher prevalence of high-risk cases relative to HbA1c, FPG may be more cost-effective. The degree to which the FPG-based prevalence would have to be higher depends very much on the uncertain relative uptake rates of the two tests. Using a risk score such as the Leicester Practice Database Score (LPDS) appears to be more cost-effective than using a RCG test to identify individuals with the highest risk of diabetes who should undergo blood testing.LimitationsWe did not include rescreening because there was an absence of required relevant evidence.ConclusionsBased on the multiethnic LEADER population, among individuals currently attending NHS Health Checks, it is more cost-effective to screen for diabetes using a HbA1ctest than using a FPG test. However, in some localities, the prevalence of diabetes and high risk of diabetes may be higher for FPG relative to HbA1cthan in the LEADER cohort. In such cases, whether or not it still holds that HbA1cis likely to be more cost-effective than FPG depends on the relative uptake rates for HbA1cand FPG. Use of the LPDS appears to be more cost-effective than a RCG test for prescreening.FundingThe National Institute for Health Research Health Technology Assessment programme.
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Cuschieri, Sarah, Johann Craus, and Charles Savona-Ventura. "The Role of Untimed Blood Glucose in Screening for Gestational Diabetes Mellitus in a High Prevalent Diabetic Population." Scientifica 2016 (2016): 1–6. http://dx.doi.org/10.1155/2016/3984024.
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Global prevalence increase of diabetes type 2 and gestational diabetes (GDM) has led to increased awareness and screening of pregnant women for GDM. Ideally screening for GDM should be done by an oral glucose tolerance test (oGTT), which is laborious and time consuming. A randomized glucose test incorporated with anthropomorphic characteristics may be an appropriate cost-effective combined clinical and biochemical screening protocol for clinical practice as well as cutting down on oGTTs. A retrospective observational study was performed on a randomized sample of pregnant women who required an OGTT during their pregnancy. Biochemical and anthropomorphic data along with obstetric outcomes were statistically analyzed. Backward stepwise logistic regression and receiver operating characteristics curves were used to obtain a suitable predictor for GDM without an oGTT and formulate a screening protocol. Significant GDM predictive variables were fasting blood glucose (p=0.0001) and random blood glucose (p=0.012). Different RBG and FBG cutoff points with anthropomorphic characteristics were compared to carbohydrate metabolic status to diagnose GDM without oGTT, leading to a screening protocol. A screening protocol incorporating IADPSG diagnostic criteria, BMI, and different RBG and FBG criteria would help predict GDM among high-risk populations earlier and reduce the need for oGTT test.
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Damnjanovic, Maja, Aneta Lakic, Dejan Stevanovic, Ana Jovanovic, Jasna Jancic, Mirjana Jovanovic, and Ljubica Leposavic. "Self-assessment of the quality of life of children and adolescents in the child welfare system of Serbia." Vojnosanitetski pregled 69, no. 6 (2012): 469–74. http://dx.doi.org/10.2298/vsp1206469d.
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Background/Aim. Children and adolescents who enter a child welfare system are at higher risk of suffering from mental disorders, physical health, and/or social and educational problems than the general population of the same age is. This study was organized with the aim to evaluate the general characteristics of quality of life (QOL) in children and adolescents living in residential and foster care in Serbia. Methods. Two hundred and sixteen children and adolescents, aged 8-18 years, from residential and foster care and 238 children and adolescents from the general population participated in the study. QOL was assessed using the Pediatric Quality of Life Inventory (PedsQL) - Serbian version. Three groups were created: residential care group (RCG), foster care group (FCG), and control group (children and adolescents from biological families - CG). Descriptive data were calculated for all questionnaires? scores, while t-test and ANOVA were used to compare them. Results. The mean value of the total PedsQL was lower in the RCG, 67.47 ? 17.75, than in the FCG and the CG, 88.33 ? 11.27 and 80.74 ? 11.23, respectively. Additionally, the RCG reported lower all PedsQL Scale scores, but the lowest value was for the psychosocial domain. These differences were statistically significant (F value ranged from 17.3 to 49.89, p < 0.000). However, only the scores of the RCG were statistically different from the FCG and the CG, while the differences between the FCG and the CG were statistically insignificant (p > 0.05). Conclusion. Children and adolescents living in residential care have significantly poorer QOL than those living in foster care or in biological families. On the other side, QOL in children and adolescents from foster care is similar to the one of those living in biological families.
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Marcinowski, Jakub, and Zbigniew Różycki. "Reinforcement of Existing Cast-Iron Structural Elements by Means of Fiber Reinforced Composites / Wzmacnianie Istniejących, Żeliwnych Elementów Konstrukcyjnych za Pomocą Włóknokompozytów." Civil And Environmental Engineering Reports 20, no. 1 (March 1, 2016): 37–46. http://dx.doi.org/10.1515/ceer-2016-0004.
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Abstract The paperdeals with tubular, cast-iron columns which should be reinforced due to the planned new structural function of these elements. According to the requirements of the monument conservator the general appearance of columns should not be altered significantly. Reinforcement with an external, thin coating (sleeve or jacket) made of composite (carbon fibre reinforced polymer - CFRP) was proposed. Details of the proposedtechniquewerepresented. The reinforcementeffect was verifiedin destructivetestsperformed on two columns without reinforcement and the two other columns reinforced with the chosentechnique. Due to the expected very high load capacity of the axially loaded column, the test rig was designed in such a manner that the force could be applied on big eccentricity. For this purpose a specialbase was prepared(comp. Fig. 1). Destructivetests have confirmed the high effectiveness of the adopted strengthening technique.
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Garcia-Manero, Guillermo, Michael E. Petrone, Steven M. Fruchtman, Bernard Brownstein, Hannes Loferer, Nozar Azarnia, Shireen Vali, et al. "Computational Analysis of Genomic Abnormalities from a Phase 3 Trial of Rigosertib in Higher-Risk MDS: Simulation of a Predictive Signature for Clinical Response." Blood 128, no. 22 (December 2, 2016): 4324. http://dx.doi.org/10.1182/blood.v128.22.4324.4324.
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Abstract Background: MDS is a marrow stem cell disorder with limited treatments. Due to outcome heterogeneity of MDS, it is imperative to identify prognostic tools for patients in clinical trials. Rigosertib (RIG) is a RAS-mimetic that inhibits cellular signaling pathways by binding to the RAS-binding Domain found in RAS effector proteins. No approved treatment options are available for Higher-risk myelodysplastic syndromes (HR-MDS) pts after Hypomethylating Agent (HMA) failure. The "ONTIME" trial was a Phase III, randomized study of rigosertib in a heterogeneous population of HR-MDS pts who failed to respond to or progressed on HMAs. Aim: To determine the predictive value of a genomics-informed computational biology method and to design a patient selection signature in HR-MDS patients who are treated with RIG. Methods: ONTIME trial included HR-MDS pts who had progressed on (37% of total enrollment), failed to respond to (25%), or relapsed after (38%) HMA treatment. Patients were randomized 2:1 to receive RIG (199 pts) or best supportive care (BSC) (100 pts) (Garcia-Manero et al, Lancet Oncology, 2016).The primary endpoint was overall survival, analyzed on an intention-to-treat basis using the Kaplan-Meier method. Genomic DNA was isolated from single microscopic slides from 153 pts and subjected to sequence analysis of a "myeloid panel" comprising of 24 selected loci frequently mutated in MDS and AML. Standardized cytogenetic investigations were performed. The chromosome aberrations and clone definition followed the International System for Cytogenetic Nomenclature. Depending on the aberrations detected during karyotyping, further probes were applied. A complex karyotype was defined as ≥3 independent aberrations within 1 clone. These genomic results were input into predictive computational biology software (Cellworks Group, Fig. 1), which generates disease-specific dysregulated protein network maps using PubMed and other resources. Digital drug simulations are conducted by quantitatively measuring drug effect on a cell growth score, which is a composite of cell proliferation, viability and apoptosis. Each patient-specific protein network map was digitally screened for the extent by which RIG reduced disease growth in a dose-respondent manner. Clinical outcomes were prospectively recorded. Results: Based on input data from cell-culture studies the predicted response was blindly correlated with the clinical outcome for 54 patients with the following predictive test statistics: positive predictive value (PPV) - 85%, negative predictive value (NPV) - 94.12%, Sensitivity - 89.47%, Specificity - 91.43% and an accuracy of the predictive test at 90.74%. The accuracy of the genomics-informed computer method was significantly greater than empiric drug administration. New genomic signature rules were discovered to correlate with clinical response after RIG treatment. The predictive computational analysis identified a novel signature for selecting HR-MDS patient's responding to RIG. We identified patients with either trisomy 8 or trisomy 21 that also do not have any of the following aberrations including: Del 5q or Del 7/7q or Del 3 or Del 14 or Del 16 or Del 20, would be responders to the drug (Trisomy 8 OR Trisomy 21) AND NOT (Del 5 q OR (Del 7/7q OR Del 3 OR Del 14 or Del 16 or Del 20). We validated this patient selection rule prospectively via statistical correlation methods and through a computer based simulation of a clinical trial generated predicted Kaplan-Meir curve with a significant p-value of 0.003 (Fig. 2). Conclusions: A predictive computational method that models multiple high-risk MDS genomic abnormalities simultaneously showed greater than 90% correlation between protein network perturbations and clinical outcomes. The computational method also helps explain reasons for lack of response to RIG and highlights resistance pathways that could be targeted to recover chemo-sensitivity. This technology also established eligibility criteria for precision enrollment in drug development trials. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Petrone: Onconova Therapeutics, Inc.: Employment. Fruchtman:Onconova: Employment. Brownstein:Onconova Therapeutics, Inc.: Consultancy. Loferer:Onconova Therapeutics, Inc.: Employment. Azarnia:Onconova Therapeutics, Inc.: Employment. Vali:Cellworks Group: Employment. Singh:Cellworks Group: Employment. Usmani:Cellworks: Employment. Grover:Cellworks Group: Employment. Abbasi:Cellworks: Employment. Silverman:Onconova Therapeutics, Inc.: Patents & Royalties: Co-Patent holder for the combination of azacitidine and rigosertib, Research Funding.
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Wang, Zheng-fang, Jing Wang, Qing-mei Sui, Xun-mei Liang, Lei Jia, Shu-cai Li, and Shi-de Lu. "Development and Application of Smart Geogrid Embedded with Fiber Bragg Grating Sensors." Journal of Sensors 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/108209.
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Smart geogrids embedded with fiber Bragg grating (FBG) for reinforcement as well as measurement of geotechnical structures have been developed. After the fabricating process of the geogrids is detailed, finite element (FE) simulations are conducted to analyze the strain distribution of geogrids and the strain transfer characteristics from geogrids to fiber optic. Results indicate that FBG should be deployed in the middle of the geogrids rib to make sure that uniform strain distribution along the FBG. Also, PVC protective sleeves, which are used to protect fiber optic when integrated with geogrids, have smaller strain transfer loss than nylon sleeves. Tensile experiments are conducted to test strain measurement performance of proposed geogrids, and the results demonstrate that proposed smart geogrids have good linearity and consistency. Temperature experiments show that FBG embedded in geogrids has higher temperature sensitivity, and the temperature induced error can be compensated by an extra FBG strain-independent sensor. Furthermore, designed smart geogrids are used in a geotechnical model test to monitor strain during tunnel excavation. The strain tendency measured by smart geogrids and traditional strain sensor agree very well. The results indicate that smart geogrids embedded with FBGs can be an effective method to measure strains for geological engineering related applications.
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Zhen, Changqing, Mei Ding, Kang Lu, Xueling Ge, Na Chen, Xiaosheng Fang, Xiaohui Sui, et al. "A Randomized Controlled Clinical Study of Peg-Rhg-CSF for Preventing Chemotherapy-Induced Neutropenia in Patients with B-Cell Non-Hodgkin Lymphoma." Blood 134, Supplement_1 (November 13, 2019): 5323. http://dx.doi.org/10.1182/blood-2019-128438.
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Introduction: B-cell non-Hodgkin lymphoma is the most frequent type of non-Hodgkin's lymphoma. RCHOP regimen is established as the standard therapy for aggressive and indolent B-cell NHL, which has a 10%-20% rate of febrile neutropenia (FN). Recently, pegylated recombinant human granulocyte colony stimulating factor (PEG-rhG-CSF) is frequently used in clinical practice. This randomized controlled clinical study was conducted to investigate the efficacy and safety of prophylactic PEG-rhG-CSF in patients with B-cell non-Hodgkin lymphoma on RCHOP chemotherapy. Methods:We included 162 patients with pathological diagnosis of B-cell non-Hodgkin lymphoma including diffuse large B-cell lymphoma, follicular lymphoma and mantle cell lymphoma (MCL),from October 2016 to May 2019 at Shandong Provincial Hospital Affiliated to Shandong University. All patients gave written informed consent in accordance with the Declaration of Helsinki. The patients were randomized into PEG-rhG-CSF and rhG-CSF groups. Each patient received three cycles of chemotherapy with identical RCHOP regimens. In the study group, the patients received PEG-rhG-CSF 6mg(weight≥45Kg)or 3mg(weight≤45Kg)once 24 hours after the end of chemotherapy drugs of every chemotherapy cycle. In the control group, they weren't preventively administered rhG-CSF. If their neutrophil count (ANC)≤1.0×109/L, they were administered rhG-CSF:5ug/kg/day until their neutrophil count (ANC)≥2.0×109/L. The primary endpoint was the incidence of III/IV grade neutropenia and febrile neutropenia(FN) after each chemotherapy cycle. Meanwhile the rate of antibiotics application and safety were observed. Analyses were performed with SPSS Statistics 20.0 (IBM-SPSS, Chicago, Illinois). The numerical data was presented as mean ± SD. Statistical analysis was performed using one-way analysis of variance and chi-square test. A p-value<0.05 was considered statistically significant. Results: Clinical characteristics for PEG-rhG-CSF and rhG-CSF groups were shown in Table1. There were no significant differences in age, gender,height, body weight, body mass index, Ann Arbor and IPI staging. The incidence of IV grade neutropenia during cycle 1 in 81 evaluable study cycles and 81 evaluable control cycles were 7.41% and 35.80%( P<0.01), with durations of 2.85±0.62 days and 3.11±1.23 days (P>0.05). The differences in I/II/III grade neutropenia between study and control groups weren't statistically significant (Table2,Fig.1). After secondary prophylactic use of PEG-rhG-CSF In the study group, the incidences of III/IV grade neutropenia decreased from 77.78% to 14.81% (P<0.01).Statistically significant differences were observed in the incidences of FN (12.35% and 34.57% for the PEG-rhG-CSF and rhG-CSF groups, respectively; P<0.01) and in the proportion of patients who received antibiotic therapy (11.11% and 37.04%, respectively; P<0.01) during cycle 1(Table2,Fig .2). The safety profiles of PEG-rhG-CSF and rhG-CSF were similar. Bone pain occurred in 7.41% of the cases during the study cycles and 2.47% in the control cycles (P>0.05 ), which were mostly mild or moderate. Patients receiving PEG-rhG-CSF who developed III/IV grade neutropenia were significantly older than those without neutropenia (53.41±14.96 vs. 63.64±4.65;years; p=0.01) (Fig.3).The incidence of III/IV grade neutropenia in patients older than 60 years was significantly higher than that in patients younger than 60 years(24.44% vs. 6.38%; P =0.038). Conclusions: Prophylactic use of PEG-rhG-CSF could effectively reduce the incidences of grade III/IV neutropenia and FN, which ensures that patients with lymphoma receive standard-dose chemotherapy to improve prognosis. III/IV grade neutropenia after prophylactic use of PEG-rhG-CSF were more likely to occur in patients older than 60 years. After the use of PEG-rhG-CSF, the elderly patients should be pay more attention to them. Disclosures No relevant conflicts of interest to declare.
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Beaussant, Yvan, Etienne Daguindau, Aurore Vivot, Mohamad Mothy, Herve Avet-Loiseau, Damien Roos-Weil, Mauricette Michallet, et al. "Reduced Intensity Conditioning Regimens Do Not Offer a Survival Advantage to Myeloma Patients Receiving Allogeneic Stem Cell Hematopoietic Transplantation: A Societe Française De Greffe De Moelle Et De Therapie Cellulaire (SFGM-TC) Registry Study,." Blood 118, no. 21 (November 18, 2011): 4113. http://dx.doi.org/10.1182/blood.v118.21.4113.4113.
