BCR-ABL1 Oncogene Down-regulates the Expression of OCT1 in CML.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3248-3248
Author(s):  
Alexandra Bazeos ◽  
David Marin ◽  
Gareth Gerrard ◽  
Richard Szydlo ◽  
Dragana Milojkovic ◽  
...  
Keyword(s):  
Organic Cation Transporter ◽  
Normal Subjects ◽  
Inhibitory Effect ◽  
Serum Drug Concentration ◽  
Loss Of Function ◽  
Duration Of Action ◽  
Transcript Levels ◽  
Log Reduction ◽  
Significant Difference ◽  
Pre Treatment

Abstract Abstract 3248 Poster Board III-1 The polyspecific organic cation transporter OCT1 (SLC22A1) exhibits broad substrate specificity and facilitates the intracellular uptake of imatinib mesylate (IM). The contribution of OCT1 to the clinical outcome of CML patients treated with IM remains controversial. The aim of this study was to compare OCT1 transcript levels in different normal cell populations, to examine the effect of BCR-ABL1 oncoprotein and IM on OCT1 expression, to investigate the predictive value of OCT1 levels and to determine whether OCT1 SNPs in CML patients correlate with altered IM response and sensitivity. We found that OCT1 mRNA expression was higher in normal PMNs than in normal MNCs (p<0.0001). In CML, total WBC OCT1 transcript levels were significantly higher in CCyR samples than in patient samples collected at diagnosis (p<0.0001). There was no significant difference between OCT1 expression at the time of cytogenetic remission in CML patients (n=60) compared with OCT1 expression in normal subjects (n=21) suggesting an inhibitory effect of Bcr-Abl1 rather than a drug inducing effect of IM. Furthermore, OCT1 transcript levels at diagnosis prior to IM therapy could predict for both a 3- and 4-log reduction in Bcr-Abl1 transcripts following IM therapy. We investigated the association of 7 previously described non-synonymous SNPs of SLC22A1 with respect to IM response in 89 CCyR responders and 44 non-responders. SNPs P283L, R287G and C88R were not subjected to statistical analysis as the frequency of polymorphisms in our cohort at these respective loci was too small. For the remaining 4 screened SNPs (rs622342, R61C, P341L and G401S), no relationship could be found between allele frequency and pre-treatment OCT1 transcript levels (n=60). This finding is expected, given that the locations of these SNPs do not involve the promoter region of SLC22A1. We were however able to demonstrate a correlation between response to IM and SNP G401S. Though numbers were small, heterozygotes for this allele had a greater probability of achieving a 3-log reduction in Bcr-Abl1 transcript levels (p=0.015). Although this genotype has been described previously as a loss of function polymorphism, we showed the opposite to be true in CML patients on IM therapy. This finding may suggest that first-pass extraction of orally administered IM by liver metabolizing cells, could be diminished and so lead to a higher serum drug concentration and hence a greater intensity and duration of action. Alternatively, this could highlight the insignificant contribution that genetic variation of SCL22A1 plays in the outcome of patients with CML. In conclusion, OCT1 transcript levels vary in different cells types, are low in untreated CML patients but return to ‘normal' after successful treatment with IM. The clinical relevance of SLC22A1 SNPs warrants further study. Disclosures: Novartis: Consultancy, Research Funding.

scholarly journals Efficacy of a Next Generation Quaternary Ammonium Chloride Sanitizer on Staphylococcus and Pseudomonas Biofilms and Practical Application in a Food Processing Environment

2021 ◽  
Vol 1 (1) ◽  
pp. 89-103
Author(s):  
Kundan Shah ◽  
Peter M. Muriana
Keyword(s):  
Foodborne Pathogens ◽  
Food Processing ◽  
Next Generation ◽  
Pseudomonas Spp ◽  
Log Reduction ◽  
Significant Difference ◽  
Biofilm Bacteria ◽  
Pre Treatment ◽  
Staphylococcus Spp ◽  
Food Processing Environment

