Comparison of UVA and UVB Induced Lesions in Human Platelets Evaluated in an Animal Model.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2883-2883 ◽  
Author(s):  
Monique P. Gelderman-Fuhrmann ◽  
Jessica L. Lewis ◽  
Elisabet K. Tassis ◽  
Alex C. Vostal ◽  
Jaroslav G. Vostal
Keyword(s):  
Animal Model ◽  
Scid Mouse ◽  
Human Platelet ◽  
Uv Light ◽  
Human Platelets ◽  
Scid Mice ◽  
Uv Exposure ◽  
Post Infusion ◽  
In Vivo Recovery

Abstract UV light can be used to irradiate platelets to reduce immune responses and activate chemically-mediated pathogen reduction agents. Platelets subjected to UV-based processing methods develop demonstrable losses of in vivo performance. We compared the “lesions” induced by the different wavelengths of UV light on human platelet performance in a SCID mouse animal model of recovery and survival. Previously we demonstrated that severe combined immunodeficient (SCID) mice could be used as an animal model to identify both severely damaged (Blood 106(11), p537a, 2005) and moderately damaged human platelets (Blood 108(11), p175–176a, 2006). Apheresis human platelets, stored for 1 or 7 days, were exposed to UVA(320–400 nm) or UVB(290–320 nm) light for 20 min (4.8 J/mL) or 40 min (9.6 J/mL). Control platelets were processed in the same manner without UV exposure. Effects on platelets were compared on platelet counts, activation measured by p-selectin (anti-human CD62P, clone AK-4) and in vivo recovery. Platelet counts and in vivo recovery are expressed as % of control platelets, p-selectin measurement represents % of cells expressing the antigen. For in vivo recovery, approximately 1×10 9 platelets (UV-treated or control) were injected into the tail vein of SCID mice (n=4 per each condition) and serial blood samples were collected. Human platelets were detected in mouse whole blood by flow cytometry using an anti-human GPIIbIIIa mAb (clone P2). Recovery was defined as percent of human platelets in mouse circulation 30 minutes post infusion. Comparison of recovery between control and UV treatment platelets was done at 2 hours post infusion as shown in Table 1. These results indicate that UVA produces less activation of platelets and less damage to human platelets recognized by the in vivo model than UVB. The UVA lesion detected by increased in vivo clearance is not cumulative in that longer exposures do not cause an increased loss of in vivo recovery. In comparison, UVB mediated damage is associated with lower in vivo recovery and the damage appears to be cumulative with longer exposure. These differences suggest that UVA and UVB exposure may produce platelet lesions through different mechanism(s). Further investigation into the molecular mechanisms of UVA and UVB lesions may lead to methods that could reduce the negative aspects of UV exposure. The findings and conclusions in this abstract have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy. Table 1 Treatment Day 1 Day 7 1= percent of control platelets;2=human platelet recovery in SCID mouse model Platelet count1 P-selectin (%) In vivo recovery2 Platelet count1 P-selectin (%) In vivo recovery2 UVA 20 min 100 13.3±2.7 55.2±7.6 100 20.3±3.8 58.2±4.9 40 min 100 9.9±0.9 55.5±2.9 100 17.3±2.9 54.3±6.7 UVB 20 min 82±3.7 34.6±5.0 30.8±8.9 86±5.3 51.1±6.4 18.5±4.6 40 min 51±10.1 29.5±1.5 6.9±2.6 63±10.5 36.2±1.8 2.47±0.9

Detection of UV Induced Damage to Human Platelets by an In Vivo Animal Model.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 582-582
Author(s):  
Monique P. Gelderman-Fuhrmann ◽  
Sheena F. Siddiqui ◽  
Jaroslav G. Vostal
Keyword(s):  
Animal Model ◽  
Scid Mouse ◽  
Uv Light ◽  
Human Platelets ◽  
In Vitro Tests ◽  
Post Infusion ◽  
Scid Mouse Model ◽  
In Vivo Recovery