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Abstract Abstract 4113 Purpose: Despite the raise of major new drugs in the management of multiple myeloma (MM), it is still an incurable disease and allogeneic stem cell transplantation (alloSCT) is currently the sole potential curative therapy mediated by a graft-versus-myeloma (GVM) effect. For over ten years, reduced intensity conditioning regimens (RIC) in alloSCT has been developed to maintain the GVM effect and to decrease the high transplanted related mortality (TRM) associated with myeloablative conditioning (MAC) in myeloma patients. Yet, as numerous studies have assessed RIC alloSCT versus autologous SCT, only few data provides a comparison between RIC and MAC for MM in large series. Our study aims to compare RIC and MAC alloSCT for MM on a large retrospective French cohort. Methods: We report a retrospective multicenter study based on the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) registry, evaluating the outcome of patients undergoing alloSCT for MM. Between 1995 and 2009, 811 patients allografted for MM were registered. Data concerning disease characteristics and the allograft procedure were screened using the French Promise® database; computerized discrepancy errors and data verification of every single file ensure data quality, important missing data were directly retrieved in each centre. We assign the type of conditioning regimen for each patient according to the registry's data reported by the local physician and check this information according to the following rules. We consider as myeloablative (MAC) all regimens containing > 8 mg/kg oral busulfan, > 600 cGY TBI, ≥ 200 mg/kg cyclophosphamide or combinations as BEAM like regimens. All other chemotherapy combinations with or without TBI are defined as RIC regimens generally including fludarabine. Patients were excluded when major data or conditioning information were not available; 566 patients (70% of the entire cohort) were finally eligible for analysis, 478 RIC and 88 MAC. Chi-squared test and T-test were used for comparisons. Survival analyses (Overall survival, OS; progression-free survival, PFS) are made using the Kaplan-Meier curve and log rank test. Multivariate analysis is made using the Cox proportional hazards model. Results: The RIC and MAC populations were statistically different regarding age (respectively 53 versus 46 years, p<.0001), number of prior transplant (> 1 prior transplant in 94% RIC versus 77% MAC, p<.0001), time to transplantation (<12 months after diagnosis in 22% RIC versus 38% MAC, p=.001) and stem cell source (peripheral blood 84% RIC versus 52% MAC, p<.0001, and bone marrow 10% RIC versus 45% MAC, p<.0001). The 2-year OS is 69.5% after RIC and 79.9% after MAC (p<.0001); 5-year OS is 49.7% after RIC and 60.2% after MAC (p<.0001, fig.1). The 2 year PFS is 49.3% and 70.1% and 5-year PFS is 29.6% and 40.8% after RIC and MAC respectively (p<.0001, fig.2). Factors associated with better OS and PFS in multivariate analysis are the following in the whole cohort: < 12 months between diagnosis and alloSCT (p=.0078 and p=.0037, respectively); disease status at transplantation (at least partial response, p=.0409 and p=.0026); no or limited acute graft-versus-host disease (GvHD) (p<.0001 and p=.0094) and presence of chronic GvHD (p<.0001 and p<.0001). On multivariate analysis, the intensity of conditioning regimen (RIC vs MAC) do not appear statistically significant for OS (p = 0.64) and PFS (p = 0.17). For patients transplanted between 2006 and 2009, neither high risk-cytogenetic nor bortezomib use before transplantation seems to affect the outcome in multivariate analysis. Conclusions: In the French practice, MAC regimens have had more limited indications due to their higher toxicity. This study suggests that the outcome after MAC-alloSCT is comparable to that after RIC-alloSCT with a trend to a better OS in the late follow-up (after 5 years) after MAC. The aspect of flattening in the survival curves suggests that the anti-tumoral action of the conditioning regimen remains essential on the anti-myeloma effect after alloSCT and that should be considered in the transplantation procedure. Disclosures: No relevant conflicts of interest to declare.
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Guo, Xuan, Wen Sun, Guangyuan Xu, Dan Hou, Zhuo Zhang, Lili Wu, and Tonghua Liu. "RNA-Seq Analysis of the Liver Transcriptome Reveals the Networks Regulating Treatment of Sitagliptin Phosphate plus Fuzhujiangtang Granule in the Zucker Diabetic Fatty Rats." Evidence-Based Complementary and Alternative Medicine 2020 (April 13, 2020): 1–23. http://dx.doi.org/10.1155/2020/8463858.
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Diabetes is one of the most serious chronic diseases. Numerous drugs including oral agents and traditional Chinese medicines, such as sitagliptin phosphate (SP) and Fuzhujiangtang granules (FJG), have been discovered to treat diabetes and used in combination in clinical practice. However, the exact effect and underlying mechanism of using combined medicine is not clear. In this study, we compared the antidiabetic effect of SP, FJG, and SP plus FJG (SP-FJG) using forty 8-week-old Zucker diabetic fatty (ZDF) rats and 10 age-matched Zucker lean rats as the normal control group. ZDF rats were treated with different therapies, respectively, for 6 weeks. The study showed that the fast blood glucose, random blood glucose (RBG), oral glucose tolerance test (OGTT), insulin tolerance test (ITT), homeostasis model of assessment-insulin resistance index, triglyceride (TC), superoxide dismutase, and malondialdehyde of each treatment group were improved when compared with the diabetes mellitus (DM) control group. Using SP-FJG in combination had better improvements in OGTT, fast serum insulin levels, TNF-α, and IL-6 compared with using SP individually. Besides, the increased LDL and TC caused by using SP was attenuated by using FJG in combination. Meanwhile, compared with the DM group, 1781 differentially expressed genes (DEGs) (including 1248 mRNA, 211 ncRNA, 202 cirRNA, and 120 miRNA) were enriched in 58 pathways. Through analysis of ceRNA networks, we found that rno-miR-326-3p, rno-miR-423-5p, rno-miR-15b-5p, rno-let-7c-5p, and rno-let-7b-5p were related to pharmacodynamics in different groups. By analyzing the protein-protein interaction (PPI) and coexpression networks of the transcriptomes of different groups, it is inferred that Lrrk2 and Irak3 may be pharmacodynamic genes for type 2 diabetes mellitus (T2DM). Our research compared the treatment of SP, FJG, and SP-FJG and acquainted the PPI network, coexpression network, mutations, and pharmacodynamics genes, which reveals the new mechanisms of pathogenesis of T2DM.
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Cheymol, G., L. Remy, A. Gusarov, D. Kinet, P. Mégret, G. Laffont, T. Blanchet, A. Morana, E. Marin, and S. Girard. "Test of Fibre Bragg Gratings samples under High Fast Neutrons Fluence." EPJ Web of Conferences 170 (2018): 04004. http://dx.doi.org/10.1051/epjconf/201817004004.
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Optical fibre sensors (OFS) are worthy of interest for measurements in nuclear reactor thanks to their unique features, particularly compact size and remote multi-point sensing for some of them. But besides non negligible constraints associated with the high temperature environment of the experiments of interest, it is well known that the performances of OFS can be severely affected by high level of radiations. The Radiation Induced Attenuation (RIA) in the fibre is probably most known effect, which can be to some extent circumvented by using rad hard fibres to limit the dynamic loss. However, when the fast neutron fluence reaches 1018 to 1019 n/cm2, the density and index variations associated to structural changes may deteriorate drastically the performances of OFS even if they are based on rad hard fibres, by causing direct errors in the measurements of temperature and/or strain changes. The aim of the present study is to access the effect of nuclear radiations on the Fabry Perot (FP) and of Fibre Bragg Grating (FBG) sensors through the comparison of measurements made on these OFS - or part of them - before and after irradiation [1]. In the context of development of OFS for high irradiation environment and especially for Material Testing Reactors (MTRs), Sake 2 experiment consists in an irradiation campaign at high level of gamma and neutron fluxes conducted on samples of fibre optics – bare or functionalised with FBG. The irradiation was performed at two levels of fast neutron fluence: 1 and 3.1019 n/cm2 (E>1MeV), at 250°± 25°C, in the SCK•CEN BR2 reactor (Mol Belgium). An irradiation capsule was designed to allow irradiation at the specified temperature without active control. The neutron fluence was measured with activation dosimeters and the results were compared with MCPN computations. Investigation of bare samples gives information on the density changes, while for the FBGs both density and refractive index perturbation are involved. Some results for bare fibres were reported recently. In this paper, we will focus on the measurements made on FBGs that have been manufactured by different laboratories on SMF 28 fibers: CEA, University of St-Etienne and University of Mons. Tested gratings have been written using various conditions (type of fibre, of laser, writing wavelength, power density, post writing thermal annealing,…), leading to various behaviours after Sake 2 irradiation. Bragg wavelength and reflectivity have been measured before and after irradiation thanks to a special mounting at the same temperature. It appears that a change in the shape after irradiation of the Bragg peak disturb the retrieval of the Bragg wavelength. The measurements show that for nearly all gratings the Bragg peak remains visible after the irradiation, and that Radiation Induced Bragg Wavelength Shifts (RI-BWSs) vary from few pm (equivalent to an error of less than 1°C for a temperature sensor) to nearly 1 nm (equivalent to 100°C) depending of the FBG types. High RI-BWSs could indeed be expected when considering the huge refractive index variation and compaction of the bare fibre samples that have been measured by other techniques. Post writing thermal annealing is confirmed as a key parameter in order to obtain a more radiation tolerant FBG. Our results show that specific annealing regimes allow making FGBs suitable to perform temperature measurements in a MTR experiment.
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Abubakar, Muhammad, and Muhammad Atif. "Impact of Pharmacist-Led Interventions on Diabetes Management at a Community Pharmacy in Pakistan: A Randomized Controlled Trial." INQUIRY: The Journal of Health Care Organization, Provision, and Financing 58 (January 2021): 004695802110362. http://dx.doi.org/10.1177/00469580211036283.
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Purpose The study aimed to determine the impact of pharmacist-led interventions on diabetes management at a community pharmacy in Pakistan. Methods A one-month follow-up, randomized controlled trial (RCT) was carried out between December 1, 2016 and June 30, 2017. Sampling population consisted of patients diagnosed with type 2 diabetes mellitus (T2DM). The study population was randomized to a control group or an intervention group to determine the impact of a community pharmacist intervention on glycemic control fasting blood glucose (FBG) and random blood glucose (RBG), medication adherence (MMAS), and health-related quality of life (HRQoL) (EQ-5D-3L). Both non-pharmacological and pharmacological interventional tools were used that consist of array of charts and verbal communication by pharmacist. Outcomes for continuous variables were analyzed using paired sample t-test for time effect and one sample t-test to evaluate the study group effect. Independent sample t-test was used to compare each independent variable with dependent variable. A P-value of <.05 was considered statistically significant. Results The control and intervention groups showed significant improvement ( P-value < .05) in glycemic control, medication adherence, and HRQoL. However, the difference between the control and intervention groups was not statistically significant in terms of blood glucose levels and HRQoL (time trade off, TTO). There was a clinically significant association between pharmacist intervention and predefined glycemic control among the study participants (FBG: P-value < .001 and RBG: P-value = .04). A clinically significant association was also found between pharmacist intervention and medication adherence at the end of the trial compared with baseline values ( P-value < .001). Similarly, a clinically significant association was found between pharmacist intervention and predefined HRQoL [TTO: P-value = .002 and EQ-VAS: P-value = .001]. Conclusion A significant proportion of T2DM patients in the intervention group achieved predefined glycemic control, medication adherence, and health related quality of life.
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Vadas, Zahava, Eti Ganon-Elazar, Yuval Nov, Israel Henig, Dina Attias, Nuhad Haddad, Riva Fineman, Jacob M. Rowe, and Tsila Zuckerman. "Semaphorin 3A Expression on Donor and Recipient Regulatory Cells: A Novel Pre-Transplant Biomarker Predicting the Development of Acute Graft-Versus-Host Disease." Blood 124, no. 21 (December 6, 2014): 3935. http://dx.doi.org/10.1182/blood.v124.21.3935.3935.
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Abstract Introduction: Acute graft-versus-host disease (aGVHD) is a major limitation of allogeneic stem cell transplantation (alloSCT) due to associated morbidity and mortality. A search for biomarkers that predict its occurrence is continuously evolving. Regulatory T cells (T regs) have been shown to suppress the early expansion of alloreactive donor T cells and limit the capacity to induce GVHD without minimizing the graft-versus-leukemia (GVL) effect. Recently, the role of regulatory B cells (B reg) in GHVD was demonstrated, with exacerbation of GVHD in both donor and host mice lacking functional regulatory B cells. Semaphorin 3A (Sema3A) is an immunoregulatory molecule secreted by activated B, T and antigen presenting cells. It enhances suppressor ability of B and T regulatory cells by increased secretion of interleukin-10 (IL-10) and transforming growth factor β (TGF-β). The aim of the present study was to explore whether Sema3A expression on B reg and T reg cells from donors and/or recipients pre- or early post-transplantation can predict occurrence of aGVHD. Methods: Thirty four consecutive patients referred to alloSCT were included in the first study cohort. Additionally, 10 donor/recipient (D/R) pairs were enrolled. All participants signed informed consent. 20 cc of fresh peripheral blood were drawn from recipients at day -7 pre-alloSCT and upon WBC engraftment, as well as from their corresponding donors. Mononuclear cells were isolated using ficoll gradient separation and subjected to FACS analysis using monoclonal antibodies evaluating the level of Sema3A expression on B reg cells (CD19/CD25high/ Sema3A), T reg cells (CD4/CD25high/Sema3A) and natural killer (NK) cells (CD3/CD56). Cutoff for positive expression of Sema3A on regulatory cells was considered only if ≥20% of cells expressed the above phenotype of T, B cell and NK population. The FACS results correlated with occurrence of clinical aGVHD grade II-IV. Descriptive statistical analysis and student t test are used to describe results. Results: Overall, 44 recipients were analyzed. Median age at transplant was 49.9 (18-69), 34 were diagnosed with acute leukemia/MDS, 8 - lymphoproliferative and 2 - myeloproliferative diseases. All patients received peripheral mobilized stem cells. Myeloablative conditioning was administered to 33 and reduced intensity to 11 patients. GVHD prophylaxis consisted of standard cyclosporine and methotrexate. Twenty patients developed aGVHD grade II-IV, mostly grade II –III (80%). Recipient expression of Sema3A on B cells pre-transplant was higher in patients without aGVHD versus those with aGVHD (79.9% vs 69.5%, respectively; p<0.005) while pre-transplant expression of Sema3A on T cells was similar in patients without and with aGVHD (57.3% vs 58.6%, respectively) (fig 1). Post-transplant, recipient expression of Sema3A on B and T cells was similar in patients without and with aGVHD (B cells: 84.1% vs 79.1%, T cells 62.6 vs 58.4, respectively) (fig 2). In donors, the expression of Sema3A on regulatory T cells was higher if their recipients did not develop aGVHD as compared to the expression in donors with recipients who developed aGVHD (51.0% vs 36.2%). Sema3A expression on regulatory B cells was not different in donors, no matter whether recipients did not or did develop aGVHD (52.2% vs 55.0%, respectively) (fig 3). Sema3A expression on NK cells was below our determined threshold. Conclusion: This is the first report of a correlation of Sema3A expression with the occurrence of aGVHD, opening a potentially important opportunity for early clinical intervention. Specifically, 1. Pre-transplant recipient Sema3A expression on B reg cells is significantly higher in patients who will not develop aGVHD. 2. Pre-transplant high expression of Sema3A on donor T reg cells is associated with a lower risk of aGVHD development in their corresponding recipients. 3. Sema3A expression on recipient T reg cells does not correlate with occurrence of aGVHD. Further studies with a larger patient cohort validation are needed to confirm the above findings. Disclosures No relevant conflicts of interest to declare.
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Braunfelds, Janis, Ugis Senkans, Peteris Skels, Rims Janeliukstis, Toms Salgals, Dmitrii Redka, Ilya Lyashuk, et al. "FBG-Based Sensing for Structural Health Monitoring of Road Infrastructure." Journal of Sensors 2021 (January 8, 2021): 1–11. http://dx.doi.org/10.1155/2021/8850368.
