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  • 1
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 1007-1007
    Abstract: Abstract 1007 Pain is a common and serious complication of sickle cell disease (SCD), which is frequently disabling and difficult to treat. Acute painful crises account for the vast majority of healthcare encounters ( 〉 90% of hospitalizations), and many patients with SCD suffer from chronic pain. Despite several well designed clinical studies, which have brought to light the high incidence and severity of pain in this patient population, sickle cell pain remains an understudied, undermanaged, and poorly understood condition. Previous work has largely relied on self-reporting instruments, such as carefully designed pain diaries to study the epidemiology of pain in this patient cohort. In contrast, very little is known about the usefulness of methods that measure pain in response to a standardized stimulus and the correlation of experimentally induced pain to more traditional instruments such as pain diaries and opioid use. In this study we explored the use of pressure algometry to measure pain thresholds in adult patients with SCD. Our study enrolled 167 adult patients with SCD [163 SS, 1 SD Los Angeles, 3 Sβ0-thal; 108 on Hydroxyurea (HU), 59 off HU; 83 females and 84 males; mean age 31 years (range 16–61)] and forty racially matched controls (23 females and 17 males; mean age 35 years (range 17–61). The pain threshold, defined as the lowest pressure at which pain is induced, was measured by pressure algometry in three anatomic muscle groups (masseter, trapezius, and ulnar). Four measurements were obtained at each site and averaged for analysis. 118 patients were tested with a manual algometer (Wagner FDIX™, Wagner Instruments, Greenwich, CT) and 49 patients with a computerized model (Algomed, Medoc Ltd., Israel). The data sets for the two algometer groups were highly correlated for each anatomic site and were therefore combined for the final analysis (Pearson's correlation coefficients: masseter readings, r=0.78, p=2.73E-09; trapezius readings, r=0.85, p=4.28E-12; ulnar readings, r=0.68, p=3.26E-06). In addition, self-reported pain and distress were monitored prospectively for six months using a validated pain diary (ordinal scales of 0–9, respectively; J Natl Med Assoc. 2005 February; 97(2): 183–193). Opioid use, expressed as morphine equivalents, and the frequency of vaso-occlusive events are being recorded prospectively for twelve months. Algometer readings were compared using a linear model with age and gender as covariates. Data are reported as mean ± SEM. A p-value of 〈 0.05 is significant. Adult patients with SCD experienced pain at significantly lower pressures at all anatomic sites tested compared to racially matched controls. Pain threshold measurements in the ulnar muscle group achieved the best discrimination between sickle cell and control subjects. (Patients vs. controls (KPa): Masseter: 150± 4.35 vs. 193± 13.24, p= 1.99E–05; trapezius: 265±10.23 vs. 383± 37.99, p= 2.78E–05; ulnar: 371±10.26 vs. 518±34.59, p= 6.28E–09). Ulnar algometer readings also correlated with self-reported pain scores (r=-0.226, p=0.0097). There was no correlation between pain threshold measurements and self-reported distress or the use of hydroxyurea. Quantitative sensory testing revealed that adult patients with SCD are hyperalgesic in response to a standardized pressure stimulus. Of the three anatomic sites tested, ulnar pain threshold readings produced the strongest separation between sickle cell and control subjects and correlated with self-reported pain. Quantitative sensory testing may provide a useful research and clinical tool to study the biological mechanisms of pain in SCD and the therapeutic efficacy of psychosocial and pharmacological interventions. Disclosures: Fillingim: Algynomics: Consultancy, Shareholder Other.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 2
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 2108-2108
    Abstract: Abstract 2108 Avascular necrosis (AVN) of the femoral head is a common complication of sickle cell disease (SCD) and is estimated to occur in approximately 50% of patients with SCD by age 35. AVN is associated with significant morbidity including debilitating pain and disability. Total hip replacement (THR) is a common intervention for AVN; however, complications of hip replacement such as infections, bone fractures, prolonged healing times, and the need for subsequent revisions begs for an alternate intervention in the young SCD patient population. Core decompression is one such intervention but there has not been a common consensus on its efficacy and few studies have analyzed its role in SCD associated AVN. Our retrospective study analyzes the long term outcomes of core decompression in SCD patients. Records of 100 patients with AVN followed at the Adult Sickle Cell Clinic at Georgia Health Sciences University were reviewed. Twenty-three patients (30 hips) had core decompression (13 female, 10 male). Of these, 21 were Hb SS, 1 was Hb Sβ+ Thalassemia, and 1 was Sβ° Thalassemia. Patient demographics, age at diagnosis, Ficat stage at diagnosis, age at core, Ficat stage at core, symptom relief, THR, time to THR, and duration of follow up were recorded. The age of the patients at the time of the coring procedure ranged from 18–42 years, with a mean age (±SD) of 26.2 ±6.6. Patients had a mean (±SD) follow up period of 10.0±7.2 years after the core decompression. At the time of coring, 6 hips were stage I (x-ray normal, MRI abnormal), 20 hips were stage II (sclerosis and lytic areas on x-ray), 3 hips were stage III (femoral head flattening and crescent sign), and 1 hip did not have data available. 