Abstract Evaluation of novel platelet products for transfusion currently involves determination of recovery and survival of radiolabelled platelets in human volunteers since in vitro studies are not predictive of platelet clinical performance and a practical animal model has not been universally accepted. We previously demonstrated that severe combined immunodeficient (SCID) mice could be used as a model to identify severely damaged human platelets (Blood 106 (11), p537a, 2005). To further characterize the sensitivity of this model we used exposure of human platelets to UV light to induce moderate damage, and quantitated this lesion by in vitro tests and in vivo recovery in the SCID mouse model. This type of damage is clinically relevant since UV radiation of blood-platelet concentrates is used to prevent the development of post-transfusion alloimmunization and has been used as part of pathogen reduction systems to inactivate bacteria and viruses. Apheresis platelet products, stored for 1 or 7 days, were exposed to UV light (280–315 nm) for either 20 or 40 min (intensity: 750 μW/cm2). In vitro testing included platelet count, pH, CD62P expression, mitochondrial membrane potential and collagen-induced (2 mg/ml) aggregation. The mitochondrial membrane potential was measured by flow cytometry (FL2-to-FL-1 ratio of platelets loaded with JC-1 (final: 2μM) showed a ratio 6.8 ± 1.5 for the 1 day old platelets and 3.25 ± 0.75 for the 7 day old platelets. Additional flow cytometric testing showed an increase of p-selectin (ant-human CD62P, clone AK-4) expression for 1 day old platelets (31.4 ± 3.5%) and 7 day old platelets (54.6 ± 6.6) after 20 min of UV light. Tables 1 and 2 show in vitro and in vivo results as percent of control (except for pH and JC-1). Table 1. 1 Day Old Platelets UV Exposure Plt Count pH JC-1 Ratio Collagen Aggregation in vivo Recovery 20 min 76.2 7.4 6.5 ± 1.15 101.6 83.8 ± 13.8 40 min 42.2 7.2 3.5 ± 0.4 66.1 56.8 ± 12 Table 2. 7 Day Old Platelets UV Exposure Plt count pH JC-1 Ratio Collagen Aggregation in vivo Recovery 20 min 78.1 7.2 2.85 ± 0.95 116.2 31.8 ± 6.2 40 min 66.1 7.1 nd 5.5 2.27 ± 0.31 For in vivo recovery, approximately 1x10 9 platelets (UV-treated or control) were injected into the tail vein of SCID mice (n=4 per each condition) and serial blood samples were collected. Human platelets were detected in mouse whole blood by flow cytometry using an anti-human GPIIbIIIa mAb (clone P2). Recovery was defined as percent of human platelets in mouse circulation five minutes post infusion. Comparison of recovery between control and UV treatments was done at 4 hours post infusion. UV light treatments, 20 and 40 minutes, reduced the in vivo recovery to 83.8 ± 13.8% and 56.8 ± 12% of control, respectively, for 1 day old platelets and to 31.8 ± 6.2% and 2.27 ± 0.31% of control, respectively, for 7 day old platelets. Our data suggest that the SCID mouse model can identify a relatively subtle UV-induced platelet lesion and that it may be more sensitive than in vitro tests. With further validation, this animal model could be useful for evaluation of the impact of new technologies on the in vivo efficacy of human platelets. The views of the authors represent a scientific opinion and should not be construed as FDA policy.

A Novel Animal Model for Detecting Damage to Human Platelet Transfusion Products: In Vivo Recovery and Survival in Severe Combined Immunodeficient Mice.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1891-1891
Author(s):  
John T. Piper ◽  
Jaroslav G. Vostal
Keyword(s):  
Animal Model ◽  
Human Platelets ◽  
Human Cells ◽  
Scid Mice ◽  
Survival Times ◽  
Post Infusion ◽  
The Impact ◽  
Induced Aggregation