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Public road infrastructure is developed all around the world. To save resources, ensure public safety, and provide longer-lasting road infrastructure, structural health monitoring (SHM) applications for roads have to be researched and developed. Asphalt is one of the largest used surface materials for the road building industry. This material also provides relatively easy fiber optical sensor technology installment, which can be effectively used for SHM applications—road infrastructure monitoring as well as for resource optimization when road building or their repairs are planned. This article focuses on the research of the fiber Bragg grating (FBG) optical temperature and strain sensor applications in road SHM, which is part of the greater interdisciplinary research project started at the Riga Technical University in the year 2017. Experimental work described in this article was realized in one of the largest Latvian road sites where the FBG strain and temperature sensors were installed into asphalt pavement, and experiments were carried out in two main scenarios. Firstly, in a controlled environment with a calibrated falling weight deflectometer (FWD) to test the installed FBG sensors. Secondly, by evaluating the real-time traffic impact on the measured strain and temperature, where different types of vehicles passed the asphalt span in which the sensors were embedded. The findings in this research illustrate that by gathering and combining data from calibrated FWD measurements, measurements from embedded FBG optical sensors which were providing the essential information of how the pavement structure could sustain the load and information about the traffic intensity on the specific road section, and the structural life of the pavement can be evaluated and predicted. Thus, it enables the optimal pavement future design for necessary requirements and constraints as well as efficient use, maintenance, and timely repairs of the public roads, directly contributing to the overall safety of our transportation system.
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Braunfelds, Janis, Ugis Senkans, Peteris Skels, Rims Janeliukstis, Toms Salgals, Dmitrii Redka, Ilya Lyashuk, et al. "FBG-Based Sensing for Structural Health Monitoring of Road Infrastructure." Journal of Sensors 2021 (January 8, 2021): 1–11. http://dx.doi.org/10.1155/2021/8850368.
Full textAbstract:
Public road infrastructure is developed all around the world. To save resources, ensure public safety, and provide longer-lasting road infrastructure, structural health monitoring (SHM) applications for roads have to be researched and developed. Asphalt is one of the largest used surface materials for the road building industry. This material also provides relatively easy fiber optical sensor technology installment, which can be effectively used for SHM applications—road infrastructure monitoring as well as for resource optimization when road building or their repairs are planned. This article focuses on the research of the fiber Bragg grating (FBG) optical temperature and strain sensor applications in road SHM, which is part of the greater interdisciplinary research project started at the Riga Technical University in the year 2017. Experimental work described in this article was realized in one of the largest Latvian road sites where the FBG strain and temperature sensors were installed into asphalt pavement, and experiments were carried out in two main scenarios. Firstly, in a controlled environment with a calibrated falling weight deflectometer (FWD) to test the installed FBG sensors. Secondly, by evaluating the real-time traffic impact on the measured strain and temperature, where different types of vehicles passed the asphalt span in which the sensors were embedded. The findings in this research illustrate that by gathering and combining data from calibrated FWD measurements, measurements from embedded FBG optical sensors which were providing the essential information of how the pavement structure could sustain the load and information about the traffic intensity on the specific road section, and the structural life of the pavement can be evaluated and predicted. Thus, it enables the optimal pavement future design for necessary requirements and constraints as well as efficient use, maintenance, and timely repairs of the public roads, directly contributing to the overall safety of our transportation system.
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Kim, Haesook T., Zhen-Huan Hu, Kwang Woo Ahn, Matthew Davids, Virginia Volpe, Edwin Alyea, Uday Popat, Ronald Sobecks, Wael Saber, and Jennifer Brownn. "Prognostic Score and Cytogenetic Risk Classification for Chronic Lymphocyteic Leukemia Patients Who Underwent Reduced Intensity Conditioning Allogeneit HCT: A CIBMTR Report." Blood 130, Suppl_1 (December 7, 2017): 667. http://dx.doi.org/10.1182/blood.v130.suppl_1.667.667.
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Abstract BACKGROUND: Despite the emerging data on the clinical effectiveness of the B cell receptor pathway inhibitors, complete remission is rarely induced and chronic lymphocytic leukemia (CLL) remains incurable. Reduced intensity/non-myeloablative conditioning (RIC/NMA) allogeneic hematopoietic cell transplantation (HCT) has been widely used in previously treated CLL patients and remains the only potentially curative therapy. The goal of this study is to develop a prognostic model and cytogenetic risk classification for CLL patients who undergo RIC/NMA HCT. METHODS: We performed a retrospective data analysis of 606 patients with previously treated CLL reported to the Center for International Blood and Marrow Transplant Research between 2008 and 2014. To develop a prognostic model, the entire data set was randomly split into training (60%) and test sets (40%). Using the training set, a prognostic model was developed and validated in the test set. Primary endpoint was progression free survival (PFS). Cytogenetic risk was also classified using a multivariable model for PFS. RESULTS: Of 606 patients who underwent RIC/NMA, the median age was58 (26, 73) and 72% were male. 32.2% had del17p and 27.3% had 3 or more cytogenetic abnormalities. The median follow up time among survivors was 47.3 months (range 3, 99). In multivariable Cox model for PFS, disease status at HCT (CR/PR vs no CR/PR), comorbidity score (0-1 vs ≥2), lymphocyte count at HCT (<2000 vs ≥2000/uL) and WBC at HCT (2-10 vs <2 or >10) were selected for the model. All other factors including age were not significant at the 0.05 level. Based on the hazard ratios (HRs) of these factors in the multivariable model, a score was assigned to each factor (1 if HR<1.5, 2 if HR>=1.5). Based on the summed score (range 0-6), patients were grouped into low (0), intermediate (1), high (2-3), and very high (≥4) risk categories. This result from the training set was validated in the test set (Fig.1A-B). For the entire cohort, the 4-year(y) PFS was 56% (95% confidence intervals [CI] 48-63), 42% (95% CI 33-51), 34% (95%CI 27-42), and 23% (95%CI 15-32) for low, intermediate, high and very high, respectively, p<0.0001 (Table 1A, Fig. 2A). This prognostic model also stratified OS, NRM and relapse. In multivariable analysis, abnormal cytogenetics due to any of del13q, del11q, trisomy 12 (typically by FISH) or 3-4 abnormalities by karyotype had no impact on PFS. Only del17p and ≥5 abnormalities by karyotype showed inferior PFS. Based on HRs from the multivariable model, cytogenetic risk was classified as low (no del17p and <5 abnormalities), intermediate (no del17p with ≥5 complex or del17p without complex) and high (del17p with complex). The 4y PFS was 48% (95% CI 41-54), 37% (95% CI 27-48), and 23% (95% CI 14-33) for low, intermediate and high cytogenetics risk, respectively, p<0.0001 (Table 1B, Fig. 2B). When the prognostic score and cytogenetic risk were combined, patients with low prognostic score and low cytogenetic risk had prolonged PFS (4y PFS 59%, 95%CI 48-67) and OS (4y OS 72%, 95%CI 62-80) whereas patients with high-risk cytogenetics did poorly irrespective of the prognostic score (4y PFS 23%, 95%CI 14-33; 4y OS 43%, 95%CI 31-55). CONCLUSIONS: In this large cohort of previously treated CLL patients who underwent RIC/NMA HCT in a multicenter setting, we successfully developed and validated a novel prognostic scoring system of HCT outcomes. This is the first score in the literature to risk stratify CLL patients at the time of HCT. We also developed a novel cytogenetic based risk stratification system. And finally we combined these two systems into one system. These data can be used for counseling patients, comparing data across different studies, and providing a platform for the evaluation of future interventions. Disclosures No relevant conflicts of interest to declare.
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He, Hairong, Jian Fen Zhang, Na Zhang, Songming Du, Shufang Liu, and Guansheng Ma. "The Influence of Fluid Intake Behavior on Cognition and Mood among College Students in Baoding, China." Annals of Nutrition and Metabolism 76, Suppl. 1 (2020): 63–64. http://dx.doi.org/10.1159/000515020.
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<b><i>Introduction:</i></b> Water is a critical nutrient, and it is important for the maintenance of the physiological function of the human body [<xref ref-type="bibr" rid="ref1">1</xref>-<xref ref-type="bibr" rid="ref3">3</xref>]. In addition to fluid amounts, fluid intake frequency is also important for hydration status [<xref ref-type="bibr" rid="ref4">4</xref>, <xref ref-type="bibr" rid="ref5">5</xref>]. At present, only few guidelines mention fluid intake behavior that recommend drinking water frequently while in small quantities, however, there is no scientific evidence to support it. Therefore, it is necessary to explore the appropriate fluid intake behavior. <b><i>Objective:</i></b> The objective of this study is to evaluate the influence of different fluid intake behavior on cognition and mood, to provide scientific basis for proposing the appropriate fluid intake behavior. <b><i>Methods:</i></b> A double-blinded randomized controlled trial was designed and implemented among college students aged 18–23 years in Baoding, China. Subjects were randomly assigned into each of 3 groups using a random number generated by computer software: the subjects consuming plain water 200 mL/2 h, that is, 1,600 mL during whole day (group 1), 100 mL/2 h, that is, 800 mL during whole day (group 2), and 110 mL/1 h, that is, 1,650 mL during whole day (group 3), respectively. Subjects were asked to fast from 11:00 p.m., without consuming any foods or drinks the day before the intervention. From 8:00 a.m. to 10:00 p.m. of the first study day, subjects consumed water according to the instructions and repeated it from 8:00 a.m. to 4:00 p.m. of the second study day. Cognition, mood, and urine osmolality were collected twice at 10:00 a.m. (time 1) and 4:00 p.m. (time 2) of the second study day (shown in Fig. <xref ref-type="fig" rid="f01">1</xref>). <b><i>Results:</i></b> A total of 92 subjects (46 males, 46 females) completed this study. It was found that the increasing fluid intake amounts lead to an increase in urine output and a decrease in urine osmolality (<i>p</i> < 0.05). Use the mixed models to compare measurements for groups 1 and 2, which showed that when compared with those drinking 800 mL per day, people who drank 1,600 mL per day scored higher in vigor (11.8 vs. 9.1, <i>p</i> < 0.05) and portrait memory test (22.6 vs. 20.8, <i>p</i> < 0.05) but lower in total mood disturbance (90.8 vs. 97.8, <i>p</i> < 0.05). By comparing groups 1 and 3, the results indicated that compared with drinking 8 times per day, people who drank 15 times per day scored lower in portrait memory test (21.8 vs. 22.6, <i>p</i> < 0.05) and hunger (3.3 vs. 3.6, <i>p</i> < 0.05). <b><i>Conclusions:</i></b> Reasonable fluid intake behavior may be beneficial to improve the cognition and mood of college students. The fluid intake behavior, which is consuming water 200 mL each time and 8 times per day, is recommended. More studies are needed to advise people to have health-beneficial fluid intake behavior.
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Reshef, Ran, James K. Mangan, Selina M. Luger, Alison Wakoff Loren, Elizabeth O. Hexner, Noelle V. Frey, Edward A. Stadtmauer, et al. "Extended CCR5 Blockade in Graft-Versus-Host Disease Prophylaxis – a Phase II Study." Blood 124, no. 21 (December 6, 2014): 2491. http://dx.doi.org/10.1182/blood.v124.21.2491.2491.
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Abstract Background: Blocking lymphocyte trafficking after allogeneic stem cell transplantation (alloSCT) may prevent graft-versus-host disease (GvHD) without interfering with graft-versus-tumor (GvT) activity. We previously reported that brief (up to day+30) CCR5 blockade using maraviroc (MVC, Pfizer) after reduced-intensity conditioned (RIC) alloSCT resulted in a low incidence of acute GvHD and absence of early liver and gut GvHD, although delayed GvHD still occurred. We designed a phase II study to test the hypothesis that extended administration of MVC would be feasible, safe and provide protection against late-onset GvHD without impairing immune reconstitution or GvT responses. Patients and Methods: In April 2013 we initiated a 37-patient (pt) phase II study to test an extended course of MVC in recipients of RIC alloSCT from unrelated donors. Pts receive fludarabine 120 mg/m2 and busulfan i.v. 6.4 mg/kg followed by peripheral blood stem cells. MVC 300 mg b.i.d. is orally administered from day -3 to day +90 in addition to standard prophylaxis with tacrolimus and methotrexate. The primary endpoint is the cumulative incidence of grade 2-4 acute GvHD by day 180. As of July 2014 we enrolled 20 pts at high risk for transplant-related toxicity by virtue of age (median=64, range 55–72), donor source (matched unrelated 80%, single-antigen mismatch unrelated 20%) or comorbidities (comorbidity index: low 15%, intermediate 35%, high 50%). Underlying diseases were AML (16), MDS, MPD, ALL and CTCL (1 each). Feasibility and Safety: The median follow-up on surviving patients is 5.7 months. The 3-month course of MVC was well tolerated with no increased toxicity; two pts did not complete their treatment due to early disease relapse and one patient discontinued therapy due to a skin reaction with eosinophilia where the histological features favored a drug reaction and the attribution to MVC was possible. Postural hypotension, a known dose-dependent toxicity, was observed in one pt who completed the course with a 50% dose reduction. Engraftment and Immune Reconstitution: The median time to ANC>500/μL was 12 d (range 10-21) and platelets>20k/μL was 14 d (range 9-28). The median whole blood and T-cell donor chimerism levels at day 100 were 95% (range 12–100%) and 80% (range 23–94%) respectively, which are similar to historical rates. Median CD4 counts on day 30 were 341 (range 206-424). Only 3/16 evaluable pts had Ig levels<500 mg/dL in the first 100 days. GvHD: Sixteen pts are evaluable with > 3 mo of follow-up. The day-180 cumulative incidence rates (± s.e.) of grade 2-4 and grade 3-4 acute GvHD are 25 ± 11% and 6 ± 6% respectively (Fig. 1). Of patients who developed acute GvHD in the first 180 days, there have been no cases of liver GvHD, 2 cases of stage 1 steroid-responsive gut GvHD and 1 case of severe diarrhea with combined features of GvHD and leukemic infiltrates in the gut. These results are comparable to the GvHD rates in our phase I/II MVC study (grade 2-4: 23.6% and grade 3-4: 5.9%), which included related and unrelated donor transplants. These results also compare favorably with a 45% day-180 acute GvHD rate seen in similar patients treated with our standard GvHD prophylaxis alone. Notably, there has been no treatment-related mortality. Five patients have relapsed at a median of 2.6 months post-transplant (range 0.93 – 3.5), which is similar to our historical rates after RIC alloSCT. PD analysis: We developed a phosphoflow assay to assess in real-time the activity of MVC in fresh blood samples. The assay quantifies the activation of CCR5 by measuring the phosphorylation of C-terminal serine residues as a result of CCL4 stimulation. In 15 evaluable patients, we observed diminished pCCR5 levels with CCL4 stimulation on day 0 as compared to day -6 (Fig. 2). In summary, our preliminary results support the feasibility, safety and protective activity of the CCR5 antagonist MVC against acute GvHD, with preferential activity against visceral GvHD. Continued pt enrollment and follow-up are ongoing. Updated safety, efficacy and PD results will be presented. A multi-center study (BMT-CTN 1203) will be initiated later this year to further clarify the role of this novel strategy in improving the outcome of alloHSCT. Fig 1. Cumulative Incidence of Acute GvHD Fig 1. Cumulative Incidence of Acute GvHD Fig 2. Phosphoflow shows CCR5 unresponsiveness to CCL4 stimulation on day 0 Fig 2. Phosphoflow shows CCR5 unresponsiveness to CCL4 stimulation on day 0 Disclosures Reshef: Pfizer: Research Funding. Off Label Use: Maraviroc for graft-versus-host disease prophylaxis.
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Aoki, Takeshi, Hongxiang Hui, Yutaka Umehara, Sergio Licalzi, Achilles A. Demetriou, Jacek Rozga, and Riccardo Perfetti. "Intrasplenic Transplantation of Encapsulated Genetically Engineered Mouse Insulinoma Cells Reverses Streptozotocin-Induced Diabetes in Rats." Cell Transplantation 14, no. 6 (July 2005): 411–21. http://dx.doi.org/10.3727/000000005783982990.
