Variations in FLT3 ligand levels during the course of AML treatment.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7026-7026 ◽  
Author(s):  
Michael Richard Grunwald ◽  
Mark J. Levis
Keyword(s):  
Kinase Inhibitors ◽  
Indirect Evidence ◽  
Flt3 Ligand ◽  
Consolidation Chemotherapy ◽  
Stromal Microenvironment ◽  
Transient Rise ◽  
High Concentrations ◽  
One Year ◽  
The Relationship

7026 Background: FLT3 ligand (FL) is a hematopoietic growth factor expressed in many tissues. AML patients who are administered myeloablative therapy exhibit a marked and transient rise in plasma FL concentrations. Furthermore, the presence of high concentrations (1000 pg/mL) of FL impedes the efficacy of FLT3 tyrosine kinase inhibitors in vitro. However, the behavior of FL concentrations throughout the course of AML treatment remains unknown. This pilot study was undertaken to track the relationship between AML therapy and FL levels over time. Methods: Ten AML patients were enrolled in an IRB-approved procurement protocol. Blood samples were collected at weekly intervals for one year, and plasma was isolated by centrifugation. Plasma FL and stem cell factor (SCF) concentrations were measured by ELISA. Results: We observed four distinct patterns in FL fluctuations. First, in all cases where induction or consolidation chemotherapy resulted in an aplastic bone marrow (nine patients), FL concentrations rose markedly and consistently to levels >1000 pg/mL following the administration of chemotherapy. Second, in three of four patients whose leukemia was refractory to induction chemotherapy, FL concentrations remained below 500 pg/mL during induction. Third, in two patients receiving the FLT3 TKI sorafenib, FL concentrations did not rise above 500 pg/mL while on this medication. Fourth, in one patient receiving the hypomethylating agent 5-azacitidine, FL concentrations remained below 100 pg/mL throughout the course of therapy. SCF concentrations did not vary throughout the course of chemotherapy. Conclusions: An “FL surge” was seen when cytotoxic chemotherapy resulted in aplasia. This FL surge was not seen with sorafenib or 5-azacitidine. In addition, the FL surge was attenuated in three patients whose leukemia was refractory to chemotherapy. These observations give rise to two new hypotheses regarding FL: 1) It is possible to maintain lower FL levels with targeted agents than with chemotherapy; and 2) Residual leukemia appears to inhibit the FL surge, providing indirect evidence of cross-talk between leukemia and the stromal microenvironment. This inhibition may be the explanation for why AML patients develop pancytopenia early in relapse.

PITUITARY GROWTH HORMONE AND THE GLUCOSE UTILIZATION OF RAT DIAPHRAGM

1955 ◽  
Vol 12 (1) ◽  
pp. 50-56 ◽  
Author(s):  
J. H. OTTAWAY ◽  
R. D. BULBROOK
Keyword(s):  
Growth Hormone ◽  
Glucose Uptake ◽  
Glucose Utilization ◽  
Rat Diaphragm ◽  
Pituitary Growth Hormone ◽  
Low Concentrations ◽  
High Concentrations ◽  
The Relationship

SUMMARY Growth hormone has been reported to cause either a depression or a stimulation of the glucose uptake of isolated rat diaphragm. The present paper describes further work on the two effects. 1. Anaerobic conditions during the preparation of the diaphragm for incubation affect the glucose uptake and alter the response of the muscle to growth hormone. By controlling the oxygen tension in the diaphragm immediately after excision, variation of the glucose uptake and the effect of the hormone is reduced. 2. Solutions of growth hormone were found to be extremely labile, but, by rigidly standardizing the method of preparing solutions, consistent results were obtained. 3. The relationship between the concentration of growth hormone and its effect on the glucose uptake of isolated diaphragm was investigated separately for muscle saturated with oxygen and with nitrogen. With oxygenated muscle at high concentrations the hormone stimulates, and at low concentrations depresses, the rate of glucose uptake. 4. The mode of action of growth hormone in vitro and in vivo is discussed.