Foodborne pathogens are known to adhere strongly to surfaces and can form biofilms in food processing facilities; therefore, their potential to contaminate manufactured foods underscores the importance of sanitation. The objectives of this study were to (1) examine the efficacy of a new-generation sanitizer (Decon7) on Staphylococcus and Pseudomonas biofilms, (2) identify biofilm bacteria from workers’ boots in relation to previous sanitizer chemistry, (3) validate the efficacy of Decon7 on biofilm from workers’ boots from an abattoir/food processing environment, and (4) compare the sensitivity of isolated boot biofilm bacteria to new- and early (Bi-Quat)-generation QAC sanitizers. Decon7 was applied at two concentrations (5%, 10%) and was shown to be effective within 1 min of exposure against enhanced biofilms of Staphylococcus spp. and Pseudomonas spp. in 96-well microplates. Decon7 was also used to treat workers’ boots that had accumulated high levels of biofilm bacteria due to ineffective sanitization. Bacteria isolated before enzyme/sanitizer treatment were identified through 16S rRNA PCR and DNA sequencing. All treatments were carried out in triplicate and analyzed by one-way RM-ANOVA or ANOVA using the Holm–Sidak test for pairwise multiple comparisons to determine significant differences (p < 0.05). The data show a significant difference between Decon7 sanitizer treatment and untreated control groups. There was a ~4–5 log reduction in Staphylococcus spp. and Pseudomonas spp. (microplate assay) within the first 1 min of treatment and also a > 3-log reduction in the bacterial population observed in the biofilms from workers’ boots. The new next-generation QAC sanitizers are more effective than prior QAC sanitizers, and enzyme pre-treatment can facilitate biofilm sanitizer penetration on food contact surfaces. The rotation of sanitizer chemistries may prevent the selective retention of chemistry-tolerant microorganisms in processing facilities.

Optimizing Early Prediction Of Outcome In CML Using The Exact Decline Of BCR-ABL Transcript Levels Within 3 Months Of Imatinib Treatment As a Prognostic Marker

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 253-253 ◽  
Author(s):  
Benjamin Hanfstein ◽  
Valeria Shlyakhto ◽  
Michael Lauseker ◽  
Rüdiger Hehlmann ◽  
Susanne Saussele ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Risk Group ◽  
High Risk Group ◽  
Hazard Ratio ◽  
Transcript Levels ◽  
Log Reduction ◽  
Pre Treatment ◽  
The Individual ◽  
Good Risk

Abstract Introduction Early assessment of BCR-ABL transcript levels at 3 months allows the prediction of survival and may serve as a trigger for treatment intensification in CML patients with slow response to imatinib. The exact decline of BCR-ABL transcript levels within the first 3 months of treatment is defined by the ratio BCR-ABL transcripts at 3 months to BCR-ABL transcripts at baseline. This ratio might better reflect the individual biology of disease and its susceptibility to tyrosine kinase inhibition. Methods A total of 408 chronic phase CML patients (pts) with baseline and 3 month blood samples available in one single laboratory were investigated. Pts with pre-treatment before first blood sampling were excluded (imatinib with or without hydroxyurea, n=58; hydroxyurea only, n=49). A total of 301 evaluable pts (median age 52 years, range 18-85, 41% female) were treated with an imatinib-based therapy within the CML-Study IV. Median follow-up was 4.8 years. Transcript levels of BCR-ABL, total ABL, and beta-glucuronidase (GUS) were determined by quantitative RT-PCR. Exploratory landmark analyses were performed with regard to overall and progression-free survival (OS, PFS) to evaluate the prognostic significance of (i) BCR-ABL/GUS before treatment, (ii) the individual reduction of transcripts given by (BCR-ABL/GUS at 3 months) / (BCR-ABL/GUS before treatment), and (iii) the 3-month 10% BCR-ABLIS landmark. Results The median BCR-ABL/GUS ratio was 15.5% at diagnosis (0.06-107) and 0.63% at 3 months (0-84) reflecting a decline to the 0.04-fold (1.4 log reduction). i) No prognostic cut-off could be identified for BCR-ABL/GUS before treatment. ii) A reduction to the 0.35-fold of the initial BCR-ABL transcript level at diagnosis (0.46 log reduction) was identified as best cut-off according to a hazard ratio of 5.6 (95%-CI 2.3-13.4, p<0.001 for PFS). Using this cut-off a high-risk group of 48 pts (16% of pts, 5-year PFS and OS: 77% and 83%) was separated from a good-risk group of 253 pts (84% of pts, 5-year PFS and OS: 96% and 98%). iii) As a comparison we investigated the 10% BCR-ABLIS landmark at 3 months with a hazard ratio of 2.4 (95%-CI 1.0-5.8, p=0.06 for PFS). With this landmark a high-risk group of 67 pts (22% of pts, 5-year PFS and OS: 87% and 90%) was separated from a good-risk group of 234 pts (78% of pts, 5-year PFS and OS: 95% and 97%). Conclusion A two-group risk stratification according to the individual reduction of BCR-ABL transcripts to the 0.35-fold of pre-treatment levels yields a superior separation of risk groups with a 5-year difference of 19% for PFS and 15% for OS. This predictive marker might identify patients at risk more precisely than 3-month 10% BCR-ABLIS. Disclosures: Hehlmann: BMS: Consultancy, Research Funding; Novartis: Research Funding. Saussele:Novartis: Honoraria, Research Funding, Travel Other; BMS: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding, Travel Other; BMS: Consultancy, Honoraria, Research Funding; ARIAD: Consultancy, Honoraria; Pfizer: Consultancy. Müller:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding.