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Pancreatic islet transplantation is limited by shortage of donor organs. Although β-cell lines could be used, their secretion of insulin is characteristically glucose independent and immunoisolation is required. Here we show that intrasplenic transplantation of encapsulated glucose-responsive mouse insulinoma cells reversed streptozotocin (STZ)-induced diabetes in rats. MIN-6 cells derived from a transgenic mouse expressing SV 40 large T antigen in pancreatic β-cells were transfected with minigene encoding for human glucagon-like-peptide-1 under the control of rat insulin promoter. The cells were encapsulated in alginate/poly-L-lysine and used for cell transplantation in STZ-diabetic rats. Rats with nonfasting blood glucose (n-FBG) greater than 350 mg/dl were used. In group I rats (n = 6) 20 million encapsulated cells were injected into the spleen. Group II rats (n = 6) received empty capsules. n-FBG was measured biweekly. After 4 and 8 weeks, an intraperitoneal glucose tolerance test (IPGTT) was performed in group I; normal rats served as controls. Plasma insulin level was measured every other week (RIA). After 8 weeks, spleens were removed 1 day before sacrifice. In rats transplanted with cells the n-FBG was 100—150 mg/dl until the end of the study. After splenectomy, all cell recipients became diabetic (glucose 400 ± 20 mg/dl). Transplanted rats showed increase in body weight and insulin production (3.3 ± 1.0 ng/ml versus 0.92 ± 0.3 ng/ml; p < 0.01) and had normal IPGTT. Spleens contained capsules with insulin-positive cells. Overall, data from this work indicate that intrasplenic transplantation of xenogeneic encapsulated insulin-producing cells without immunosuppression reversed diabetes in rats. Excellent survival and function of the transplanted cells was due to the fact that the cells were separated from the bloodstream by the immunoisolatory membrane only and insulin was delivered directly to the liver (i.e., in a physiological manner).
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Karaesmen, Ezgi, Abbas A. Rizvi, Junke Wang, Michael Sovic, Qianqian Zhu, Li Yan, Leah Preus, et al. "Genome Wide Interaction Analysis Identifies Expression Quantitative Trait Loci Associated with Reduced Survival after Reduced Intensity Conditioning HLA-Matched Unrelated Donor Allogeneic Hematopoietic Cell Transplant." Blood 134, Supplement_1 (November 13, 2019): 4595. http://dx.doi.org/10.1182/blood-2019-129182.
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Conditioning regimen intensity before allogeneic blood or marrow transplant (BMT) can be modified from myeloablative (MAC) to reduced intensity (RIC) to promote a graft versus tumor effect or minimize toxicity in older patients or those with comorbidities. However, the benefits of using RIC over MAC remain inconclusive as overall survival (OS) rates are similar. Prior genome wide association studies (GWAS) in solid tumor and autoimmune patients have shown that single nucleotide polymorphisms (SNPs) can affect patient response and toxicity after treatment with cyclophosphamide, busulfan and melphalan. Thus, it is possible SNPs may also affect patient response or toxicity to a given conditioning regimen or regimen intensity, guide regimen selection for a given patient or determine if disease recurrence is more likely for a given regimen or intensity. SNPs associated with patient response are significantly enriched for expression quantitative trait loci (eQTLs). eQTLs are genomic loci that explain significant proportions of inter-individual variability in mRNA levels in a given tissue for one or more genes. This suggests that selecting eQTLs a priori for the identification of genetic predictors for patient response could provide important insights into the likely function of identified SNPs. We hypothesized that recipient eQTL SNPs may interact with conditioning intensity to impact post-BMT OS and performed a genome wide interaction study (GWIS) to test the interaction of eQTL SNPs with conditioning intensity (MAC or RIC) and post-BMT OS in a large cohort of AML, MDS and ALL patients. Our GWIS included European ancestry patients from the DISCOVeRY-BMT study, a GWAS of >3,000 ALL, AML or MDS patients and their 8/8 HLA-matched unrelated donors reported to the CIBMTR between 2000-2011 (Table 1). SNPs were selected for inclusion in OS models if there was significant evidence that they modified expression in whole blood tissue in an independent study of over 30,000 samples (eQTLGen). After quality control and filtering (minor allele frequency >1% and info score > .8) 1,401,296 recipient eQTL SNPs were tested for interaction with MAC/RIC in the two DISCOVeRY-BMT cohorts; multiple test correction for the number of independent eQTLs (R2 < .2) was P < 9.41×10-7. We constructed Cox proportional hazard models for OS with clinical covariates including patient age, disease status at transplant, source of graft (bone marrow or peripheral blood) and an interaction term for each eQTL SNP and conditioning intensity (SNP×MAC/RIC). For significant interactions, we performed stratified analyses by conditioning regimen (Table 1) and by the causes of death which comprise OS, disease related mortality (DRM) and transplant related mortality (TRM). Meta analyses of the two cohorts identified two correlated (R2=1) eQTL SNPs: rs10437630 (imputed) and rs3911014 (typed) with GWIS meta p-values of 8.4x10-7 and 9.3x10-7, respectively in a ~25kb haplotype block located adjacent to TRIM44 (Chromosome 11) (Fig.1). This SNP is in a ~2 kb enhancer region that shows chromatin looping interactions with the transcription start site of TRIM44. TRIM44 has been shown to promote cancer cell survival in multiple cancers, including multiple myeloma. To better understand the interaction between rs3911014 and conditioning regimen intensity, we conducted stratified analyses of rs3911014 by MAC and RIC. Analyses of MAC regimen group (Table 1) with rs3911014 was not significantly associated with OS, DRM or TRM (Pmeta >.2). Among patients who received RIC, the C allele in rs3911014 associated with 1 year post-BMT OS (Pmeta= 1.0×10-5, HRmeta = 1.4, [1.2-1.6]) and was driven by a higher risk of death due to disease (Pmeta= 3.7×10-6, HRmeta = 1.6, [1.3-1.9]) and not TRM (Figs 2 and 3). The rs3911014 C allele associated with increased risk of DRM in RIC regimens (Table 1) A (P=.12), B (P=7.8x10-5), C (P=.03) and D (P=.012). TRIM44 involvement with cancer cell survival suggests the SNP association in RIC patients could be attributable to partial ablation of tumor cells which is supported by the observation that most RIC patients with this variant die of disease in the first few months after BMT. In contrast, the variant posed no increased risk in MAC patients due to a higher degree of myeloablation and tumor cell killing. Further analyses may be able to identify RIC or MAC regimens that are not associated with worse survival in patients with this genotype. Disclosures Pasquini: Medigene: Consultancy; Novartis: Research Funding; Kit Pharma: Research Funding; BMS: Research Funding; Pfizer: Other: Advisory Board; Amgen: Consultancy.
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Ivanov, Vadim, Catherine Faucher, Patrick Ladaique, Sabine Furst, Mohamad Mothy, Jean El Cheikh, Thomas Prebet, et al. "Early Post-Transplant Administration of Recombinant Erythropoietin Decreases Transfusion Needs and Hastens Haemoglobin Reconstitution in Reduced Intensity Conditioned (RIC) Allogeneic Stem Cell Transplantation (ASCT) for Non-Myeloid Malignancies." Blood 110, no. 11 (November 16, 2007): 2997. http://dx.doi.org/10.1182/blood.v110.11.2997.2997.
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Abstract We have reported that RBCT needs inversely correlated to the conditioning intensity (Transfusion, 2004). Moreover, Hb level prior to RIC ASCT significantly influenced Hb recovery and RBCT needs (BMT, 2005). These findings invited us to test the hypothesis that post RIC allo SCT might represent an attractive setting for rHuEPO use. Here we analysed RBCT needs in the first 60 days after transplantation in 125 consecutive RIC allo geno-identical sibling PBSC ASCTs treated for lymphoid malignancies (LM) and solid tumours (ST) performed in our institution from 01/2001: age: 48 (23–68) ; M/F: 63/62 ; LM/ST: 96/39; RIC: FBA (Fludarabine (FLU)+ Busulfan (BU) + Thymoglobulin (ATG))(74), FBTLI (FLU + BU + 1 Gy TLI) (23), FLU+ 2 Gy TBI (26), FLU + Endoxan (2). 45 pts were treated with rHuEPO started on day 1 (EPO+ group). First 10 pts received epoetine-beta (Neorecormon, Roche) (10.000 IU × 3/week). The remaining 35 pts received Darbopoietine alpha (Aranesp, Amgen), (150 mkg/week: 10 pts; 500 mkg/3 weeks: 25 pts). Trt was continued until Hb level reached 12 g/dL or day +60. 80 pts did not receive EPO stimulation (EPO- group). There were no significant differences between the 2 groups in terms of patient and graft characteristics. AGVHD grade II–IV appeared before day +60 in both groups in 36% of cases. The 4 year survival probability estimates did not differ between the 2 groups (EPO+: 49.7% (32–67); EPO-: 44.7% (32–60)). Potential risk factors for RBCT needs were assessed in a univariate analysis: patient and donor age (NS), patient and donor gender (NS), donor/recipient gender compatibility (NS), ABO compatibility (NS), diagnosis (lymphoid malignancies vs solid tumours (NS)), conditioning regiments (ATG-based vs no ATG (NS) and BU-containing vs. no BU (NS)), CD34+ cell dose (<6 ×106/kg vs. ≥6 ×106/kg) (NS), Hb level prior to conditioning (Hb < 12 g/dl vs. Hb ≥ 12 g/dL (p<0.005)) and rHuEPO use (Y vs N (p<0.02)). In a multivariate analysis, Hb level (Hb < 12 g/dl vs Hb ≥ 12 g/dL; p=0.0001) and rHuEPO use (EPO+ vs EPO-; p=0.0096) independently influenced RBCT needs. The cohort of 45 EPO+ pts experienced a quicker Hb recovery allowing patients lo leave the “anaemic” zone associated with higher fatigue on day 20 (Fig) and significantly lower RBCT needs (EPO+ group: 1.8±0.3 RBC units; EPO- group 3.3±0.4 units (p<0.02)). In conclusion, in pts grafted with RIC the use of early rHuEPO is associated with a significant reduction of RBCT needs and has a major positive impact on early Hb recovery potentially limiting the fatigue syndrome post-transplant. This data provide proof of principle and rational of starting the rHuEPO early after RIC transplantation. Figure: Post graft Hb level evolution (mean ± SEM): group EPO+ (plain curve) vs. group EPO- (dashed curve). Figure Figure
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Weston, Steve, Mark Olsson, Ray Merewether, and John Sanderson. "Flotation in Ocean Trenches Using Hollow Ceramic Spheres." Marine Technology Society Journal 43, no. 5 (December 1, 2009): 110–14. http://dx.doi.org/10.4031/mtsj.43.5.24.
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AbstractSpherical flotation units of 99.9% Al2O3 ceramic have been successfully produced by DeepSea Power & Light for application to ocean trench systems, such as the Woods Hole Oceanographic Institution (WHOI) hybrid remotely operated vehicle (HROV) Nereus and other high-performance systems requiring maximum buoyancy with minimum air weight. WHOI successfully operated their HROV in the Mariana Trench Challenger Deep in Summer 2009, scooting across the trench floor for a total of 11 h at 36,000 feet (11,000 m). More than 1,750 3.6-inch (91.45 mm), OD seamless hollow ceramic spheres, each generating 0.6 lb (272 g) of lift, provided Nereus its buoyancy. The spheres, with a 0.34 weight/displacement ratio, withstood proof testing to 30,000 psi (207 MPa), 1,000 h of sustained pressurization to 25,000 psi and 10,000 pressure cycles to 20,000 psi (138 MPa). In addition, each of the WHOI spheres withstood 15 h at 18 ksi static pressure hold. When encased in a 0.2-inch thick buoyant elastomeric boot, they withstood impact on a concrete floor from a 6-foot elevation. An extensive quality assurance (QA) procedure is applied to 100% of manufactured spheres, with strict adherence to tight dimensional and thickness specifications as well as pressure test acoustic emission criteria (<xref ref-type="fig" rid="fig1">Figure 1</xref>).<fig id="fig1"><label>FIGURE 1</label><caption>Engineers at WHOI demonstrate the toughness of DSPL’s jacketed hollow ceramic spheres they use to provide lift at extreme pressures for their deep diving HROV, Nereus. (Photo by Tom Kleindinst, WHOI).</caption><graphic href="MTS43524fig01.tif"/></fig>DeepSea Power & Light has additionally demonstrated the process for casting larger alumina ceramic spheres with an 8.6-inch (218.4 mm) outside diameter for the whole range of ocean depths from 10,000 feet (3000 m) to 36,000 feet (11,000 m). The larger spheres were successfully used offshore by Scripps Institution of Oceanography/UCSD in summer 2005 in an experimental free vehicle sediment sampler that impacted the seafloor at 2 m/s at a water depth of 2,200 m, dropped a weight, then rebounded to the surface with its cargo of sediment.
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Yeasmin, Nahid, Qazi Shamima Akhter, Sayeeda Mahmuda, Mahmudul Hasan, Rukhshana Rabbani, and Rumana Afroz. "Correlation of Estrogen with Serum Insulin and Blood Glucose Levels in Post-menopausal Women." Bangladesh Medical Journal 46, no. 1 (November 21, 2017): 32–37. http://dx.doi.org/10.3329/bmj.v46i1.34637.
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Hyperglycemia is a major risk factor for cardiovascular diseases in postmenopausal women. Increased incidence of cardiovascular diseases in postmenopausal women may be due to hyperglycemia caused by lower level of estrogen hormone. This cross sectional study was conducted in the Department of Physiology, Dhaka Medical College, Dhaka, Bangladesh during the period of January to December 2011 to observe the correlation of estrogen with fasting serum insulin (FSI) and fasting blood glucose (FBG) levels in postmenopausal women. A total of 90 women were selected from different areas of Dhaka city, among them, 60 postmenopausal women of age group 50 to 60 years were taken as study group and 30 apparently healthy premenopausal women of age group 20 to 30 years were included as comparison group. The study parameters fasting blood glucose level was estimated by enzymatic method in both groups. Serum insulin level was estimated by Enzyme Linked Immunosorbent Assay (ELISA) and serum estrogen level by RIA method in order to assess the hormonal level of both groups. Data was analyzed by Unpaired Student’s‘t’ test and Pearson's correlation co-effcient (r) test as applicable. Mean serum fasting insulin level and mean blood glucose level was higher in postmenopausal women than premenopausal and result was statistically significant. In postmenopausal women serum estrogen level was lower than premenopausal and serum estrogen level showed negative correlation with serum fasting insulin level. Blood glucose level also showed negative correlation with serum estrogen level. All these correlation were statistically non-significant. It may be concluded that the serum fasting insulin and blood glucose levels are significantly higher in postmenopausal women that may be due to low level of estrogen.Bangladesh Med J. 2017 Jan; 46 (1): 32-37
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Myllymaki, Mikko, Robert A. Redd, Corey S. Cutler, Wael Saber, Zhen-Huan Hu, Tao Wang, Stephen R. Spellman, et al. "Telomere Length and Telomerase Complex Mutations Predict Fatal Treatment Toxicity after Stem Cell Transplantation in Patients with Myelodysplastic Syndrome." Blood 132, Supplement 1 (November 29, 2018): 796. http://dx.doi.org/10.1182/blood-2018-99-117031.