Abstract Clinical performance of platelet products processed or stored under novel conditions is difficult to predict based on in vitro studies alone. Evaluation of such products involves determination of recovery and survival of radiolabeled platelets in human volunteers as a surrogate endpoint for platelet efficacy. Such human studies pose some risk to volunteers, are a financial burden on the sponsor, and stifle innovation in the development of platelet products. The development of an animal model for evaluating human platelets has been limited by rapid, immunemediated clearance of human cells. In the current studies, severe combined immunodeficient (SCID) mice were used to circumvent the need to block the reticuloendothelial system and prolong circulation of human cells. Human platelets were infused via tail vein into normal and SCID mice, and the recoveries and survival times compared. Mouse whole blood was collected at various time points post-infusion, and human platelets were detected by flow cytometry using an anti-human CD41 monoclonal antibody. Recovery was defined as percent human platelets in circulation relative to time zero, and survival time in circulation as the t1/2 of the human platelets. Recoveries and survival times were different between normal and SCID mice, with a maximal difference in recovery of 60.3% at 4 hours post-infusion (normal recovery, 11.1 ± 9.1%; SCID recovery, 71.4 ± 8.8%), and survival times of 1.4 ± 0.4 hours and 10.7 ± 2.3 hours in normal and SCID mice, respectively (N=3). Chemically treated and aged platelets were used to evaluate the ability of the model to detect differences in control and damaged platelets. Chemical damage was induced by carbonyl cyanide 3-chlorophenylhydrazone (CCCP), a mitochondrial uncoupler which mimics the platelet storage lesion. Platelets were exposed to 10 μM CCCP in methanol, control platelets were exposed to an equal volume of methanol (N=3). CCCP treatment of platelets decreased agonist-induced aggregation (Control aggregation, 73.3 ± 6.8%; CCCP-treated platelet aggregation, 13.8 ± 5.3%). Recovery of control and CCCP-treated platelets were 31.5 ± 16.9% and 7.9 ± 5.1%, respectively, at 4-hours post-infusion. Survival times were 1.3 hours for control and 1.9 hours for CCCP-treated platelets. For storage studies, in vitro cell quality parameters were evaluated in three products, and each product was infused into 3 animals on Day 1 and 3 different animals on Day 7. In Day 7 platelets, in vitro platelet parameters were decreased compared to Day 1. Platelet counts decreased an average of 22.8% ± 2.2% between Day 1 and Day 7. pH decreased from 6.7 ± 0.1 at Day 1 to 5.8 ± 0.1 at Day 7. All platelet products had visible swirl on Day 1 and no swirl on Day 7. Platelets stored for 7 days showed decreased recovery over Day 1 platelets at 4 hours post-infusion (Day 1, 66.9 ± 12.8%; Day 7, 0.2 ± 0.08%). The SCID mouse may be a useful model for evaluating the impact of new technologies (apheresis devices, anticoagulants, storage containers, pathogen inactivation systems) on the in vivo efficacy of human platelets. In two different models of platelet damage (chemical and storage induced damage), this model can distinguish between normal and damaged platelets. Recovery of Infused Day 1 and Day 7 Human Platelets in SCID Mice Recovery of Infused Day 1 and Day 7 Human Platelets in SCID Mice

Temperature Cycling Improves In Vivo recovery of Cold Stored Human Platelets

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 720-720
Author(s):  
Fei Xu ◽  
Monique Gelderman-Fuhrmann ◽  
John Farrell ◽  
Jaroslav Vostal
Keyword(s):  
Flow Cytometry ◽  
Cold Storage ◽  
Room Temperature ◽  
Human Platelets ◽  
Scid Mice ◽  
Temperature Cycling ◽  
Post Injection ◽  
Platelet Recovery ◽  
In Vivo Recovery