Expression of Peroxisome Proliferator-Activated Receptor Alpha (PPARα) in Non-Somatotroph Pituitary Tumours and the Effects of PPARα Agonists on MMQ Cells

2018 ◽  
Vol 50 (08) ◽  
pp. 640-647 ◽  
Author(s):  
Michela Polidoro ◽  
Sandra Rotondi ◽  
Roberta Morace ◽  
Liliya Rostomyan ◽  
Alessandro Colapietro ◽  
...  
Keyword(s):  
Tumour Volume ◽  
Cell Number ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Interacting Protein ◽  
Receptor Alpha ◽  
Aryl Hydrocarbon ◽  
High Concentrations ◽  
The Relationship

AbstractPeroxisome proliferator-activated receptor alpha (PPARα) has been involved in the regulation of somatotroph tumour cells and may be targeted by different drugs, some of them are in current clinical use. The aim of this study was to investigate the expression of PPARα in additional phenotypes of pituitary adenomas (PA), the relationship between PPARα and its potential molecular partner aryl hydrocarbon receptor interacting protein (AIP) in these tumours, and the effects of PPARα agonists on lactotroph cells. Seventy-five human PA – 57 non-functioning (NFPA) and 18 prolactinomas (PRL-PA) – were characterised for PPARα and AIP expression by real time RT-PCR and/or immunohistochemistry (IHC), and the effects of fenofibrate and WY 14 643 on MMQ cells were studied in vitro. PPARα was expressed in a majority of PA. PPARα immunostaining was observed in 93.7% PRL-PA vs. 60.6% NFPA (p=0.016), the opposite being found for AIP (83.3% in NFPA vs. 43.7% in PRL-PA, p=0.003). PPARα expression was unrelated to gonadotroph differentiation in NFPA, but positively correlated with tumour volume in PRL-PA. Both drugs significantly reduced MMQ cell growth at high concentrations (100–200 μM). At the same time, despite modest stimulating effects on PRL secretion were observed, these were overcome by the reduction in cell number. In conclusion, PPARα is commonly expressed by PRL-PA and NFPA, regardless of AIP, and may represent a new target of PPARα agonists.

scholarly journals Response of Four Lemon (Citrus limon L. Burm) Cultivars Cultured in vitro to BAP, KIN and 2,4- D Combinations

2017 ◽  
Vol 27 (1) ◽  
pp. 39-50
Author(s):  
Abdul Mohsin Radah Obiad Al Sayed Abdul Mohsin Radah Obiad Al Sayed
Keyword(s):  
Culture Medium ◽  
Citrus Limon ◽  
High Concentration ◽  
Low Concentrations ◽  
Micro Propagation ◽  
King Abdulaziz University ◽  
High Concentrations ◽  
One Year ◽  
The One

The present study was carried out in the lab. of plant tissue culture at King Abdulaziz University to test the response of four lemon cultivars to micro-propagation using BAP, Kin and 2,4- D combinations. The used explants in this study were intermodal segments and collected from the one year old lemon seedlings which obtained from the Citrus Research Center, Najran, Saudi Arabia. The experiments were laid out in a split plot design using 4 replicates. The results revealed that there were significant differences due to genotypic and growth regulators effects and their interaction for all measured parameters except no of days to buds sprouting. Explants of ‘Shehri’ registered maximum values of no. of days to buds sprouting with 0.5mg/l-1 Kin +0.5mg/l-1 2,4-D, % sprouted buds with 0.5mg/l-1 BAP, % dead shootlets with 2mg/l-1 BAP+0.5mg/l-1 2-,4- D and length of primary shoots (mm) 1mg/l-1 BAP+0.5mg/l-1 2-,4- D. Shoots of ‘AlnEurka’ formed the highest no. of leaves with 0.5mg/l-1 BAP+1mg/l-1 2-,4- D. Low responses were observed for explants from ‘Shaary’, ‘Banzahir’ and ‘Aln-Eurka’ on culture medium supplemented with high concentration of BAP alone or with combination of 2,4- D. There were observed no sprouted buds for explants of ‘Shehri’ on culture medium complemented with high concentrations of Kin in combinations with 2,4- D. Lemon explants were successfully in vitro propagated using intermodal segments and combinations of BAP, Kin and 2,4- D at low concentrations.