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Abstract Introduction: Identifying patients at high risk of fatal treatment toxicity is a central challenge in hematopoietic stem cell transplantation (HSCT). Objective metrics that enable more accurate prediction of non-relapse mortality (NRM) could inform clinical decisions about timing and modality of HSCT. Short telomere length, mediated by inherited or acquired factors, impairs cellular response to genotoxic and replicative stress. We therefore evaluated the impact of recipient telomere length on clinical outcomes based on treatment intensity in patients with myelodysplastic syndrome (MDS) receiving HSCT. Methods: We used qPCR to measure relative telomere lengths in whole blood DNA samples from 1514 patients who received allogeneic HSCT for MDS and were enrolled in the Center for International Blood and Marrow Transplant Research Repository. Within the cohort, patients age 40 and older were grouped into those with short (<25th), intermediate (25-75th) or long (>75th percentile) telomeres. To evaluate germline determinants of telomere length, we sequenced 7 genes involved in telomere maintenance and mutated in dyskeratosis congenita: TERC, TERT, DKC1, TINF2, NHP2, WRAP53 and CTC1. Putative germline variants were classified as "rare" if the allele frequency was <0.001 in all Genome Aggregation Database (gnomAD) populations. Results: Among patients age 40 and older (n=1267), those with short (HR 1.52, 1.24-1.85, p<0.001) or intermediate (HR 1.35, 1.13-1.61, p<0.001) telomere length had poor overall survival compared with those having long telomeres (Fig 1A). In a competing risks regression model, the adverse effect of shorter telomeres was driven by a significantly higher risk of NRM among patients with short (HR 1.57, 1.20-2.06, p=0.001) and intermediate (HR 1.32, 1.03-1.69, p=0.03) telomere length. The association between telomere length and NRM was evident in patients receiving myeloablative (MAC, p=0.002) but not reduced-intensity conditioning (RIC, p=0.2) regimens (Fig 1B). We observed no association between telomere length and disease relapse in patients receiving MAC or RIC regimens. In a multivariable regression model, the prognostic significance of telomere length was independent of clinical and genetic factors, including age, Karnofsky performance status, hematologic parameters, IPSS-R risk category, donor mismatch, donor age, and TP53 mutation. We identified 40 patients (2.6% of the cohort) with rare germline TERT variants. Patients with rare TERT variants had significantly shorter telomeres than patients with common (p=0.001) or no (p<0.0001) TERT variants and were diagnosed with MDS at an earlier age than patients with common (52.2 vs. 58.4 years, p=0.01) or no (52.2 vs. 57.9 years, p=0.01) TERT variants. The domain distribution of rare TERT variants mirrored that of validated pathogenic germline TERT mutations, primarily affecting the reverse transcriptase and C-terminal extension domains. Rare variants in TERC (0.4%) and DKC1 (0.2%) were also associated with shorter telomeres (p=0.02 and p=0.04, respectively). In total, we identified germline telomerase complex mutations in 49 of 1514 MDS patients (3.2%), even though only 1 patient had a clinical diagnosis of dyskeratosis congenita. Together, patients with telomerase complex mutations had shorter overall survival than those without mutations (unadjusted p=0.008), attributable to a marked increase in the risk of early NRM among those receiving MAC (1 year cumulative incidence of NRM 48% vs. 26%, p=0.03). The impact of shorter telomeres on NRM was similar in patients with and without identified core telomerase complex mutations, suggesting that additional mechanisms of impaired telomere length maintenance may contribute to MDS pathogenesis and outcome. Conclusion: Recipient telomere length is independently associated with overall survival after allogeneic HSCT for MDS. Patients age 40 or older with shorter blood cell telomere length have a significantly elevated risk of early NRM with myeloablative conditioning regimens. Clinically unrecognized germline mutations in the telomerase genes TERT, TERC, and DKC1 define a distinct subset of adult patients with sporadic MDS and short telomeres who have poor transplant outcomes. Together, these results indicate that short telomere length in MDS patients mediates fatal treatment toxicity that may be attenuated by lower intensity conditioning approaches. Disclosures Antin: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.
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Szabolcs, Paul, Xiaohua Chen, Mark Vander Lugt, and Memphis J. Hill. "Clonal Deletion Plays a Major Role to Achieve Immune Tolerance after Reduced Intensity Unrelated Donor Cord Blood Transplantation (UCBT)." Blood 128, no. 22 (December 2, 2016): 4584. http://dx.doi.org/10.1182/blood.v128.22.4584.4584.
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Abstract Generation of tolerance to transplanted hematopoietic cells or organs is essential if elimination of immunosuppressive therapy (IST) is desired. Immune tolerance is the expected outcome after successful hematopoietic stem cell transplantation (HSCT). It is characterized byimmunocompetencewithout any alloreactivity (GVHD) in the absence of IST. However, the mechanism(s) required to prevent alloreactivity are not fully understood. Both central (clonal deletion) and peripheral (anergy, suppression byTreg, Tr1) mechanisms are suspected. In this study, we set up serial experiments to test for these mechanisms after unrelated donor cord blood transplant (CBT) in theGvHdirection. We also studied these mechanisms at the time of GVHD. Methods: Seven patients (age range from 1m to 9y) with non-malignant diseases were transplanted and studied for host-specific alloreactivity following reduced intensity conditioning (RIC) regimen (NCT01852370) that also utilizedAlemtuzumab(1.2mg/kg) ~ 2 weeks prior to UCBT. Five of the patients were off immunosuppression therapy when blood was drawn (6 -12 months after UCBT) while two were not and had either limited chronic GVHD or recently resolved acute GVHD. Donor T cellchimerismat the time of blood draw was a median 97% (range 87-100%). Purified T cell responses to host APC (EBV-LCL for EBV seronegative patients, or monocyte derived DC) were measured by mixed lymphocyte reaction (MLR) and cytotoxic lymphocyte (CTL) reaction after 5 or 7 days in culture, respectively. Th1/Th2/Th17 cytokines along with IL-10 secreted during MLR were quantified from day 5 supernatant by bio-plexassay. To track host-reactive T cell clones, TCRbrepertoire was monitored and quantitated using targeted amplification of rearranged TCR genes followed by high-throughput sequencing (Adaptive Biotechnologies®). The data was analyzed withImmunoSEQ® Analyzer Software. To further identify the key mechanism(s) of tolerance, we attempted to break tolerance by inhibiting or amplifying putative pathways using the following methods: Regulatory T cell (Treg) deletion was achieved byDenileukindiftitox(Ontak) treatment prior to MLR and CTL reactions. Involvement of Tr1 or anergy was examined either by blocking IL10R or by adding low dose IL2, respectively. Results and Discussion: Patients with clinical tolerance (n=5): There was no significant proliferative or cytotoxic T cell response towards recipient APC while T cells responded vigorously to 3rd party APC (Fig 1, 2). Similarly, Th1/Th2/Th17 cytokine profiles revealed recipient-specific non-responsiveness by both proliferation and cytokine secretion (Fig 1A,B) fulfilling a critical tenet of tolerance in three independent assays (MLR, CTL, cytokine secretion). In addition, tracking TCRb clonal profiles withImmunoSEQ® revealed the disappearance of recipient-specific T cell clones that were amplified from the cord blood graft itself by 7 days of stimulation with purified host APC (labeled pre-UCBT in Fig 1.C). There was no indication ofTreg or Tr1 involvement in sustaining tolerance since neither deletion ofTregs by IL-2 IT, nor IL-10R blockade had any impact on T cell hypo-reactivity in MLR, CTL, andbioplex assays. Interestingly, addition of IL-2 in MLR did enhance T cell proliferative responses in 1 out of 5 tolerant patients tested, but did not activate host-specific CTL responses. Nevertheless, here we can not exclude the possibility ofanergy playing some role in preventing host-specific alloreactivity. Patients with GvHD at time of examination: T cells isolated from patients with recently resolved or still active limited chrGVHD receiving some IST (n=2) did proliferate against recipient APC in MLR, but were not cytotoxic against host APC (Fig 3). IL-2 and IL-13 secretion towards host APC was detectable in both (data not shown). In summary, the rapid acquisition of immune tolerance in theGvH direction post-UCBT on our prospective RIC clinical trial is characterized by hypo-reactivity in all assays employed towards host APC. The proliferation, cytotoxicity, and TH1/TH2, TH17 cytokine secretion data suggest that host-specific clonal deletion is a significant mechanism of tolerance in most if not all patients. In one, there is possibility foranergy as exogenous low dose IL-2 was able to overcome absent proliferation by MLR, while having no impact on host-reactive CTL activity or TH1/TH2/Th17 cytokine secretion. Disclosures No relevant conflicts of interest to declare.
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Soroka, B. S., V. V. Horupa, and R. S. Karabchievskaya. "SCIENTIFIC AND ENGINEERING PRINCIPLES OF EFFICIENT FUEL USE AND ENVIRONMENTALLY FRIENDLY GAS COMBUSTIONIN STOVE PLATES. PART 2. STANDARD BASIS AND METHODOLOGY OF EVALUATION THE POWER EFFICIENCY AND ECOLOGICAL CHARACTERISTICS OF DOMESTIC GAS DEVICES." Energy Technologies & Resource Saving, no. 3 (September 20, 2020): 4–20. http://dx.doi.org/10.33070/etars.3.2020.01.
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Gas stoves belong to the number of the most wide — spread domestic devices. Research activity concerning these appliances has been stopped in Ukraine some decades ago despite an increase of the natural gas using in municipal economy.
Operation data, power efficiency characteristics and pollution indicators related to on air state by gas combustion in the living accommodation are regulated by the normative documents: national and international standards, regional technical (engineering) conditions of Ukraine, EU countries, Russia, USA, China and other states.
Practically any gas stove is equipped with an atmospheric ejection burner. The principal characteristics of the gas burners, operation peculiarities peculiarities for the atmospheric burners are systematized and analyzed in the presented paper. The following qualitative and quantitative indicators of the atmospheric burners have been considered in this paper: the fuel types to be used (natural gas, liquefied gas), working gas pressure ahead of stove, nominal heat capacity, limit range of operation adjustment, noise by burner operation.
Gas burning under the atmospheric burners operation makes the two-stage process. The physical background of the stable combustion have been considered along with the specific reasons and generalized criteria of the unstable combustions modes: flash-back, blow-off, appearance of the «yellow tips» in the flame.
The atmospheric burners possess both the power and environmental advantages in comparison with the burners of total preliminary mixing of fuel gas and combustion air. Application of primary air excess lpr < 1.0, provides higher efficiency of the burners and need for lower gas pressure ahead of the domestic stoves while the two-stage combustion makes one of the principle techniques of environmentally benign combustion technologies. It has been shown that energetic experiences in ejection burners are proportional to the cube of the air access coefficient, in case of the atmospheric burners — are raised two the third power: ea ~ l3a,pr.
An original methodology experimental researchers for the atmospheric burners of various design and of different companies — manufacturers has been proposed. The methods of the tests performing fully meet to Ukrainian norms and international standards. The computerized firing rig stand with a diagnostic facility has been created providing both power and environmental research of the atmospheric burners with definition of the boundaries of stable operation and breach the combustion stability. An example of the water heating thermogram within the test vessel has been presented providing an opportunity to evaluate the peculiarities of head transfer process by time and space for the system «atmospheric burner – the vessel to be heated and liquid to be boiled». Bibl. 31, Fig. 7, Tab. 5.
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Mehra, Varun, Daniele Avenoso, Ximena Cabrera Castellano, Adrian Choy, Stefani Widya, Mili Shah, Shafqat Inam, et al. "Differential Alemtuzumab Dosage Effects in T-Cell Deplete Allogeneic Haematopoietic Stem Cell Transplants for Myeloid Malignancies- King's College Hospital London Experience." Blood 134, Supplement_1 (November 13, 2019): 4622. http://dx.doi.org/10.1182/blood-2019-131239.
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Introduction Alemtuzumab is a monoclonal anti-CD52 antibody, a pan-lymphodepleting immunosuppressive agent in common use as part of conditioning for allogeneic stem cell transplantation (Allo-HSCT) in United Kingdom and many other centres across the globe, with benefits related to reduced graft versus Host disease (GVHD) and lower non-relapse mortality (NRM). However, evidence for effective dose schedule in Allo-HSCT remains debatable with some concerns related to delayed immune reconstitution and increased relapses with higher dosages; but increased risk of acute and chronic GVHD observed with lower doses. We present a large single-centre UK experience evaluating differential dosage effect of Alemtuzumab on HSCT outcomes. Methods: We retrospectively evaluated 330 patients undergoing Allo-HSCTs for myeloid malignancies (AML/MDS/MPNs) during a 10-year period (Jan 2010 to April 2019) at King's College Hospital, London. Two dosage schedules of Alemtuzumab based T-cell deplete conditioning regimen using 100mg (n-96) were compared to those receiving 60mg (n-234; <100mg dose) with respect to HSCT outcomes. Alemtuzumab based T deplete conditioning regimens included Fludarabine(Flu)-Busulphan(Bu) (2 doses as reduced intensity) while Flu-Bu4 or Bu4-Cyclophosphamide used as myeloablative protocol. Standard supportive care for GVHD prophylaxis (ciclosporin), viral/bacterial and anti-fungal prophylaxis was used. Close monitoring for infections, GVHD, chimerism (included fractionated lymphoid/myeloid) and disease assessments post HSCT were undertaken as per institutional policy. The data was compared and statistically analysed using Log-rank test for overall survival (OS), Cox regression for adjusted multivariate analysis and Gray method for cumulative incidences for NRM and relapses. Results Baseline characteristics (Table-1) were similar between the 2 groups in terms of conditioning intensity, patient age, underlying disease (AML/MDS), disease risk and donor HLA matching. Median follow up of survivors was 34 months (range 01-112months) with significantly longer follow up available for 100mg dose group (median 90 months vs 28 months; p<0.001). Higher Alemtuzumab dosage (100mg) was associated with a significant improvement in GVHD & Relapse free survival (GRFS)(32% vs 20% at 12 months;p-0.003; Fig 1a) and significantly lower incidence of both grade 3-4 acute (18% vs 42% at D100;p-<0.001; Fig 1b) and chronic GVHD (all grades)(21% vs 42% at 12 months; p<0.001; Fig 1c) compared to <100mg dose. No differences in OS (66% vs 71% at 12 months; p-0.62; Fig 1d), NRM (17% vs 16% at 12 months; p-0.37; Fig 1e) and relapse incidences (24% vs 24% at 12 months;p-0.71; Fig 1f) were observed with no impact on rates of CMV/EBV reactivation, disseminated Adenoviraemia or invasive fungal disease(IFD) between the 2 cohorts. Multivariate adjusted cox analysis (MVA) confirmed older age>60 years, mismatched unrelated donor, absence of chronic GVHD, disease relapse, ITU admission event, CMV reactivation and absence of any EBV reactivation post HSCT as significant predictive factors for poor OS. This was not affected by different Alemtuzumab dosages, disease risk index or type of disease. However, GFRS was positively influenced by standard 100mg Alemtuzumab dose (HR 0.67; 95%CI: 0.51-0.86; p-0.005), no ITU admission event (HR-0.51; 95%CI:0.38-0.70; p<0.001) and EBV reactivation (HR-0.67; 95%CI:0.52-0.86; p-0.02) on multivariate analysis. NRM was worse for patients admitted in ITU, no known chronic GVHD, mismatched unrelated donor, presence of CMV and absence of EBV reactivation (p<0.001), but not affected by differential alemtuzumab dosages. Conclusions With improved supportive care, effective infection management and pre-emptive cellular therapy approaches available in current era, standard dosage (100mg) of alemtuzumab is safe and effective in both RIC and myeloablative allo-HSCTs for myeloid malignancies, with significantly lower GVHD related morbidity and overall better GFRS. Despite concerns of relapses and delayed immune reconstitution, this report on a homogenous cohort of allo-HSCTs in myeloid malignancies confirms the contrary with no impact on OS, NRM or relapses and no significant increase in opportunistic infections with 100mg dose. Disclosures Mufti: Celgene: Consultancy, Research Funding. De Lavallade:Bristol Myers Squibb: Research Funding; Bristol Myers Squibb: Research Funding.
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Oestgaard, Lene S. G., Henrik Sengeloev, Mette S. Holm, Hans E. Johnsen, Marianne T. Severinsen, Eigil Kjeldsen, Olav J. Bergmann, et al. "Extramedullary Leukemia and Myeloid Sarcoma in AML: Results From a Population-Based Registry Study of 2261 Patients." Blood 118, no. 21 (November 18, 2011): 2003. http://dx.doi.org/10.1182/blood.v118.21.2003.2003.