Abstract Abstract 720 Platelets are currently limited to 5 days of storage at room temperature to prevent growth of bacteria to high levels. Cold storage of platelets could reduce bacterial proliferation but platelets stored in cold for over 48 hours are cleared rapidly from circulation through the hepatocyte Ashwell-Morell (AM) receptor thus limiting the applicability of cold temperatures to platelet storage. We used a temperature cycling method to store human platelets in the cold without decreasing their in vivo recovery in an immunodeficient (SCID) animal model of transfusion. Temperature cycled (TC) apheresis human platelets were stored in the cold (4°C) for 12 hours and then incubated at 37°C for 30 minutes before returning back to cold storage. The TC (37°C pulses for 30 minutes at 12 hour intervals) was continued for 2, 5 and 7 days. Human platelets stored either at room temperature (RT), cold or TC for 2, 5 and 7 days were infused into 6 to 8 SCID mice per group and their in vivo recovery in circulation was determined at 5, 20 and 60 minutes after transfusion by flow cytometry. Carbohydrate exposure on the surface of the platelets was analyzed for galactose by Erythrina cristagalli agglutinin (ECA), and for β-GlnNAc by succinyl wheat germ agglutinin (sWGA) using flow cytometry. Involvement of the AM receptor was examined by monitoring clearance of cold stored platelets in the presence of asialofetuin, a competitive ligand for the receptor. In vivo recovery of human platelets stored for two-days in SCID mice circulation is shown in Figure 1. As expected, cold platelets had significantly decreased recovery compared to RT platelets, from 22.1±2.5% to 11.1±3.3% (P<0.01), 11.5±2.9% to 5.5±3.6% (P<0.01) and 11.2±1.4% to 6.2±1.8% (P<0.01) respectively at 5, 20 and 60 min post platelets injection. Compared to cold platelets, TC platelets recovery increased significantly from 11.1±3.3% to 15.9±4.4% (P<0.01), 5.5±3.6+% to 10.5±4.7% (P<0.01) and 6.2±1.8% to 9.5±2.2% (P<0.05) respectively at 5, 20 and 60 min post platelets injection. At 20 and 60 min post injection, the TC platelets have recovery of 10.5±4.7% and 9.5±2.2% respectively, that are comparable (P>0.05%) to RT platelet recoveries of 11.5±2.9% and 11.2±1.4% for the same time points. Similar increases of in vivo recovery for TC platelets as compared to cold platelets were obtained for at 5 and 7 days.Figure 1Human Platelet Recovery (% of total platelets circulating) * p< 0.05, ** p< 0.01, *** p< 0.001Figure 1. Human Platelet Recovery (% of total platelets circulating) * p< 0.05, ** p< 0.01, *** p< 0.001 Binding of the galactose specific lectin, ECA, was increased by 142±22% from RT to cold platelets (P<0.01) as previously reported. However, binding of ECA was also increased by 134±16% from RT to TC platelets (P<0.01). β-GlnNAc exposure, as measured by sWGA lectin binding, was increased after cold and TC storage by 222±65% (P<0.01) and 197±14% (P<0.01), respectively, when compared to RT platelets. Platelets stored in the cold for >48 hours have been reported to be cleared through the hepatic AM receptor which recognizes asialocarbohydrates. Co-injection of asialofetuin significantly improved the recovery of two-day cold stored platelets from 9.5±5.1% to 18.4±7.3% (P<0.05) and 4.8±3.7% to 12.1±4.9% (P<0.01), at 5 min and 20 min post injection, respectively. Native fetuin did not alter the clearance of cold platelets. However, there was no significant increase in the recovery of TC platelets in the presence of asialofetuin as compared to fetuin injection (P>0.28), even though the TC platelets, like cold platelets, have significantly increased β-galactose exposure. Our results indicate that ‘temperature cycling' during cold storage of platelets may be an effective method to store human platelets up to 7 days without loss of in vivo recovery after transfusion when compared to RT platelets. Temperature cycling does not alter the cold induced increases in β-gal or β-GlcNAc expression which suggests that there are other mechanisms besides binding to the AM receptor that mediate clearance of platelets stored in the cold for >48 hours. The findings and conclusions in this abstract have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy. Disclosures: No relevant conflicts of interest to declare.

An Animal Model Suitable for Predicting In Vivo Behavior of Platelets in Humans: A Tool for New Product Development.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3628-3628
Author(s):  
Morris A. Blajchman ◽  
Junzhi Li ◽  
Myron Kulczycky ◽  
Zofia Woskowska ◽  
Henry Pieters ◽  
...  
Keyword(s):  
Animal Model ◽  
New Product Development ◽  
Isotope Labeling ◽  
Uv Light ◽  
Human Platelets ◽  
Light Dose ◽  
Blood Component ◽  
Survival Times ◽  
And Control