Ultrastructural Correlations between Clonal Human Tumor Colonies and in Vivo Neoplasms

1982 ◽  
Vol 40 ◽  
pp. 210-211
Author(s):  
M.J. Murphy ◽  
R.R. Price ◽  
J.C. Sloman
Keyword(s):  
Cultured Cells ◽  
Human Tumor ◽  
Cell Type ◽  
Tumor Mass ◽  
Initial Cell ◽  
Cloning Assay ◽  
Human Tumor Cloning ◽  
The Relationship

The in vitro human tumor cloning assay originally described by Salmon and Hamburger has been applied recently to the investigation of differential anti-tumor drug sensitivities over a broad range of human neoplasms. A major problem in the acceptance of this technique has been the question of the relationship between the cultured cells and the original patient tumor, i.e., whether the colonies that develop derive from the neoplasm or from some other cell type within the initial cell population. A study of the ultrastructural morphology of the cultured cells vs. patient tumor has therefore been undertaken to resolve this question. Direct correlation was assured by division of a common tumor mass at surgical resection, one biopsy being fixed for TEM studies, the second being rapidly transported to the laboratory for culture.

In Vitro Effects of Ethanol on Rabbit Platelet Aggregation, Secretion of Granule Contents, and Cyclic AMP Levels in the Presence of Prostacyclin

1989 ◽  
Vol 61 (02) ◽  
pp. 254-258 ◽  
Author(s):  
Margaret L Rand ◽  
Peter L Gross ◽  
Donna M Jakowec ◽  
Marian A Packham ◽  
J Fraser Mustard
Keyword(s):  
Cyclic Amp ◽  
Inhibitory Effect ◽  
Rabbit Platelet ◽  
Inhibitory Effects ◽  
Low Concentrations ◽  
Rabbit Platelets ◽  
High Concentrations ◽  
In Vitro Effects ◽  
Aggregation Of Platelets

SummaryEthanol, at physiologically tolerable concentrations, inhibits platelet responses to low concentrations of collagen or thrombin, but does not inhibit responses of washed rabbit platelets stimulated with high concentrations of ADP, collagen, or thrombin. However, when platelet responses to high concentrations of collagen or thrombin had been partially inhibited by prostacyclin (PGI2), ethanol had additional inhibitory effects on aggregation and secretion. These effects were also observed with aspirin- treated platelets stimulated with thrombin. Ethanol had no further inhibitory effect on aggregation of platelets stimulated with ADP, or the combination of ADP and epinephrine. Thus, the inhibitory effects of ethanol on platelet responses in the presence of PGI2 were very similar to its inhibitory effects in the absence of PGI2, when platelets were stimulated with lower concentrations of collagen or thrombin. Ethanol did not appear to exert its inhibitory effects by increasing cyclic AMP above basal levels and the additional inhibitory effects of ethanol in the presence of PGI2 did not appear to be brought about by further increases in platelet cyclic AMP levels.

Plasminogen Depletion during Streptokinase Treatment or Two-Chain Urokinase Incubation Correlates with Decreased Clot Lysability Ex Vivo and In Vitro

1993 ◽  
Vol 70 (06) ◽  
pp. 0998-1004 ◽  
Author(s):  
Páll T Önundarson ◽  
H Magnús Haraldsson ◽  
Lena Bergmann ◽  
Charles W Francis ◽  
Victor J Marder
Keyword(s):  
Myocardial Infarction ◽  
Ex Vivo ◽  
Time Dependent ◽  
State Variables ◽  
Thrombolytic Treatment ◽  
Direct Proportion ◽  
Plasmin Activity ◽  
Plasma Exposure ◽  
The Relationship

SummaryThe relationship between lytic state variables and ex vivo clot lysability was investigated in blood drawn from patients during streptokinase administration for acute myocardial infarction. A lytic state was already evident after 5 min of treatment and after 20 min the plasminogen concentration had decreased to 24%, antiplasmin to 7% and fibrinogen 0.2 g/1. Lysis of radiolabeled retracted clots in the patient plasmas decreased from 37 ± 8% after 5 min to 21 ± 8% at 10 min and was significantly lower (8 ± 9%, p <0.005) in samples drawn at 20, 40 and 80 min. Clot lysability correlated positively with the plasminogen concentration (r = 0.78, p = 0.003), but not with plasmin activity. Suspension of radiolabeled clots in normal plasma pre-exposed to 250 U/ml two-chain urokinase for varying time to induce an in vitro lytic state was also associated with decreasing clot lysability in direct proportion with the duration of prior plasma exposure to urokinase. The decreased lysability correlated with the time-dependent reduction in plasminogen concentration (r = 0.88, p <0.0005). Thus, clot lysability decreases in conjunction with the development of the lytic state and the associated plasminogen depletion. The lytic state may therefore limit reperfusion during thrombolytic treatment.