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Abstract Abstract 2003 The prognosis of patients suffering from AML with manifestations of accompanying extramedullary leukemia (EML) including myeloid sarcoma (MS) compared to that of AML patients not exhibiting EML manifestations is still an open question as results from previous studies have been contradictory most likely due to selection bias. Here we present an analysis performed in a cohort of 2261 patients representing >90% of all AML patients diagnosed and treated in Denmark during the eleven-year period January 2000 through December 2010. The goal was to investigate the prognostic impact of presence of EML at time of AML diagnosis by a retrospective population- and registry-based analysis Of these patients, 219 (9.7%) showed signs of EML at time of AML presentation. Anatomic sites of EML were: lymph nodes (3.0%), skin (2.7%), spleen (1.7%), oral (1.3%), CNS (0.4%), testes (0.2%), other sites (1.1%), and two or more anatomical sites (0.5%). In 27 cases myeloid sarcoma was not accompanied by AML in the bone marrow and, thus, presented as isolated MS. In total, 1168 of the 2261 (52 %) patients were treated with curative intention. Allogeneic stem cell transplantation (Standard allo in 105 cases, and reduced intensity conditioning (RIC) transplant in 90 cases) was conducted in a total of 195 patients (118 in CR1, 65 in CR2, and 12 during other disease stages). Overall the frequencies of allogeneic transplantations in curatively treated patients were 13.7% in patients with EML and 8.5% in patients without EML. The presence of EML at time of leukemia diagnosis had no statistical significance to probability of obtaining complete remission (CR), nor to duration of overall survival (OS) (Table 1. and Fig. 1). By contrast, well-established prognostic parameters such as presenting cytogenetic abnormalities (categorized according to revised MRC-criteria, D. Grimwade et al. Blood, 2010), age, leukocyte count, and type of leukemia (secondary vs de novo) were all found to be statistically significant to probability of attainment of (CR) and to duration of OS in uni- as well as multivariate analyses. Gender was of borderline statistical significance with respect to probability of attainment of CR and to OS (Table 1).Figure 1Years from AML diagnosisPatients with EML(n = 132)Patients without EML(n = 1007)p-value (log-rank test) = 0.51Figure 1. Years from AML diagnosis. / Patients with EML. / (n = 132). / Patients without EML. / (n = 1007). / p-value (log-rank test) = 0.51Table 1.Factors of significance to probability of attainment of CR and to overall survival (OS)Probability of CR (Logistic regression, nevaluable = 927)Probability of overall survival (Cox regression, nevaluable = 958)VariableOdds ratio (OR)95% CI of ORP valueHazard ratio95% CI of HRP valueEML––0.82––0.54Age1.061.04–1.08<10−41.041.03–1.04<10−4Cytogenetics2.291.63–3.21<10−41.931.65–2.25<10−4Male gender1.481.03–2.070.03––0.06 WBC1.0051.002–1.007<10−41.0011.000–1.0020.02 Secondary2.151.47–3.14<10−41.391.15–1.680.001 Additionally, patients with EML at leukemia presentation who were subjected to an allogeneic stem cell transplantation had a prognosis no different from that of AML patients not exhibiting signs of EML (Fig.2). Analyses of progression free survival are ongoing and will be presented at the meeting.Figure 2Years from AML diagnosisPatients without EML(n = 165)Patients with EML(n = 30)p-value (log-rank test) = 0.75Figure 2. Years from AML diagnosis. / Patients without EML. / (n = 165). / Patients with EML. / (n = 30). / p-value (log-rank test) = 0.75 From this analysis we conclude that presence of EML does not predict for an inferior CR-rate or for shorter survival in AML. We find no clear justification for a more aggressive therapeutic approach or performance of allogeneic stem cell transplantation in AML patients with EML. Therapeutic decisions should be guided by other prognostic parameters, e.g., age and cytogenetic aberrations which are of far greater importance than the presence of EML. Disclosures: No relevant conflicts of interest to declare.
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Bug, Gesine, Andreas Burchert, Kroeger Nicolaus, Sabine Huenecke, Ulrich Duenzinger, Andrea Wolf, Peter Bader, Hubert Serve, and Oliver G. Ottmann. "Post-Transplant Maintenance With The Deacetylase Inhibitor Panobinostat In Patients With High-Risk AML Or MDS: Results Of The Phase I Part Of The Panobest Trial." Blood 122, no. 21 (November 15, 2013): 3315. http://dx.doi.org/10.1182/blood.v122.21.3315.3315.
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Abstract Inhibitors of class I/II histone deacetylases (HDACi) possess anti-leukemic activity and have been reported to modulate the function of immune effector cells. Thus, they could provide specific clinical benefit in the allogeneic hematopoietic stem cell transplantation (HSCT) setting. Panobinostat (PAN) is a potent, orally available pan-HDACi reported to either suppress or stimulate regulatory T cells (T reg), depending on the administered dose (Shen L & Pili R, OncoImmunology 1;7:948, 2012). The feasibility and efficacy of PAN treatment following HSCT for patients (pts) with high risk acute myeloid leukemia (AML) has not been established. We report clinical and translational results of the dose-escalation phase of the PANOBEST study with PAN as post-HSCT maintenance. Primary objectives were, based on dose-limiting toxicity (DLT), determining the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D) of PAN in patients with high risk AML or myelodysplastic syndromes (MDS) in complete remission (CR) after reduced-intensity conditioning HSCT. Secondary objectives were the evaluation of safety, tolerability and immunoregulatory properties of PAN, and overall (OS) and disease-free survival (DFS) of treated patients. PAN was started at 10 mg p.o. three times a week (TIW) and escalated to 20 and 30 mg TIW using a 3+3 design. Treatment was initiated 60-150 days after HSCT and continued for up to one year. Eligibility criteria included: recovery of peripheral blood counts, adequate organ function and no severe graft versus host disease (GvHD). All pts gave written informed consent. DLT was defined as prolonged grade 4 hematologic or grade 3/4 non-hematologic toxicity within 28 days of the first PAN dose. Immunophenoytyping of lymphocyte subsets was performed pre-treatment and on days 3, 8, 30, 90, 180 and 360. 12 pts (11 AML, 1 MDS), median age of 52 years (21-62) were enrolled. PAN was started within a median of 73 days (60-126) after HSCT, which was performed with active disease (n=11) or in CR2 (n=1). The RP2D was determined to be 20 mg TIW based on one DLT (fatigue grade 3) at 20 mg and two DLTs (nausea/emesis and colitis grade 3 each) at 30 mg. Grade 2-4 adverse events (AEs) were reported in 10 out of the 12 pts (83%). Grade 3/4 AEs included hematologic toxicity (50% of pts), laboratory alterations (33%), gastrointestinal symptoms (25%), fatigue, pulmonary infection (17% each), sepsis, herpes stomatitis, diabetes, syncope, deep vein thrombosis and pulmonary embolism (8% each). Toxicity was reversible and required at least one PAN dose reduction in 3 pts. Acute GvHD grade 2 (1 pt) and 3 (2 pts) was responsive to steroids in 2 pts or salvage therapy in 1 pt. Four pts developed mild (n=3) or moderate (n=1) chronic GvHD. To date, 5 pts have completed one year of PAN and 2 pts remain on treatment (days 238, 290). Five pts discontinued treatment prematurely after 10-217 days due to grade 3 toxicities (n=4) or AML relapse (n=1). With a median follow up of 579 days (129-911), 11/12 pts are alive and 10/12 in continuous CR after HSCT. Seven pts received prophylactic donor lymphocyte infusions (DLIs, 1-5 doses of 0.1-20x106 CD3+ cells/kg). Immunophenotyping revealed no impact of PAN on absolute T reg numbers (9 pts), but a significantly reduced proportion of CD4+CD25++CD127dim/- T reg to CD3+CD4+ T helper (Th) cells by day 8 after 3 doses of PAN (mean±SEM: 14.6±2.6 vs. 9.6±1.2%, p value of t test =0.03). While Treg/Th proportion continuously decreased in pts with ongoing CR, it again increased after PAN discontinuation or remained stable under PAN treatment in both relapsing patients. Outcome of the study population was compared with a historical cohort of 29 consecutive pts with active AML transplanted in Frankfurt in 2000-2009. Both cohorts were similar in age, gender, disease stage or BM blasts at time of HSCT, donor type and use of DLIs. In a landmark analysis including all pts who were in CR and without severe GvHD on day 73 after HSCT, probabilities for DFS and OS at 18 months after HSCT were 83±11% vs. 55±9% (p=0.145, log-rank test) and 92±8% vs.66±9% (p=0.085) in the PANOBEST vs. historical cohort (Fig 1). PAN is well tolerated after HSCT at a RP2D of 20 mg TIW. Comparison with a historical control cohort of pts transplanted with active AML shows a low relapse rate, which appears to be associated with a PAN-induced modulation of the T reg/Th proportion. Disclosures: Bug: Novartis: Honoraria, Travel grants, support for the clinical study Other. Ottmann:Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.
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Subramaniam, Landstrom, and Hayes. "Genetic Permissiveness and Dietary Glycemic Load Interact to Predict Type-II Diabetes in the Nile rat (Arvicanthis niloticus)." Nutrients 11, no. 7 (July 6, 2019): 1538. http://dx.doi.org/10.3390/nu11071538.
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Objective: The Nile rat (Arvicanthis niloticus) is a superior model for Type-II Diabetes Mellitus (T2DM) induced by diets with a high glycemic index (GI) and glycemic load (GLoad). To better define the age and gender attributes of diabetes in early stages of progression, weanling rats were fed a high carbohydrate (hiCHO) diet for between 2 to 10 weeks. Methods. Data from four experiments compared two diabetogenic semipurified diets (Diet 133 (60:20:20, as % energy from CHO, fat, protein with a high glycemic load (GLoad) of 224 per 2000 kcal) versus Diets 73MBS or 73MB (70:10:20 with or without sucrose and higher GLoads of 259 or 295, respectively). An epidemiological technique was used to stratify the diabetes into quintiles of blood glucose (Q1 to Q5), after 2-10 weeks of dietary induction in 654 rats. The related metagenetic physiological growth and metabolic outcomes were related to the degree of diabetes based on fasting blood glucose (FBG), random blood glucose (RBG), and oral glucose tolerance test (OGTT) at 30 minutes and 60 minutes. Results. Experiment 1 (Diet 73MBS) demonstrated that the diabetes begins aggressively in weanlings during the first 2 weeks of a hiCHO challenge, linking genetic permissiveness to diabetes susceptibility or resistance from an early age. In Experiment 2, ninety male Nile rats fed Diet 133 (60:20:20) for 10 weeks identified two quintiles of resistant rats (Q1,Q2) that lowered their RBG between 6 weeks and 10 weeks on diet, whereas Q3-Q5 became progressively more diabetic, suggesting an ongoing struggle for control over glucose metabolism, which either stabilized or not, depending on genetic permissiveness. Experiment 3 (32 males fed 70:10:20) and Experiment 4 (30 females fed 60:20:20) lasted 8 weeks and 3 weeks respectively, for gender and time comparisons. The most telling link between a quintile rank and diabetes risk was telegraphed by energy intake (kcal/day) that established the cumulative GLoad per rat for the entire trial, which was apparent from the first week of feeding. This genetic permissiveness associated with hyperphagia across quintiles was maintained throughout the study and was mirrored in body weight gain without appreciable differences in feed efficiency. This suggests that appetite and greater growth rate linked to a fiber-free high GLoad diet were the dominant factors driving the diabetes. Male rats fed the highest GLoad diet (Diet 73MB 70:10:20, GLoad 295 per 2000 kcal for 8 weeks in Experiment 3], ate more calories and developed diabetes even more aggressively, again emphasizing the Cumulative GLoad as a primary stressor for expressing the genetic permissiveness underlying the diabetes. Conclusion: Thus, the Nile rat model, unlike other rodents but similar to humans, represents a superior model for high GLoad, low-fiber diets that induce diabetes from an early age in a manner similar to the dietary paradigm underlying T2DM in humans, most likely originating in childhood.
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Naylor, Peter, Terence Fishlock, David Mogford, and Robert Smith. "Relative Permeability Measurements for Post-Waterflood Depressurization of the Miller Field, North Sea." SPE Reservoir Evaluation & Engineering 4, no. 04 (August 1, 2001): 276–80. http://dx.doi.org/10.2118/72502-pa.
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Summary This paper describes a determination of critical gas saturations and relative permeabilities relevant to the depressurization of the Miller field. A series of reservoir-condition coreflood experiments and associated numerical simulations is described. Three experiments were conducted with aged Miller core and fluids at 120°C. Each was comprised of a waterflood at about 414 barg, followed by depressurization at different rates. The laboratory data included extensive three-phase in-situ saturation measurements that were used to derive gas relative permeabilities through the simulations. The rate-dependent critical gas saturations varied between 0.06 and 0.21, and gas relative permeabilities of the order of 0.0001 were deduced. These laboratory results are consistent with published data and suggest that conventional Corey-type gas relative permeabilities are an order of magnitude too large and do not represent the depressurization process. Introduction Significant quantities of hydrocarbons can be left in reservoirs after waterflooding. In those reservoirs with a high solution gas/oil ratio (GOR), depressurization as an improved recovery project can be an attractive possibility.1,2 An assessment of the potential for a depressurization project in the Miller field, North Sea, has been published.3 Risk analysis was used to quantify the economic impact of each uncertainty. Critical gas saturation had the highest impact on the net present value of the project: by varying the critical gas saturation from 0 to 0.15, the peak in gas-production rate was delayed by about 12 years, and the total gas production was significantly reduced. Many papers have used external gas drive experiments to investigate three-phase relative permeabilities. However, this flow regime is quite different from the in-situ evolution of gas during the depressurization of a volatile oil. Consequently, laboratory studies of depressurization must involve internal gas drive, which is representative of the processes occurring in a reservoir.4,5 Most studies have focused on the critical gas saturation at which gas becomes mobile under virgin conditions. There appear to be fewer laboratory studies of the depressurization of waterflooded oil, and critical gas saturations in the range 0.03 to 0.27 have been observed.6–10 This parameter is believed to be reservoir-specific and dependent upon the depressurization rate. It is believed that this paper is the first publication of reservoir-condition depressurization experiments involving high-GOR North Sea crude and aged, waterflooded cores. Thus, these may be the most representative measurements of gas relative permeabilities during solution gas drive that have been published to date. Experimental Procedure Rig Description. The experiments were conducted in a purpose-built high-pressure rig; the development of laboratory methods is described more fully in Ref. 11. A simplified flow circuit is presented in Fig. 1. It consisted of a vertical core holder, visual cell, separator vessel, and two parallel extraction circuits, all housed within a large temperature-controlled oven. Each extraction circuit comprised a 15-mL vessel into which the visual cell fluids were withdrawn, and a 500-mL vessel into which the nitrogen from the gas spring was collected. Flow rate was controlled by extracting fluid with alternate sides of a twin-barreled, constant-volume extraction pump. The ultra-low depressurization rates required in these experiments were achieved by using the extraction pump in conjunction with a large nitrogen gas spring in the core outlet circuit. This arrangement enabled extraction rates to be as low as 0.0125 mL/hr over a depressurization period of 141 days. Pressures, temperatures, flow rates, produced fluid volumes, and in-situ saturations were measured throughout the experiments. During coreflooding, it is important that any leak rates are much smaller than the target flow rates. Because the flow rates were relatively low in these depressurization experiments, an extremely high level of leak tightness was required. A great deal of effort was spent to ensure that the leak rates were as low as could reasonably be achieved. The rig was designed with a minimum number of valves and connections in critical parts of the circuit. Extensive leak testing was performed, and it confirmed that leak rates in critical parts of the circuit were as low as 0.0003 mL/hr at full test conditions. Three-phase in-situ saturation measurements have been conducted throughout these experiments using the gamma-emission technique, which involved labeling the oleic and aqueous phases with gamma-emitting radioactive tracers. This method has been used routinely for nearly 20 years and is described more fully in Refs. 12 and 13. The amount of tracer is too small to affect the phase behavior, but some tracer adsorption was experienced; this is discussed in Ref. 11. The overall uncertainty in in-situ gas saturation was estimated to be approximately ±5% of the saturation measurement. Core and Fluid Selection. Three experiments have been conducted for the Miller field using core material supplied by BP plc. All cores were relatively homogeneous, well-consolidated sandstone and two core assemblies were used in this study. Experiment 1 involved a relatively low-permeability core (27 md), while Experiments 2 and 3 used a different core with a higher permeability of 492 md. To obtain an acceptably large pore volume, it was necessary to butt two cores together. The cores for each assembly were selected on the basis of matching porosity, absolute permeability, and pore-size distribution. There was concern relating to the possibility of calcium carbonate scaling during the depressurization; although this may be an issue in some development plans, it was decided that it might obscure the fundamental mechanisms associated with depressurization. The decision was taken to make synthetic formation brines without the calcium, using a modified live brine recipe. Neither bottomhole fluids nor separator gas was available for use in these experiments, so the live oil was made from stock-tank oil and synthetic gas. The measured bubblepoint pressure was about 338 barg, and the GOR was between 2,290 and 2,479 scf/STB.