Abstract Testing platelet in vivo activity in an animal model remains an attractive approach for the pre-clinical evaluation of platelets that have been treated or manipulated by a new technology or product. Mirasol PRT™ is a novel pathogen reduction technology based on riboflavin photochemistry for the safety of blood component transfusion. In this study, rabbit platelets were tested for viability after exposure to 2, 3 and 5 J/cm2 of UV light in the presence of 50 μM riboflavin in a polypropylene bag (Sangewald). In order to minimize the potential variations caused by different isotope labeling and by individual rabbit differences, a pool of platelets was split into two for the treatment and control groups. Eight to ten rabbits were used in each group as recipients for each dose of light. Half of the rabbits in the group received concurrent injections of 111In-labeled PRT treated platelets and 51Cr-labeled control platelets. The other half received 51Cr-labeled PRT-platelets and 111In-labeled control platelets. The recovery and survival times were determined post-infusion for both treated and control platelets using the multiple hit model (γ-function) and data from the various groups were pooled and analyzed. The platelets treated with 2, 3 and 5 J/cm2 retained recoveries of 63.2% (SD=17, n=9), 55.3% (SD=10.8, n=10) and 44.0% (SD=12.8, n=8) of control platelets, respectively. The survival times of the platelets treated with 2, 3 and 5 J/cm2 were 59.5% (SD=15.7, n=9), 60.1% (SD=19.5, n=10) and 55.1% (SD=18.1, n=8) of control, respectively. Both values of recovery and survival times were correlated with UV light dose with correlation coefficients of 0.90 (r2) and 0.73 (r2) respectively. In a subsequent single site human clinical study, human platelets were treated with UV light at a dose of 3 J/cm2 in a Sangewald bag, radiolabelled with Indium at day 5 of storage and infused into autologous subjects. Recovery and survival values for these subjects were obtained. At a dose of 3 J/cm2, recovery and survival activities retained 54.9% (SD=3.1, n=4) and 71.7% (SD=21.5) of control platelets, respectively. Good agreement with observations made in the rabbit model was thus obtained. Based on this work, a light dose was selected for standard treatment of human platelets using the Mirasol PRT system. In conclusion, this kinetic study on UV light dose in an animal model was predictive of human platelet in vivo activity, making it a potentially valuable model for estimating human clinical trial outcomes for new platelet storage and treatment methodologies.

A SCID Mouse Model for Monitoring in Vivo Viability of Human Platelet Concentrates Using Flow Cytometry

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4549-4549
Author(s):  
Jia-hua Ding ◽  
Cheng-yin Huang ◽  
Shiyun Xu
Keyword(s):  
Flow Cytometry ◽  
Whole Blood ◽  
Human Platelet ◽  
Human Platelets ◽  
Scid Mice ◽  
Test Method ◽  
Platelet Concentrates ◽  
Tail Vein

Abstract Objective To develop an animal test method for evaluating the in vivo quality of human platelet concentrates. Methods Human platelets were transfused to mice by tail vein with a 1mL insulin syring fitted with a 29-gauge ultra-fine needle. Blood samples were taken at 30 minutes,2,4,6,8,12, and 24hours after infusion with a tail vein nick technique, whole blood was collected into heparinized capillary tubes. Human platelets in mouse whole blood were detected by flow cytometry with monoclonal anti-human CD61-PE–conjugated antibodies. All subsequent recoveries were calculated as a percentage of the initial collection. Results The survival time of human platelets were significantly prolonged in SCID than in BALB/c,FVB mice. Recoveries at 4 hours after transfusion in SCID, BALB/c,FVB mice were 68.6%±8.1%(n =10),29.9%±6.5%(n =8),28.1%±5.5%(n =8), respectively, and with a T½ estimate of 8 hours for SCID, 2.5 hours for BALB/c and 2 hours for FVB mice. platelet storage lesions either by chemical treatment or by suboptimal conditions storage exhibited decreased recoveries in SCID mice. Conclusion The quality of platelet Products can be evaluated by assessing the survival of human platelets in SCID mice using flow cytometry.

scholarly journals P38 mitogen activated protein kinase inhibitor improves platelet in vitro parameters and in vivo survival in a SCID mouse model of transfusion for platelets stored at cold or temperature cycled conditions for 14 days

PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0250120
Author(s):  
Andrey Skripchenko ◽  
Monique P. Gelderman ◽  
Jaroslav G. Vostal
Keyword(s):  
Mouse Model ◽  
Cold Storage ◽  
Scid Mouse ◽  
Room Temperature ◽  
Human Platelet ◽  
Human Platelets ◽  
Bacterial Proliferation ◽  
Scid Mouse Model