Monitoring Anticoagulant Therapy by Activated Partial Thromboplastin Time: Hirudin Assessment

1994 ◽  
Vol 72 (05) ◽  
pp. 685-692 ◽  
Author(s):  
Michael T Nurmohamed ◽  
René J Berckmans ◽  
Willy M Morriën-Salomons ◽  
Fenny Berends ◽  
Daan W Hommes ◽  
...  
Keyword(s):  
Whole Blood ◽  
Partial Thromboplastin Time ◽  
Ex Vivo ◽  
Fold Increase ◽  
Heparin Therapy ◽  
Activated Partial Thromboplastin Time ◽  
Recombinant Hirudin ◽  
Interindividual Differences ◽  
The Relationship

SummaryBackground. Recombinant hirudin (RH) is a new anticoagulant for prophylaxis and treatment of venous and arterial thrombosis. To which extent the activated partial thromboplastin time (APTT) is suitable for monitoring of RH has not been properly evaluated. Recently, a capillary whole blood device was developed for bed-side monitoring of the APTT and it was demonstrated that this device was suitable to monitor heparin therapy. However, monitoring of RH was not evaluated.Study Objectives. To evaluate in vitro and ex vivo the responsiveness and reproducibility for hirudin monitoring of the whole blood monitor and of plasma APTT assays, which were performed with several reagents and two conventional coagulometers.Results. Large interindividual differences in hirudin responsiveness were noted in both the in vitro and the ex vivo experiments. The relationship between the APTT, expressed as clotting time or ratio of initial and prolonged APTT, and the hirudin concentration was nonlinear. A 1.5-fold increase of the clotting times was obtained at 150-200 ng/ml plasma. However, only a 2-fold increase was obtained at hirudin levels varying from 300 ng to more than 750 ng RH/ml plasma regardless of the assays. The relationship linearized upon logarithmic conversion of the ratio and the hirudin concentration. Disregarding the interindividual differences, and presuming full linearity of the relationship, all combinations were equally responsive to hirudin.Conclusions. All assays were equally responsive to hirudin. Levels up to 300 ng/ml plasma can be reliably estimated with each assay. The manual device may be preferable in situations where rapid availability of test results is necessary.

Aggregation of Cat Platelets in Vitro

1970 ◽  
Vol 23 (03) ◽  
pp. 601-620 ◽  
Author(s):  
Th. B Tschopp
Keyword(s):  
Adenosine Monophosphate ◽  
Blood Collection ◽  
Base Line ◽  
Reversible Aggregation ◽  
Low Concentrations ◽  
Irreversible Aggregation ◽  
High Concentrations ◽  
Two Phases ◽  
Improved Technique

SummaryAggregation of cat platelets in the citrated plasma is examined by means of Born’s absorptiometer. A marked tendency of the platelets of this species to spontaneous aggregation necessitated first of all the development of an improved technique of blood collection.A hypothesis according to which 5-HT is released from the platelets, explains the absence of oscillations on the base line of the absorptiometer, the absence of platelet swelling, when ADP is added, and the effect of stirring on the aggregation curves in cat PRP. The average volume of cat platelets amounts to 10.46 μ3 when directly fixed in the blood, when fixed from PRP to 12.17 μ3, when fixed from stirred PRP to 13.51 μ3.In low concentrations (0.3-2 μM) ADP produce reversible aggregation; in narrowly restricted, individually dissimilar mean concentrations irreversible aggregation in two phases and in high concentrations, irreversible aggregation in one phase. Like ADP serotonin produces 2 phase irreversible aggregation in concentrations of 3-10 μM, but unlike ADP, the aggregation velocity decreases again with high 5-HT concentrations (>100 μM). Adrenaline does not produce aggregation and it is likely that adenosine and adenosine monophosphate inhibit the aggregation by serotonin but not by ADP. Species differences in the aggregation of human, rabbit and cat platelets are discussed.