23/29 (79%) hips had symptom relief. Of these, 5/6 stage I, 16/19 stage II (1 hip was only 1 month post-op so was not included), 1/3 stage III, and 1/1 for the hip without the stage information available. Two of these hips that had symptom relief did eventually have THR (71 and 157 months after core). Five of these hips underwent re-coring procedures (4, 6, 6, 7, and 13 years after 1st core) and none of these went on to THR. Of the 6/29 hips that had no relief from the core, 4 went on to THR (range 5–20 months, mean=11.5± 7.2 months median=10.5 months) and 2 have been advised of the need for THR and/or are currently considering it (both currently stage IV). Including the 2 hips that were determined to be successful in relieving symptoms that had THR, there were 6/29 hips that had THR, and the time to THR ranged from 5–157 months, mean=45.7±59.8 months, median= 17.5 months. Our data suggests that core decompression is a practical option for SCD patients with early stage AVN of the femoral head. If our results pan out across multiple Sickle Cell Centers, core decompression can provide significant pain relief and delay the need of THR greatly reducing morbidity from chronic pain and improving functional outcomes. Our data, however, are contrary to the results of a multi-center study of core decompression which compared physical therapy and core decompression to physical therapy alone in 35 patients with SCD in which the follow-up period was only three years. In contrast, the strength of our study is the mean follow-up of ten years. Age range of patients from our study did not differ from that of the multicenter study. Data collection on a larger number of patients from multiple centers, perhaps in the form of a registry or a randomized trial with adequate number of patients to answer the question of the value of core decompression in SCD might be informative in this regard. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 3
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2568-2568
    Abstract: Abstract 2568 Poster Board II-545 Reversing the perinatal switch from fetal to adult hemoglobin synthesis has been an attractive therapeutic goal for β-hemoglobinopathies such as sickle cell disease (SCD) and β-thalassemia. Fetal hemoglobin (Hb F) inhibits the polymerization of deoxy Hb S (anti-sickling effect) in SCD and ameliorates the globin chain imbalance by compensating for severely diminished or absent β-globin synthesis in β-thalassemia. Different classes of compounds have been used for this purpose; only hydroxyurea (HU), an S-phase specific chemotherapeutic agent, an inhibitor of ribonucleotide reductase, has been FDA approved for use in adults with SCD and is currently in phase III trials for infants and children. Despite the established efficacy of HU in many patients with SCD, there is a need for alternative Hb F inducing agents and therapies; an estimated 30% of patients do not respond to HU therapy. In addition, some patients are intolerant of HU due to a number of side effects. The development of novel, more effective anti-switching agents is hampered by a lack of a clear and complete understanding of the molecular mechanism(s) underlying the perinatal switch from fetal (γ-globin) to adult (β-globin) synthesis despite three decades of intensive research. Nevertheless, it has been established that epigenetic mechanisms such as histone deacetylation and DNA methylation do play an important role in the silencing of the γ-globin genes during the perinatal period. In vitro studies and early phase clinical trials in a small number of patients have provided the proof-of-principle for the efficacy of a number of histone deacetylase (HDAC) inhibitors and hypomethylating agents (DNA methyl transferase I inhibitors). Butyrate derivatives are an example of HDAC inhibitors whose efficacy in inducing Hb F has been proven in both SCD and β-thalassemia. More recently, other HDAC inhibitors (SAHA, Depsipeptide, Trichostatin A) have been shown to induce Hb F synthesis in erythroid cultures. DNMT-1 inhibitors, 5-Azacytidine and decitabine, have also been used in small clinical trials to enhance Hb F production and ameliorate the course of severe SCD. LBH589 (panobinostat, Novartis Pharma) is a pan-HDAC inhibitor that belongs to the hydroxamic acid class of HDAC inhibitors that is currently being investigated in Phase I/II trials in hematologic malignancies and a number of solid tumors. We monitored the Hb composition of 21 patients with relapsed/refractory hematologic malignancies enrolled into a Phase I/b trial of panobinostat conducted at the MCG Cancer Center. Hb quantification was done by a cation exchange HPLC procedure. Eight patients were on panobinostat for 2 months or longer with a starting dose of 40–60 mg PO administered thrice weekly (MWF). Three patients carried a diagnosis of Primary Myelofibrosis and one each had Chronic Lymphocytic Leukemia, Mantle Cell Lymphoma, Multiple Myeloma, Refractory Non-Hodgkins Lymphoma, and Chronic Myelogenous Leukemia-accelerated phase. Of these, 4 patients displayed an increase in Hb F over baseline values. None of the patients had an inherited hemoglobinopathy (SCD or β-thalassemia). The median Hb F was 0.33% at entry (range: 0–2.3) and increased to 1.1% (range 0–17%) at the end of the study period. The maximal response was seen in a patient with Primary Myelofibrosis whose Hb F increased from a pretreatment value of 0.2% to 17.0% over a period of 16 months. Overall, patients who were on panobinostat for longer periods of time (≥ 2 months) had a more pronounced increase in Hb