AN ASSESSMENT OF STABILITY, GAIT PERFORMANCE AND ENERGY CONSUMPTION IN INDIVIDUALS WITH TRANSFEMORAL AMPUTATION

2015 ◽  
Vol 15 (04) ◽  
pp. 1550049 ◽  
Author(s):  
FATOMEH KHIRI ◽  
MOHAMMAD TAGHI KARIMI ◽  
FRANCIS FATOYE ◽  
NIMA JAMSHIDI
Keyword(s):  
Energy Consumption ◽  
Walking Speed ◽  
Force Plate ◽  
Normal Subjects ◽  
Quiet Standing ◽  
Loss Of Function ◽  
Transfemoral Amputation ◽  
Cost Index ◽  
Gait Performance ◽  
Significant Difference

Transfemoral amputation (TFA) results in reduced sensation, altered body image and loss of function. Energy expenditure is known to be significantly higher in individuals with TFA compared with their healthy counterparts. Kinetic and kinematics characteristics of individuals with TFA have been evaluated; however, stability during quiet standing has not been examined. This study evaluated stability, gait performance and energy consumption in individuals with TFA during standing and walking. A total of subjects (5 healthy and 5 with TFA) participated in this study. The motion of lower limb joints and the force applied on the leg were evaluated using a motion analysis system, Qualysis. Stability during standing was examined using a force plate and energy consumption during walking was evaluated based on physiological cost index (PCI). Group comparisons were made using the independent t-test. There was no significant difference in stability between subjects with TFA and normal subjects during standing. However, walking speed in subjects with TFA decreased significantly compared to normal subjects (p = 0.014). PCI of subjects with TFA was 0.525 ± 0.13 compared to 0.298 ± 0.059 beats/m in normal subjects (p < 0.05). It seems that stability in subjects with TFA was similar to their healthy counterparts. However, energy consumption was higher in the TFA group than in normal subjects, which may be due to slow walking speed. Clinicians are to be aware of these findings as they may be useful for effective management of the patients with TFA.