Thrombin Generation Measured Ex Vivo Following Microvasculor Injury Is Increased in SLE Patients with Antiphospholipid-protein Antibodies

1997 ◽  
Vol 78 (04) ◽  
pp. 1173-1177 ◽  
Author(s):  
Jacek Musiał ◽  
Jakub Swadźba ◽  
Miłosz Jankowski ◽  
Marek Grzywacz ◽  
Stanisława Bazan-Socha ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Thrombin Generation ◽  
Ex Vivo ◽  
Skin Incision ◽  
Anticardiolipin Antibodies ◽  
Small Blood Vessel ◽  
Anionic Phospholipids ◽  
Increased Risk ◽  
High Concentrations

SummaryAntiphospholipid-protein antibodies (APA) include lupus-type anticoagulant (LA) and antibodies recognizing complexes of anionic phospholipids (e.g. cardiolipin) and proteins (e.g. prothrombin and (β2-glycoprotein I). The presence of APA is associated with an increased risk of both arterial and venous thrombosis. However, the pathogenic mechanism leading to thrombosis in patients with APA remains unclear. We studied 32 patients with systemic lupus erythematosus (SLE) who were divided into two groups depending on the presence (n = 19) or absence (n = 13) of APA. Healthy volunteers (n = 12) matched by age and sex served as controls. In all subjects LA and IgG class anticardiolipin antibodies (ACA) were determined. Thrombin generation was monitored ex vivo measuring fibrinopeptide A (FPA) and prothrombin fragment F1 + 2 (F1 + 2) in blood emerging from a skin microvasculature injury, collected at 30 second intervals. In subjects with antiphospholipid antibodies mean FPA and F1 + 2 concentrations were signiF1cantly higher at most blood sampling times than in controls. In some SLE patients with APA the process of thrombin generation was clearly disturbed and very high concentrations of F1brinopeptide A were detected already in the F1rst samples collected. Two minutes after skin incision SLE patients without APA produced slightly more FPA, but not F1 + 2, as compared to healthy subjects. Mathematical model applied to analyze the thrombin generation kinetics revealed that APA patients generated signiF1cantly greater amounts of thrombin than healthy controls (p = 0.02 for either marker). In contrast, in the same patients generation of thrombin in recalciF1ed plasma in vitro was delayed pointing to the role of endothelium in the phenomenon studied. In summary, these data show for the F1rst time that in SLE patients with antiphospholipid-protein antibodies thrombin generation after small blood vessel injury is markedly increased. Enhanced thrombin generation might explain thrombotic tendency observed in these patients.

Inhibition of Platelet Function by Antiarrhythmic Drugs, Verapamil and Disopyramide

1982 ◽  
Vol 47 (02) ◽  
pp. 150-153 ◽  
Author(s):  
P Han ◽  
C Boatwright ◽  
N G Ardlie
Keyword(s):  
Platelet Aggregation ◽  
Platelet Function ◽  
Antiarrhythmic Drugs ◽  
Adenosine Diphosphate ◽  
Inhibitory Effect ◽  
Second Phase ◽  
Ionophore A23187 ◽  
High Concentrations ◽  
Artery Disease

SummaryVarious cardiovascular drugs such as nitrates and propranolol, used in the treatment of coronary artery disease have been shown to have an antiplatelet effect. We have studied the in vitro effects of two antiarrhythmic drugs, verapamil and disopyramide, and have shown their inhibitory effect on platelet function. Verapamil, a calcium channel blocker, inhibited the second phase of platelet aggregation induced by adenosine diphosphate (ADP) and inhibited aggregation induced by collagen. Disopyramide similarly inhibited the second phase of platelet aggregation caused by ADP and aggregation induced by collagen. Either drug in synergism with propranolol inhibited ADP or collagen-induced platelet aggregation. Disopyramide at high concentrations inhibited arachidonic add whereas verapamil was without effect. Verapamil, but not disopyramide, inhibited aggregation induced by the ionophore A23187.

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