Platelets for transfusion are stored at room temperature (20–24°C) up to 7 days but decline in biochemical and morphological parameters during storage and can support bacterial proliferation. This decline is reduced with p38MAPK inhibitor, VX-702. Storage of platelets in the cold (4–6°C) can reduce bacterial proliferation but platelets get activated and have reduced circulation when transfused. Thermocycling (cold storage with brief periodic warm ups) reduces some of the effects of cold storage. We evaluated in vitro properties and in vivo circulation in SCID mouse model of human platelet transfusion of platelets stored in cold or thermocycled for 14 days with and without VX-702. Apheresis platelet units (N = 15) were each aliquoted into five storage bags and stored under different conditions: room temperature; cold temperature; thermocycled temperature; cold temperature with VX-702; thermocycled temperature with VX-702. Platelet in vitro parameters were evaluated at 1, 7 and 14 days. On day 14, platelets were infused into SCID mice to assess their retention in circulation by flow cytometry. VX-702 reduced negative platelet parameters associated with cold and thermocycled storage such as an increase in expression of activation markers CD62, CD63 and of phosphatidylserine (marker of apoptosis measured by Annexin binding) and lowered the rise in lactate (marker of increase in anaerobic metabolism). However, VX-702 did not inhibit agonist-induced platelet aggregation indicating that it does not interfere with platelet hemostatic function. In vivo, VX-702 improved initial recovery and area under the curve in circulation of human platelets infused into a mouse model that has been previously validated against a human platelet infusion clinical trial. In conclusion, inhibition of p38MAPK during 14-days platelet storage in cold or thermocycling conditions improved in vitro platelet parameters and platelet circulation in the mouse model indicating that VX-702 may improve cell physiology and clinical performance of human platelets stored in cold conditions.

Effects of a Monoclonal Antibody to Glycoprotein IIb/IIIa (P256) and of Enzymically Derived Fragments of P256 on Human Platelets

1991 ◽  
Vol 65 (04) ◽  
pp. 432-437 ◽  
Author(s):  
A W J Stuttle ◽  
M J Powling ◽  
J M Ritter ◽  
R M Hardisty
Keyword(s):  
Monoclonal Antibody ◽  
Flow Cytometry ◽  
Platelet Aggregation ◽  
Calcium Ions ◽  
Human Platelet ◽  
Human Platelets ◽  
In Vivo Detection ◽  
Fibrinogen Binding ◽  
Specific Antagonist

SummaryThe anti-platelet monoclonal antibody P256 is currently undergoing development for in vivo detection of thrombus. We have examined the actions of P256 and two fragments on human platelet function. P256, and its divalent fragment, caused aggregation at concentrations of 10−9−3 × 10−8 M. A monovalent fragment of P256 did not cause aggregation at concentrations up to 10−7 M. P256–induced platelet aggregation was dependent upon extracellular calcium ions as assessed by quin2 fluorescence. Indomethacin partially inhibited platelet aggregation and completely inhibited intracellular calcium mobilisation. Apyrase caused partial inhibition of aggregation. Aggregation induced by the divalent fragment was dependent upon fibrinogen and was inhibited by prostacyclin. Aggregation induced by the whole antibody was only partially dependent upon fibrinogen, but was also inhibited by prostacyclin. P256 whole antibody was shown, by flow cytometry, to induce fibrinogen binding to indomethacin treated platelets. Monovalent P256 was shown to be a specific antagonist for aggregation induced by the divalent forms. In–111–labelled monovalent fragment bound to gel-filtered platelets in a saturable and displaceable manner. Monovalent P256 represents a safer form for in vivo applications

Optimization of zinc oxide nanoparticle-catalyzed in vitro bilirubin photolysis and in vivo treatment of hyperbilirubinemia

Nanomedicine ◽  
2021 ◽  
Author(s):  
Haq Nawaz ◽  
Iqra Naseem ◽  
Tanzila Rehman ◽  
Mubashir Nawaz
Keyword(s):  
Zinc Oxide ◽  
Zinc Oxide Nanoparticles ◽  
Uv Light ◽  
Uv Exposure ◽  
Uv Treatment ◽  
Blood Samples ◽  
Positive Effects ◽  
Oxide Nanoparticle