Favorable Molecular Responses to Imatinib in CML Patients in Early Chronic Phase in Comparison to Late Chronic Phase Patients after Treatment with Hydroxyurea and Interferon.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4794-4794
Author(s):  
Frank Schüler ◽  
Malte Leithäuser ◽  
Thomas Kiefer ◽  
Saskia Richter ◽  
Gottfried Dolken
Keyword(s):  
Chronic Phase ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
Transcript Levels ◽  
Log Reduction ◽  
First Line Therapy ◽  
Line Therapy ◽  
Pre Treatment

Abstract Peripheral blood samples from 70 patients treated with imatinib were regularly sent to us for the determination of bcr-abl transcript levels by a standardized quantitative real-time PCR (TaqMan®). 45 patients with early chronic phase CML were treated with imatinib as a first line therapy and 25 patients in late chronic phase received imatinib as a second line therapy after hydroxyurea plus interferon. The median pre-treatment time with hydroxyurea plus interferon in these late chronic patients was 43 months (6 – 130). The median follow-up was 18.4 months (1–51) for first line patients and 18.0 months (1–48) for second line patients. Patients received a median dosage between 400–600 mg imatinib in both groups. At the time of diagnosis the median bcr-abl/abl ratio was 248 % (26–460%, SD: 148%) in patient receiving imatinib as a first line treatment. Patients receiving imatinib as second line treatment had a median bcr-abl/abl ratio of 24,84% (1–256%, SD: 78%) just before the imatinib treatment was initiated. Early chronic phase CML patients treated with imatinib as a first line therapy showed a strong biphasic decay of their bcr-abl transcript with a fast reduction between 1-2-log during the first 6–9 months followed by a slower rate of reduction afterwards. A bcr-abl/abl ratio &lt;0.1% could be observed in 19/51 (37%) patients and in 12/51 (23%) patients a bcr-abl/abl ratio &lt; 0.01% was found. After 18 months of therapy the median reduction of bcr-abl was about 2.5-log, after 36 months about 3-log. 12/51 (23%) patients showed a suboptimal response or had a subsequent increase of their bcr-abl transcript levels. Best responding patients could be identified by a &gt;2-log reduction after 6 months and &gt; 3-log reduction after 18 months of therapy. In late chronic phase CML patients pre-treated with hydroxyurea and interferon the overall median decrease of bcr-abl transcript levels was about 1-log after a median follow-up of 18 as well as after 36–48 months. Obviously, there are at least three subgroups of patients with a different molecular response. We identified 7/25 (28%) patients with no significant reduction of bcr-abl transcripts after 18 months as well as after 36 months of imatinib therapy. In contrast, another group of 4/25 (16%) patients showed a 2-log reduction of bcr-abl/abl ratio after 18 months with a subsequent reduction of 3-log after 36 months. Within the largest group of 14/25 (56%) patients a 1-log reduction after 18 months and a 1-2-log reduction after 36 months was observed. No patient had &gt; 3-log reduction within the whole group of 25 late chronic phase patients. The reduction of bcr-abl transcript levels as a result of imatinib therapy is significantly superior in CML patients receiving imatinib as first line treatment for CML in early chronic phase compared to patients treated with imatinib after a long term pre-treatment with hydroxyurea and interferon.

Auditory Selective Attention in Cerebral-Palsied Individuals

1985 ◽  
Vol 16 (4) ◽  
pp. 260-266 ◽  
Author(s):  
Lee Ann Laraway
Keyword(s):  
Selective Attention ◽  
White Noise ◽  
Normal Subjects ◽  
Auditory Selective Attention ◽  
Normal Individuals ◽  
Significant Difference

The purpose of this study was to determine whether there is a statistically significant difference between the auditory selective attention abilities of normal and cerebral-palsied individuals. Twenty-three cerebral-palsied and 23 normal subjects between the ages of 5 and 21 were asked to repeat a series of 30 items consisting of from 2 to 4 digits in the presence of intermittent white noise. Results of the study indicate that cerebral-palsied individuals perform significantly poorer than normal individuals when the stimulus is accompanied by noise. Noise was not a significant factor in the performance of the normal subjects regardless of age.