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Haq, Rouseli, R. P. Bichha, Md Ashraf Uddin, Pronab Kumar Modak, and Md Mojibur Rahman. "Study on challenges in diagnosis of TB and MDR TB by Gene-Xpert in Bangladesh." SAARC Journal of Tuberculosis, Lung Diseases and HIV/AIDS 14, no. 2 (March 13, 2018): 1–11. http://dx.doi.org/10.3126/saarctb.v14i2.19332.
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TB is a leading cause of morbidity and mortality worldwide. However, public health services globally reported only 66% of the estimated TB cases in 2014. Moreover, less than 5% of notified TB cases were tested for drug resistance capacity and an over reliance on chest radiography and/or sputum smear microscopy as diagnostic tools. The relying on conventional culture and drug susceptibility testing (DST). Detecting more cases, detecting them early and rapidly identifying drug resistance are essential for improving individual patient health and avoiding transmission resents a paradigm shift in the diagnosis of TB and drug-resistant TB by simultaneously detecting Mycobacterium tuberculosis and Rifampicin resistance-conferring mutations in a closed system suitable for use outside conventional laboratory settings in less than 2 hours, directly from sputum samples.Objective: To find out the challenges in diagnosis of TB and MDR TB by Gene-Xpert in Bangladesh Methodology; Both quantitative and qualitative methods study designs were used. All the 43 Centres in Bangladesh where the Gene X pert test are carried out were included. In addition selective officials/staff from national and sub-national level were included as respondents for focus group discussion (FGD) and in-depth interview. Verbal informed consent was obtained from participants before starting interviews. Analysis of data was done using SPSS software program.Results: Xpert MTB/RIF was first introduced in Bangladesh in March 2012. Till December 2015, a total of 61 Xpert MTB/ RIF machines were functioning at 43 sites in the country. In 42 sites the GeneXpert machines are placed in a separate room and in one site it is placed along with other general pathological laboratory activities. It was found that in all sites necessary physical support like air-cooler, dust control, UPS as well as regular electricity and water supply were available. Out of 43 sites, 38 have 4-module and 5 sites have 16-module machine. In totall, 55 four module machines and 6 sixteen module have been established. Out of these only one 4modul machine was non-functioning. In about half (48.8%) of the sites machines are run twice a day and in 17 sites (39.5%) only once while in 5 sites (NGO supported sites) machines are run 3 times a day. In 19 (44.2%) sites 1-4 samples are tested per day and in 16(37.2%) sites 5-8 samples/day. Per day 9-20 samples are tested in 4(9.3%) centres while in other 4 centres 21-30 samples are tested daily. In all the centres a total of about 300 samples are tested in a single working day. In total, 38 sites informed about problems they faced in operating the machine. The most common problem was module failure (67.4%), followed by delay in maintenance support (46. 5%). Inadequate cartridge supply and load shading were faced by 16.3% and 11.6% respectively. In 42 sites there were needs for support. The most common support they need is refresher training (93%), followed by maintenance training by 79.1%, and Software training by 18.6%. The responses from both FDG and in-depth interviews were as follows: Most common problem faced by the heath workers were lack of timely maintenance of Machines, false result of Rifampacin Resistance due to low bacterial load, module failure, no proper sputum transport mechanism, lack of appropriate centrifuge machine for processing of samples of EP cases and inadequate man power. From the past experience the group provided some valuable suggestions and comments as follows; A well maintained sputum transportation mechanism to be established. Stable power supply is absolutely necessary as discontinuation of electricity even for a fraction of second will cause erroneous test result. More machines need to made available for easier access. Machine operator needs refresher training including training related to day- today maintenance and software system. Good quality sample in suffi cient amount to be ensured for Xpert testing to produce accurate results.Conclusion: Gene-Xpert machine is very useful in diagnosis of MDR and Rifampacin Resistance M. tuberculosis. Module failure is a common problem and their replacement takes longer time. Frequent errors are shown that might be due to poor quality of sample, unstable electricity supply or poor skill of machine operators. Proper training of operators and proper sputum transport system is urgently needed for efficient use of these machines.SAARC Journal of Tuberculosis, Lung Diseases and HIV/AIDS, Vol. 14, No. 2, 2017, Page: 1-11
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Le Bris, Yannick, Thierry Guillaume, Marina Iliaquer, Jerome Martin, Pierre Peterlin, Audrey Menard, Marion Eveillard, et al. "Expansion of T or B Lymphocytes after Unrelated Cord Blood (UCB) Allogeneic Stem Cell Transplantation in Adults Correlates with CMV Reactivation and Is Associated with a Better Outcome." Blood 126, no. 23 (December 3, 2015): 1947. http://dx.doi.org/10.1182/blood.v126.23.1947.1947.
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Abstract Introduction: Peripheral lymphocytosis encountered after myeloablative (MAC) or reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT) is an ill-defined feature. Most reports in the literature deal with large granular lymphocytes (LGL) expansions and only seldom of B-cell increases (Bellucci, Blood, 2002). With an incidence of 3 to 18%, LGL proliferations occur generally late after allo-SCT with a median onset of 9 to 16 months. Such expansions can be polyclonal, oligoclonal or monoclonal, arising from either CD3+ T-cells or CD3- NK cells or both. LGL expansion has been frequently linked to CMV reactivation, indolent clinical course and a usually favorable outcome. Most available data were mainly described in the setting of allo-SCT using bone marrow (BM) or peripheral blood (PBSC) as stem cell source. Here, we report data regarding the incidence and features of lymphocyte expansions after unrelated cord blood (UCB) transplantation. Patients and Methods: Ninety-nine UCB allo-SCT performed in adults between October 2005 and October 2014 were considered for the purpose of this study. Most patients received double CB units (n=94) and a RIC regimen (n=89), for various hematological diseases. Whenever detected, we collected the date of onset and termination of peripheral blood lymphocyte expansions (4x109/L) among the 86 UCB-SCT patients alive at 3 months post-transplant. LGL expansion was defined as sustained LGL above 0.5x109/L and/or >40% of LGL in peripheral blood (Zambello, Haematologica, 1998). Concomitant immunophenotypic results, allowed to discriminate expansions of cytotoxic T-cells (CD3+CD8+CD56+), NK-cells (CD3-CD16+/CD56+) and B-cells (CD19+). LGL expansion data were also analyzed with respect to viral reactivation episodes, acute or chronic graft vs host disease, relapse and survival. Results: Lymphocytosis was observed in 21 cases (24%; 10 females and 11 males; median age: 58 y., range: 32-69). Most patients had a myeloid-lineage disease (67%) and were in complete remission at time of UCB-SCT (76%). The median onset of lymphocyte expansion after UCB-SCT was 12.6 months (range, 1.4-49). The median initial lymphocyte count was 4.76x109/L at time of expansion diagnosis. The median duration of expansion was 12 months (range: 1-52). Twenty patients could be further analyzed phenotypically, showing 8 CD8+ T, 1 NK and 1 T-NK LGL expansions. Interestingly, 7 cases of polyclonal B-lymphocytes expansions were also documented while 3 patients presented both T CD8+ and B expansions. Of note, B-cell expansions were CD5+. For 6 patients with T-cell expansion, concomitant DNA from CD3+ sorted cells is available to test clonality. Lymphocyte expansion were from donor origin for 12/14 tested patients. Acute and chronic GVHD developed respectively in 31% and 68% of lymphocytosis patients, and in 57 and 45% of the 65 patients without lymphocyte expansion (P=NS). Comparing these two groups for viral reactivations, the rates were 86% and 76% for HHV-6 (P=NS) and 23% and 39% for EBV (P=NS) respectively. CMV reactivation was significantly more frequent in the group of lymphocytosis patients (76% vs. 29%, P=0.0001). Interestingly, CMV reactivation was significantly higher in the 10 patients of the T or NK group compared to the 7 patients with B cell expansion (100% vs 57%, P=0.05). At time of analysis, 1 patient had relapsed and 4 had died, the causes of death being disease in 1 case and transplant-related mortality in 3. These events were significantly lower than in the group of patients without lymphocytosis (p=0.003 for relapses and p=0.04 for death). Two-year disease-free survival (Fig A) and overall survival (Fig B) were significantly different at respectively 85% vs. 55% (p=0.01) and 85% vs. 63%. (p=0.03). Conclusion: Lymphocyte expansion, at 24%, is not a rare event in adults receiving UCB allo-SCT. These expansions involve equally the T or B-lineages. The latter are often CD5+ suggesting a proliferation of innate B1 cells from the UCB. Lymphocyte expansions are significantly associated with previous reactivation of CMV, but not HHV-6 or EBV. Because these cells were of donor origin, it can be postulated that they represent primo-activation upon encounter with CMV. Finally, both types of lymphocyte expansions are associated with a significant favorable outcome, suggesting a possibly bystander anti-GVL effect. Figure 1. Figure 1. Disclosures Moreau: Celgene, Janssen, Takeda, Novartis, Amgen: Membership on an entity's Board of Directors or advisory committees.
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Bashey, Asad, Xu Zhang, Lawrence E. Morris, H. Kent Holland, Melhem Solh, and Scott R. Solomon. "Improved Survival of Patients Diagnosed with Severe (Grade 3-4) Acute GVHD or Severe NIH Grade Chronic GVHD in the Current Era Compared to Historic Controls." Blood 134, Supplement_1 (November 13, 2019): 2006. http://dx.doi.org/10.1182/blood-2019-123230.
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Severe (grade 3-4) acute GVHD (aGVHD) and NIH grade severe chronic GVHD (cGVHD) have historically been associated with poor survival. However, earlier diagnosis, improved treatment and supportive care, may result in an improvement in outcomes for patients recently diagnosed with severe GVHD compared to prior cohorts. Our institution has prospectively documented onset, grading and therapy of patients with GVHD using a single dedicated practitioner since 2005. We assessed 851 consecutive patients who received allografts at our center between 1/2005 and 12/ 2016 and identified 130 patients (15.3%) who developed severe aGVHD through Dec 2017 without prior relapse of malignancy. Characteristics were: median age 52.5, 51% male, race-81% white -17% black, diagnosis- AML 31% - MDS/MPD 20%- NHL/HL/CLL-23%, -ALL 11%, donor - MRD 21% - MUD 49% - haplo 30%, PBSC 78%, BM 17%, CBU 5%, preparative regimen MAC 44% - RIC/NST 56%, median time from BMT to onset of severe aGVHD was 49 days (7-376). Maximum grade = gd 3 (85%), gd 4 (15%), Median follow-up for survivors from date of onset was 59 months (23-155m). Survival estimates for the entire cohort from date of onset of grade 3-4 aGVHD at 1, 2 and 3 years were 62%, 49% and 47% respectively. Patients who developed severe aGVHD in 2016-2017 had significantly improved overall survival compared to patients who developed severe acute GVHD in prior years (2005-2015) -1 and 2 yr survival 86% & 79% vs 55% & 41% respectively, p=0.002 log-rank test, Fig 1). No significant differences were found between earlier cohorts. On multivariable analysis assessing the following variables: age, gender, race, diagnosis, donor type, cell source, regimen intensity, DRI, HCT-CI, CMV status, grade of aGVHD (3 vs 4), days from transplant to gd 3-4 aGVHD onset, year of development of severe acute GVHD (2016-2017 vs earlier) remained significant for survival (HR 0.36, p=0.018). Other significant variables were grade 4 vs 3 GVHD (HR 3.78, p<0.001) and DRI (high/very high vs low/intermediate, HR 1.84, p=0.011). For cGVHD we assessed 522 consecutive patients who underwent allografts between 4/2011 (start date of prospective documentation of NIH grade cGVHD )and 12/2016, and identified 146 (28%) patients who developed moderate to severe NIH grade chronic GVHD without prior relapse by Dec 2017 (85 severe, 61 moderate). Patient characteristics were: median age 53, 55% male, race-74% white -22% black, AML 40% - MDS/MPD 31%- NHL/HL/CLL-15%, -ALL 12% , donor - MRD 34% - MUD 40% - haplo 25%, graft- PBSC 82%, BM 18%, preparative regimen MAC 54% - RIC/NST 44%, median time from BMT to onset of moderate/severe cGVHD was 289 days (27-1364). Median follow-up for survivors from date of onset of moderate to severe GVHD was 48 months (19-94m). Estimated rates of survival from date of onset of moderate to severe cGVHD for the entire cohort at 1, 2 and 3 years were 82%, 73% and 71% respectively. For patients who developed severe cGVHD the corresponding survival estimates were 77%, 67% and 63%. No significant difference in post-onset survival was encountered when comparing patients developing moderate cGVHD in 2011-2013, 2014-2015 and 2016-2017. However, for severe cGVHD, 1 and 2 year estimated survival rates for the three cohorts were : 53% & 41%, 79% & 73% and 87% and 74% respectively (p=0.004 for 2011-2013 vs 2014-2015 but p=NS for 2014-2015 vs 2016-2017, Fig 2). On a multivariable analysis considering age, gender, race, diagnosis, donor type, graft source, regimen intensity, DRI, HCT-CI, and days from transplant to cGVHD onset, none of these variables was significantly associated with post-cGVHD survival. In the Cox model including year of onset of severe cGVHD, onset in recent years was linked to lower risk of mortality compared to onset in earlier years (onset 2014-2015 vs 2011-2013 - HR=0.34, p-0.012; onset 2016-2017 vs 2011-2013 - HR=0.28, p=0.006). These data suggest that survival of patients developing either severe aGVHD or severe NIH grade cGVHD has significantly improved in recent years compared to historical controls. More than two-thirds of such patients now survive two years from onset of severe GVHD. This must be taken into account when evaluating novel therapies for severe GVHD. Disclosures Solh: ADC Therapeutics: Research Funding; Celgene: Speakers Bureau; Amgen: Speakers Bureau.
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Bashey, Asad, Xu Zhang, Lawrence E. Morris, H. Kent Holland, Scott R. Solomon, and Melhem Solh. "Improved Survival in Patients Who Undergo Relapse of Acute Myeloid Leukemia Following Allogeneic Hematopoietic Cell Transplantation." Blood 134, Supplement_1 (November 13, 2019): 2014. http://dx.doi.org/10.1182/blood-2019-125229.
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Relapse of leukemia (RL) is the most common cause of treatment failure following allogeneic hematopoietic cell transplantation (alloHCT) in patients with AML. Historically, patients who suffer RL following alloHCT have had a dismal prognosis. A number of therapeutic options have recently become available for relapsed/refractory AML, including some that are associated with limited toxicity and may be well tolerated in the post-alloHCT setting. These therapies, and advances in supportive care have the potential to prolong survival of recently transplanted patients who suffer RL post post-alloHCT compared to prior cohorts. We hypothesized that patients suffering RL post-alloHCT within the last 5 years will have improved post-relapse survival compared to patients experiencing RL before this period. In order to test this hypothesis, we analyzed 309 patients who underwent a first allo-HCT for AML between Jan 2002 and Dec 2016 at our center and identified 112 patients (36%) who suffered RL post-alloHCT. Data were extracted from our institutional BMT database where they had been prospectively entered. Patient characteristics of those who experienced RL were: median age 53 (19-74); male - 51%; race- white-86%, black 12%, Asian -2%; donor-MRD 33%, MUD 41%, Haplo 26%; graft source - PBSC 86%, BM 11%, CBU 2%, PBSC+BM 1%; regimen intensity - MAC 61%, NST/RIC 39%%; DRI - intermediate 46%, high 50%, v. high 5%; HCT-CI 0-2 (58%), >3 (42%); KPS > 90 (39%) <90 (61%), CMV - pos 70%, neg 29%, year of relapse -2003-2013 (68%), 2014-2018 (32%). Median time from alloHCT to relapse was 170 days (25-1106). Median follow-up of surviving patients was 50 months (15-143). DLI: A first DLI was administered to 19 patients at a median of 41 days post relapse. The corresponding number of patients receiving 2nd, 3rd and 4th DLI were 12, 6 and 2 patients given at a median of 62, 48 and 38 days following the prior DLI. A second alloHCT post RL was performed in 33 patients (29%) at a median of 85 days (22-772d) post relapse using the same donor as the first allo-HCT in 45% and a different donor in 55%. The second transplant was from a MRD, MUD and Haplo donor in 10, 11 and 12 patients respectively. Estimates of post-relapse survival at 1, 2 and 3 years following relapse for all patients are 39%, 23% and 15% (Fig 1). For patients whose AML relapsed between 2003-2013, and 2014-2018 estimated 1, 2, and 3 year survival rates following relapse were 34%, 18% and 9% vs 50%, 32% and 28% respectively (p=0.017, Fig 2). A multivariable Cox model was developed for post-relapse survival considering the following variables: at relapse, gender, race, time from transplant to relapse, donor type, graft source, regimen intensity DRI, HCT-CI, KPS, CMV status, DLI post relapse , second alloHCT post relapse, year of relapse. Second alloHCT post-relapse was tested as a time-dependent covariate. Variables were selected if the p value was less than 0.05. Proportionality was tested for selected variables and all variables passed the test. On multivariable analysis, survival was significantly better for patients who relapsed in 2014-2018 vs patients relapsing in prior years (2003-2013) - HR 0.55. p=0.018. Other variables associated with post-relapse survival were time from BMT to relapse >250 d vs <100 d - HR 0.55, p=0.025 and haplo donor vs MRD for first alloHCT- HR 2.41, p=0.002. The use of DLI or the occurrence of a second alloHCT post-relapse tested as a time-dependent co-variate were not significantly associated with survival in this analysis. These data suggest that survival for AML patients who suffer relapse of malignancy following alloHCT has improved in recent cohorts when compared to historic controls. Approximately one-half and one-third of the patients are now estimated to live 1 and 2 years following relapse and prolonged survival is possible in some cases. The impact of specific interventions that help promote survival following relapse should be further studied Disclosures Solh: ADC Therapeutics: Research Funding; Celgene: Speakers Bureau; Amgen: Speakers Bureau.