Aim: To optimize the Zinc oxide nanoparticles (ZnONPs)-catalyzed in vitro photolysis of bilirubin and to test their effect on bilirubin clearance in vivo. Materials & methods: ZnONPs, synthesized in an alkaline medium, were characterized. Response surface methodology was used to optimize the in vitro photolysis catalyzed by the nanoparticles (NPs). Blood samples from phenylhydrazine-induced hyperbilirubinemic rabbits which had been administered ZnONPs and UV light were analyzed to assess in vivo clearance of bilirubin. Results: The ZnONP-assisted UV treatment showed the linear and quadratic positive effects on the in vitro bilirubin photolysis with an optimal photolysis of bilirubin at 225 mg dl-1 concentration of ZnONPs and a UV exposure of 1.80 h. The ZnONP-assisted phototherapy of hyperbilirubinemic animals was also found to be more effective for in vivo clearance of bilirubin than phototherapy alone. Conclusion: After further trials, ZnONP-assisted phototherapy could be a potential treatment for hyperbilirubinemia in humans.

scholarly journals Human t(1;19)(q23;p13) pre-B acute lymphoblastic leukemia in mice with severe combined immunodeficiency

Blood ◽  
1993 ◽  
Vol 81 (11) ◽  
pp. 3052-3062 ◽  
Author(s):  
FM Uckun ◽  
JR Downing ◽  
R Gunther ◽  
LM Chelstrom ◽  
D Finnegan ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Acute Lymphoblastic Leukemia ◽  
Poor Prognosis ◽  
Scid Mouse ◽  
Lymphoblastic Leukemia ◽  
Fusion Transcript ◽  
Scid Mice ◽  
Newly Diagnosed ◽  
In Vivo Growth

Severe combined immunodeficient (SCID) mice were injected intravenously with 5 x 10(6) primary bone marrow (BM) blasts from newly diagnosed patients with E2A-PBX1 fusion transcript positive t(1;19)(q23;p13) pre- B acute lymphoblastic leukemia (ALL). A marked variation existed in the pattern and extent of leukemic cell engraftment in SCID mice challenged with t(1;19) pre-B ALL blasts. Blasts from some patients caused disseminated leukemia that was detected by histopathology and/or flow cytometry, whereas blasts from other patients produced occult leukemia that was only detected by flow cytometry and/or polymerase-chain reaction. Notably, the ability of primary t(1;19) pre-B ALL blasts to cause disseminated leukemia in SCID mice was associated with poor prognosis. Six of six patients whose blasts caused disseminated leukemia in SCID mice relapsed at a median of 7.8 months (range: 5.7 to 25.2 months). In contrast, the remaining four patients whose blasts did not engraft or only partially engrafted remain in complete remission at 28 to 47 months. A new E2A-PBX-1 fusion transcript positive t(1;19) pre- B ALL cell line (designated LC1;19) with the composite immunophenotype CD7-CD10+CD19+CD45-HLA-DR+C mu+ was established by expanding BM blasts from a SCID mouse, which died of human t(1;19) ALL at 7 weeks after inoculation of primary leukemic blasts from a t(1;19) ALL patient. This cell line caused disseminated and invariably fatal leukemia when greater than 10(4) cells were injected intravenously into SCID mice. Total body irradiation followed by syngeneic BM transplantation (BMT) showed limited efficacy against LC1;19 leukemia in SCID mice. To our knowledge, this study is the first to (1) examine the in vivo growth of primary t(1;19) pre-B ALL blasts in SCID mice and (2) show that leukemic blasts from a majority of newly diagnosed t(1;19) pre-B ALL patients cause disseminated human leukemia in SCID mice. Our results indicate that t(1;19) pre-B ALL is biologically heterogeneous with regard to its in vivo growth pattern in SCID mice, a feature that may be predictive of prognosis. The described LC1;19 SCID mouse model may prove particularly useful for designing more effective treatment strategies against poor-prognosis t(1;19) ALL.

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