A Specific Immunologic Assay for Functional Plasminogen Activator Inhibitor 1 in Plasma – Standardized Measurements of the Inhibitor and Related Parameters in Patients with Venous Thromboembolic Disease

1992 ◽  
Vol 68 (05) ◽  
pp. 486-494 ◽  
Author(s):  
Malou Philips ◽  
Anne-Grethe Juul ◽  
Johan Selmer ◽  
Bent Lind ◽  
Sixtus Thorsen
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Normal Subjects ◽  
Tissue Type ◽  
Blood Collection ◽  
Plasminogen Activator Inhibitor 1 ◽  
Type Plasminogen Activator ◽  
Significant Difference ◽  
Activator Inhibitor ◽  
Pai 1

SummaryA new assay for functional plasminogen activator inhibitor 1 (PAI-1) in plasma was developed. The assay is based on the quantitative conversion of PAI-1 to urokinase-type plasminogen activator (u-PA)-PAI-l complex the concentration of which is then determined by an ELISA employing monoclonal anti-PAI-1 as catching antibody and monoclonal anti-u-PA as detecting antibody. The assay exhibits high sensitivity, specificity, accuracy, and precision. The level of functional PAI-1, tissue-type plasminogen activator (t-PA) activity and t-PA-PAI-1 complex was measured in normal subjects and in patients with venous thromboembolism in a silent phase. Blood collection procedures and calibration of the respective assays were rigorously standardized. It was found that the patients had a decreased fibrinolytic capacity. This could be ascribed to high plasma levels of PAI-1. The release of t-PA during venous occlusion of an arm for 10 min expressed as the increase in t-PA + t-PA-PAI-1 complex exhibited great variation and no significant difference could be demonstrated between the patients with a thrombotic tendency and the normal subjects.

Comparative Plasma Heparin Levels after Subcutaneous Sodium and Calcium Heparin

1978 ◽  
Vol 40 (02) ◽  
pp. 397-406 ◽  
Author(s):  
Joyce Low ◽  
J C Biggs
Keyword(s):  
Peak Plasma ◽  
Plasma Concentrations ◽  
Factor Xa ◽  
Normal Subjects ◽  
Sodium Salts ◽  
Sodium Heparin ◽  
Significant Difference ◽  
Heparin Plasma ◽  
Calcium Heparin ◽  
Plasma Heparin

SummaryComparative plasma heparin levels were measured in normal subjects injected subcutaneously with 5,000 units of the sodium and calcium salts of heparin. Plasma heparin levels were measured up to 7 hr post-injection by an anti-factor Xa assay (Denson and Bonnar 1973). Preliminary studies indicated that heparin levels were reproducible in subjects who received two injections of the same heparin. Peak plasma concentrations (Cmax) and the time at which peak concentration was reached (Tmax) varied greatly from subject to subject. In one group of subjects (15) two commonly used heparins, a sodium heparin (Evans) and a calcium heparin (Choay) were compared. Peak heparin concentrations were not significantly different. However the Tmax for the sodium heparin (1.5 hr) was significantly earlier than the Tmax for the calcium heparin (3 hr) and this was not due to a difference in the volume of the two heparin injections. No significant difference could be detected in the plasma clearance rate and the molecular weight distribution of the two heparins.In two other groups of subjects, sodium and calcium preparations from two manufacturers were compared. In general, the sodium salts gave rise to significantly higher plasma concentrations, which could be interpreted as a greater bioavailability of sodium salts. These results indicate that the salt of the heparin can influence the plasma concentration achieved after subcutaneous injection.

Selective Inhibition of Thromboxane Synthetase with Dazoxiben - Basis of Its Inhibitory Effect on Platelet Adhesion

1983 ◽  
Vol 49 (02) ◽  
pp. 096-101 ◽  
Author(s):  
V C Menys ◽  
J A Davies
Keyword(s):  
Arachidonic Acid ◽  
Platelet Adhesion ◽  
Fold Increase ◽  
Selective Inhibition ◽  
Inhibitory Effect ◽  
Selective Inhibitor ◽  
Coated Glass ◽  
Thromboxane Synthetase ◽  
Pre Treatment