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DeFor, Todd E., Chap Le, Angela R. Smith, Erica D. Warlick, Nelli Bejanyan, and Daniel J. Weisdorf. "Validation of a Modified Comorbidity Index for Allogeneic Hematopoietic Cell Transplant." Blood 128, no. 22 (December 2, 2016): 1167. http://dx.doi.org/10.1182/blood.v128.22.1167.1167.
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Abstract INTRODUCTION Among adult allogeneic hematopoietic cell transplant (HCT) recipients, the HCT-specific comorbidity index (HCT-CI) is a standard measure of baseline comorbidity. This measure incorporates 17 different comorbidities into a combined, categorically weighted score of standard, intermediate and high risk. Using the specific weights for each comorbidity from the single center analysis, the HCT-CI has been validated in other studies, most notably in a recent analysis including 8115 HCT recipients from the United States. The HCT-CI has been useful in controlling for confounding of comorbidities among patients. We previously reported that the efficiency and predictive power could be improved by removing the conversion of adjusted hazard ratios (HR) for non-relapse mortality (NRM) to three possible weights (1-3) for each comorbidity. METHODS Because some comorbidities show effects on a continuous scale and others show no effect, we proposed a weighting scheme in which each comorbidity is assigned the natural weight based on Fine and Gray regression analysis on NRM. The final modified comorbidity index (MCI) is based on a multiplicative model controlling for age, disease risk index, donor type and stratified by conditioning intensity. In this current study, we tested validation of calculations for the MCI by randomizing 2/3 of 1114 adult allogeneic patients with prospectively collected (2000-2015) comorbidities to a training set and 1/3 of patients to a test set. Using weights from the training set, we compared the MCI to the HCT-CI for the endpoints of NRM and overall survival (OS) in the test set. We did this using regression analysis and bootstrapping the difference in C-statistics for each method. RESULTS The median patient age was 51 (IQR: 39-59), 59% were male, donors included 41% HLA-matched sibling donors, 7% matched unrelated donors (URD) and 52% umbilical cord blood (UCB). Patients had malignant diagnoses with a disease risk index (DRI) of 19% low, 62% intermediate and 19% high or very high. Conditioning intensity included 65% reduced intensity (RIC) regimens. Using the HCT-CI, 19% were classified as low, 31% as intermediate and 39% as high risk. Based on the MCI, 34% were classified as low, 54% as intermediate and 12% as high risk. After adjusting for other factors, the independent weights for each comorbidity were calculated in our training set. We calculated the MCI by exponentiating the sum of all parameter coefficients from the regression analysis. The revised index score is: MCI = exponent [0.40*(binary indicator for cardiac disorders) + 0.85*(heart valve disease) + 0.05*(inflammatory bowel disease) + 0.48*(peptic ulcer) + 0.46* (diabetes) + 0.03*(psychiatric disturbance) + 0.20*(mild hepatic function) + 0.93*(moderate/severe hepatic function) + 0.19*(infection) + 2.00*(renal insufficiency) + 0.17*(moderate pulmonary abnormalities) + 0.39*(severe pulmonary abnormalities) + 0.16*(prior solid tumor)]. Comorbidities including obesity, cerebrovascular disease and rheumatologic disorders had no influence on NRM. This on-line calculator facilitates scoring of the modified index--MCI: http://bmt.ahc.umn.edu:8082/hct. In the test set (N=372), MCI was more predictive of NRM (table, fig 1a and 1b) and showed a trend toward increased sensitivity for OS compared to the original HCT-CI. The HR for intermediate and high risk categories increased (≥60% for NRM and >30% for OS). The adjusted likelihood ratio (showing model fit) increased from 20.3 to 22.5 for NRM and from 38.9 to 40.7 for OS when substituting MCI for HCT-CI. An increase shows better prediction of the endpoint. The C-statistic reflecting more NRM with a higher score and worse survival increased from 0.540 to 0.562 for NRM (P=0.02) and increased from 0.567 to 0.594 for OS (P=0.08). DISCUSSION This new MCI showed higher discriminating and predictive power for post-HCT NRM and a trend towards more predictive power for OS. As many HCT recipients have pre-existing comorbidities, the greater discrimination in assigning patient comorbidity will better inform decision-making for HCT recipients and HCT studies by better adjustment of these important risk factors. This MCI methodology should be used to create more efficient and predictive assessments in a larger multi-center study. Disclosures No relevant conflicts of interest to declare.
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Perales, Miguel-Angel, Christina Cho, Anne Eaton, Alison J. Moskowitz, Victoria Nguyen, Anne Marie R. Gonzales-Dadiz, Sean Devlin, et al. "A Prospective Study of Allogeneic Hematopoietic Stem Cell Transplantation in Relapsed/ Refractory Hodgkin Lymphoma." Blood 126, no. 23 (December 3, 2015): 4383. http://dx.doi.org/10.1182/blood.v126.23.4383.4383.
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Abstract INTRODUCTION: Patients with Hodgkin Lymphoma (HL) relapsing post autologous transplant (ASCT) are not cured with standard chemotherapy. In addition, a subset of patients with relapsed or primary-refractory HL fare poorly with ASCT. Such patients may benefit from allogeneic transplantation (allo-HCT) with its graft-versus-lymphoma (GVL) effect. METHODS: We performed a phase II study of salvage therapy (ST) followed by allo-HCT in adult patients with relapsed/refractory (rel/ref) HL (NCT00574496, Fig. 1a). Conditioning was dictated by PET status after ST, with NMA flu/cy/TBI 200 cGy for patients in CR and RIC mel/flu for those with PR/SD. Patients in the intent-to-treat (ITT) cohort were enrolled prior to ST and proceeded to allo-HCT if in CR, PR, or SD after 1 line of ST. The primary endpoint was successful allo-HCT and PFS at 1 year after allo-HCT (estimated as a proportion as all patients had at least 1 year of followup). Landmark analysis (from end of ST) with Kaplan-Meier curves and log-rank test were used to compare OS and PFS in the ITT cohort. A second cohort of patients referred with CR, PR, or SD after ST received HCT on protocol, but was not included in the ITT analysis. No differences in OS or PFS after HCT were seen between ITT and non-ITT cohorts, and patients were combined for further analysis. OS and PFS from time of HCT were estimated using all HCT patients, and PFS was compared based on baseline covariates. Cumulative incidence of GVHD, relapse/POD and nonrelapse mortality (NRM) were estimated using competing risks methodology. P-values less than 0.05 were considered significant. RESULTS: From 6/2008 to 6/2014, 25 patients were consented, 15 on the ITT analysis and 10 on the post-ST arm (Table 1). All had relapse after ASCT, primary refractory or high-risk HL relapsed within 1 year of 1st-line therapy. Allografts (n = 18) were PBSC from matched or single-allele mismatched related (n = 8) or unrelated (n = 3) donor, or double unit cord blood grafts (n = 7). Eleven were in PET CR before HCT and 7 in PR. ITT analysis (n=15): 5 patients had POD on ST and were ineligible for allo-HCT. Of the remaining 9, 1 withdrew during conditioning. 1-year and 3-year OS were 50% (95% CI 22.5, 100) and 16.7% (95% CI 2.8, 99.7), respectively, in patients with POD after ST, and 100% at both time points if no POD after ST (Fig 1b). At median 5.6 years of follow-up, 5 patients survive. The percent of patients successfully meeting the primary endpoint was 33% (95% CI 13, 61). Allo-HCT analysis (n=18): Cumulative incidence (CI) of grade 2-4 and 3-4 aGVHD at d+100 were 23.3% (95% CI 13.1, 55.3) and 11.1% (95% CI 1.70, 30.4), respectively. CI of cGVHD at 1 year and 3 years was 11.1% (95% CI 1.7, 30.7) and 35.6% (95% CI 13.2-59.0), respectively, and of mild severity in all but 1 patient. 3-year CI of relapse/POD was 34.3% (95% CI 13.2-56.7), and NRM 23.6% (95% CI 6.8, 46.1). Estimated 3-year PFS was 42.1% (95% CI 24.1, 73.6) and OS 70.3% (95% CI 51.5, 96.1) (Fig 1c). There was no significant association between PFS and disease stage or status (CR vs. PR). There was a trend toward poorer PFS in the 5 patients without prior ASCT (3 year PFS 20.0% vs. 50.8%, p = 0.088), 3 of whom had primary refractory HL. CONCLUSION: We demonstrate that allo-HCT provides long-term survival for a substantial portion of patients with rel/ref HL. Though limited by small sample size, the ITT analysis showed more than 1/3 of patients never attained sufficient disease control for allo-HCT, and have a dismal prognosis. Of note, none had received brentuximab or a checkpoint inhibitor, and the long-term impact of these agents in those patients remains to be seen. In patients undergoing allo-HCT with chemosensitive disease, proceeding to allo-HCT in PET PR vs. CR had no significant negative impact on PFS in this limited sample. The trend toward poor outcomes in patients who had not previously undergone ASCT likely reflects poor prognosis in patients with primary refractory disease. Factors informing prognosis after allo-HCT, and interventions to attenuate risk, remain an important area for further investigation. Table. Patient characteristics Median (range) age in yrs Median (range) prior lines of therapy N (%) prior ASCT Stage at relapse Disease status pre-ST Disease status pre-HCT ITT (n = 15) 32 (22-51) 3 (1-4) 8 (53.3) III: 4 IV: 11 1st relapse: 6 ≥ 2nd relapse: 5 Refractory: 4 7 CR 2 PR 5 POD 1 withdrew All HCT (n = 18) 36 (24-53) 4 (2-6) 13 (72.2) II: 1 III: 4 IV: 13 1st relapse: 3 ≥ 2nd relapse: 11 Refractory: 4 11 CR 7 PR Disclosures Perales: BeTheMatch/ National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Astellas: Honoraria; Merck: Honoraria; Amgen: Honoraria. Giralt:TAKEDA: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding. Straus:Millenium Pharmaceuticals: Research Funding. Moskowitz:GSK: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding.
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Bora, R., B. B. Maini, and A. Chakma. "Flow Visualization Studies of Solution Gas Drive Process in Heavy Oil Reservoirs Using a Glass Micromodel." SPE Reservoir Evaluation & Engineering 3, no. 03 (June 1, 2000): 224–29. http://dx.doi.org/10.2118/64226-pa.
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Summary A series of flow visualization experiments was carried out to examine the pore scale behavior of the solution gas drive process in heavy oil reservoirs. The main objective was to testify several speculative theories that had been put forward to explain the anomalous production behavior of heavy oil reservoirs producing under the solution gas drive process. Contrary to previous postulations, the asphaltene constituents did not appear to play a significant role in the nucleation and stabilization of the gas bubbles that evolved during the solution gas drive process. Experimental evidence also suggests that the production of heavy oil is not accompanied by a large population of microbubbles. These observations suggest that the production enhancement in the solution gas process in heavy oil reservoirs may be related to other mechanisms such as viscous coupling effects, sand production, wormhole effects, etc. Introduction Primary production of heavy oil reservoirs operating under the solution gas drive mechanism exhibits an unexpectedly higher primary recovery with a slower pressure decline rate, lower than expected gas oil ratios, and higher oil production rates. These reservoirs which are prolific during the primary production phase have shown very poor response to secondary recovery techniques, such as thermal recovery. Ongoing observations in the fields 1–4 and preliminary observations in laboratories 5–7 strongly suggest that the cold production process of heavy oil reservoirs by the solution gas drive process involves a multitude of effects. A detailed analysis of such unusual production behavior was first provided by Smith.1 He suggested that the solution gas drive in heavy oil reservoirs involves simultaneous flow of oil and gas in the form of microbubbles. Following this, the flow behavior of such gas-oil dispersions has been the subject of several investigators and considerable speculation.2–9 However, the solution gas mechanism in heavy oil reservoirs remains controversial and poorly understood. Background In the solution gas drive process, the main source of energy driving the oil towards the wellbore is the evolution and expansion of the gas bubbles initially dissolved in the oil. The role of the gas bubbles in the oil displacement process has been studied for a long time.10--16 The first visual studies of the behavior of the solution gas process at the microscopic level was performed by Chatenever et al.14 using thin glass bead packings and thin sections of natural sandstone and limestone. With the advent of glass micromodels, flow visualization studies were conducted to examine the microscopic behavior of the solution gas drive process.17–22 All these studies provided a direct observation of pore level events. However, a comprehensive understanding of the pore scale physics in the solution gas drive process has not yet been attained. Moreover, recent observations in the field led to revised thinking of the mechanisms involved in the solution gas drive process in heavy oil reservoirs. The flow of heavy oil under the solution gas drive process appears to be more complex than what is expected from conventional solution gas drive theories. None of the previous studies focused on the behavior of the solution gas process in heavy oil reservoirs. To acquire an improved understanding of the solution gas drive mechanisms, it is necessary to consider the pore scale physics. Most of the questions concerning nucleation, growth, coalescence, and flow of the gas bubbles dispersed in oil can be answered only by direct examination of individual pore scale events. Although it is not possible to visually examine the processes occurring at the pore level in actual reservoir rocks, a very close approximation can perhaps be achieved in a micromodel. Micromodels provide a very convenient means of directly observing the formation, growth, flow, and trapping of gas bubbles. The main objective of this work was to carry out a series of flow visualization experiments, using a high pressure etched glass micromodel, to make a detailed investigation of the effects of asphaltene particles, pressure depletion rates, and sand wettability on the pore level flow mechanisms in the solution gas drive process. To the best of our knowledge, there has been no such systematic investigation of pore scale physics of the solution gas drive process in heavy oil reservoirs. The applications and technical contributions of such a study include the following:an improved understanding of the solution gas drive mechanism in heavy oil reservoirs,planning optimum development strategies for heavy oil reservoirs, andunderstanding of the condition of the reservoir at the end of the primary production phase which is helpful for developing an effective follow-up secondary recovery technique. Micromodel Apparatus The experimental setup is shown schematically in Fig. 1. The heart of the test rig is the high pressure etched glass micromodel. Conceptually, it is simple in design. Two glass plates were held together by overburden pressure inside a windowed pressure vessel. One of the glass plates had a detailed flow pattern chemically etched onto it, the other plate was unetched and had parallel sides. The flow pattern used in this work is displayed in Fig. 2. Here, the black dots represent sand grains while the white area represents the flow channels. The center to center distance between adjoining "sand grains" was 500 µm and the diameter of each dot was 334 µm. The average depth of etched flow channels was about 50 µm. The pore volume within the boundaries of the etched pattern was approximately 75 µL. The etched flow patterns were illuminated with high intensity halogen light bulbs underneath the bottom window of the pressure vessel. The overburden pressure in the pressure vessel was maintained at 600 psi (4.14 MPa) throughout the entire study.