SummaryPlatelet adhesion to rabbit aortic subendothelium or collagen-coated glass was quantitated in a rotating probe device by uptake of radio-labelled platelets. Under conditions in which aspirin had no effect, dazoxiben, a selective inhibitor of thromboxane synthetase, reduced platelet adhesion to aortic subendothelium by about 40% but did not affect adhesion to collagen-coated glass. Pre-treatment of aortic segments with 15-HPETE, a selective inhibitor of PGI2-synthetase, abolished the inhibitory effect of dazoxiben on adhesion. Concentrations of 6-oxo-PGFlα in the perfusate were raised in the presence of dazoxiben alone, and following addition of thrombin (10 units/ml) there was a 2-3 fold increase in concentration. Perfusion of damaged aorta with platelets labelled with (14C)-arachidonic acid in the presence of thrombin and dazoxiben resulted in the appearance of (14C)-labelled-6-oxo-PGFiα. Inhibition of thromboxane synthetase limits platelet adhesion probably by promoting vascular synthesis of PGI2 from endoperoxides liberated from adherent platelets, which subsequently promotes detachment of cells from the surface.

The Effect of Antiplatelet Drugs on Plasma Betathromboglobulin in Coronary Artery Disease

1979 ◽  
Author(s):  
P Han ◽  
A Turpie ◽  
E Genton ◽  
M Gent
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Crossover Trial ◽  
Specific Protein ◽  
Antiplatelet Drugs ◽  
Significant Difference ◽  
Pre Treatment ◽  
Artery Disease ◽  
Therapeutic Doses ◽  
Granule Release

Platelets play a role in the development and complications of coronary artery disease (CAD) and a number of abnormalities of platelet function which can be corrected by antiplatelet drugs have been described. Betathromboglobulin (BTG), a platelet-specific protein which is released from α-granules during platelet activation is significantly elevated in patients with angiographically demonstrated CAD (51.0 ± 31.0 ng/ml., n = 50) compared to normal (28.0 ± 8.0 ng/ml., n = 70) p < 0.001. The effect of sulphinpyrazone (800 mg.) or aspirin (1200 mg.)/dipyridamole (200 mg.) on plasma BTG in CAD was studied in a blind prospective crossover trial in 25 patients. Mean BTG concentration pre-treatment was 52.3 ng/ml. and after 1 month’s treatment with placebo, sulphinpyrazone or aspirin/dipyridamole mean plasma BTG concentrations were 53.5, 49.6 and 56.7 ng/ml. respectively. Analysis of variance showed no significant difference between the means (p > 0.1) . This study confirms increased plasma BTG concentrations in patients with CAD and indicates that therapeutic doses of these antiplatelet drugs do not significantly effect the BTG level and thus appear not to prevent α-granule release in CAD.

A COMPARISON OF TWO METHODS FOR MEASUREMENT OF ALDOSTERONE SECRETION RATE IN MAN

1966 ◽  
Vol 53 (2) ◽  
pp. 177-188 ◽  
Author(s):  
P. Lund-Johansen ◽  
T. Thorsen ◽  
K. F. Støa
Keyword(s):  
Urinary Excretion ◽  
Normal Subjects ◽  
Secretion Rate ◽  
Aldosterone Secretion ◽  
Simple Method ◽  
Mean Values ◽  
Pathological Conditions ◽  
Significant Difference ◽  
Derivative Method ◽  
The Mean

ABSTRACT A comparison has been made between (A), a relatively simple method for the measurement of aldosterone secretion rate, based on paper chromatography and direct densitometry of the aldosterone spot and (B) a more elaborate isotope derivative method. The mean secretion rate in 9 normal subjects was 112 ± 26 μg per 24 hours (method A) and 135 ± 35 μg per 24 hours (method B). The »secretion rate« in one adrenalectomized subject after the intravenous injection of 250 μg of aldosterone was 230 μg per 24 hours (method A) and 294 μg per 24 hours (method B). There was no significant difference in the mean values, and correlation between the two methods was good (r = 0.80). It is concluded that the densitometric method is suitable for clinical purposes as well as research, being more rapid and less expensive than the isotope derivative method. Method A also measures the urinary excretion of the aldosterone 3-oxo-conjugate, which is of interest in many pathological conditions. The densitometric method is obviously the less sensitive and a prerequisite for its use is an aldosterone secretion of 20—30 μg per 24 hours. Lower values are, however, rare in adults.

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