F. The remaining 13 patients were on study drug for 〈 2 months. In studies of other Hb F inducing agents, optimal response is not generally reached in less than 6 months. The slight but significant increase in Hb F in this small group of patients without an underlying hemoglobinopathy is encouraging and provides the rationale for a trial of panobinostat as an anti-switching agent in clinically significant hemoglobinopathies such as SCD and β-thalassemia. This effect will likely be enhanced in patients with hemoglobinopathies given the erythropoietic stress and the selection of RBCs containing Hb F. Studies in transgenic mouse models of SCD and a phase I study in patients with SCD who have failed or intolerant of HU are underway. Disclosures: Kutlar: Novartis Pharmaceuticals, Inc.: Research Funding; Celgene Corporation: Research Funding; HemaQuest Pharmaceuticals, Inc.: Research Funding. Meiler:Celgene Corporation: Research Funding; Novartis Pharmaceuticals, Inc.: Research Funding. Bhalla:Novartis: Honoraria, Research Funding; Merck: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 4
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 429-429
    Abstract: Ischemic stroke occurs in 11% of patients with sickle cell disease (SCD) by age 20. The STOP and STOP-II trials showed that the risk of ischemic stroke increases with Transcranial Doppler (TCD) velocities in major intracranial arteries in children with SCD 2–16 years of age, and that the risk in children with abnormal velocities ( 〉 200 cm/sec) can be significantly reduced by prophylactic transfusions. Risk factors for development of high TCD phenotype are not clearly established. In an ancillary study to STOP/STOP-II, we analyzed 28 polymorphisms in 20 candidate genes for association with elevated TCD velocity. DNA was extracted from 130 patients randomized in the STOP trial, all of whom had abnormal TCD velocities, and from 355 patients who were screened for STOP II at 8 participating centers. None of the subjects from either trial had histories of overt stroke when they were screened. Samples from STOP subjects were anonymized according to an IRB-approved plan; informed consent/assent was obtained from subjects screened for the STOP-II trial. Hb phenotype was ascertained by HPLC. High throughput genotyping was performed using the MassARRAY™ System (Sequenom Inc., San Diego, CA) at Mass U. TCD status was classified as normal ( 〈 170 cm/sec) or not normal ( 〉 170 cm/sec) using the average of all TCDs on each patient, excluding any TCDs obtained after starting transfusion (median: 2 TCD exams, range 1–16). Genotyping results for each SNP were also reduced to a binary classification (mutation present or absent) by combining heterozygous subjects with those homozygous for the mutation. Conditional logistic regression was employed to model the probability of having at least 1copy of the mutant allele as a function of TCD status stratified on age class. Under this approach, the odds ratio (OR) relating TCD status to genotype is assumed to be the same at all ages but the prevalence of abnormal or conditional TCD is allowed to vary with age. Seven SNPs were excluded from analyses: all subjects studied (479) were homozygous for the common allele for 5 SNPs, and only 2 subjects were heterozygous for the minor allele for 2 SNPs. The prevalence of abnormal TCD varied with age; the highest prevalence was found in 8–9 year old subjects. Only one SNP, VCAM G1238C, had a significant OR of 0.6 (p=0.03) suggesting this SNP is protective from high TCD. The same polymorphism was found to be protective from stroke with an OR of 0.3 in a different cohort of patients by Taylor et al (Blood, 100:4303–9, 2002). Several published studies have reported on association of stroke with candidate gene polymorphisms with differing results. This is the first large scale study of the association of abnormal TCD (stroke risk) with genetic polymorphisms. To our knowledge, it is also the first confirmatory genetic association study in SCD and cerebrovascular disease in a different population of subjects. Functional analyses of this polymorphism and association of stroke and candidate gene polymorphisms in this cohort are planned.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 5
    Online Resource
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    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 1051-1051
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 1051-1051
    Abstract: Abstract 1051 Several genetic polymorphisms are known to influence baseline hemoglobin F (HbF) levels in patients with sickle cell disease (SCD). These include XmnI polymorphisms in the Gγ globin promoter, polymorphisms of HBS1L-MYB and more recently BCL11A. Over the past several years, many studies have shown that polymorphisms in the BCL11A gene are strongly associated with baseline HbF levels in various populations with SCD. The strongest association has been found with a SNP (G→A) in the intron2 of the BCL11A gene (rs4671393). SCD patients on hydroxyurea (HU) therapy display a wide range of HbF responses. The factors underlying this heterogeneity are not clearly delineated. We undertook a study of the BCL11A rs4671393 polymorphism in a population of adult SCD patients who have been on HU therapy for an extended period. Fifty-nine African-American patients with SCD (25 male, mean age 33.9 and 34 female, mean age 34.5) were studied for BCL11A rs4671393 polymorphism and its correlation to HbF response (percent change in HbF from baseline to maximal response). The minor allele frequency (MAF) of A was 0.288. The distribution of HbF response (δHbF) was plotted against the genotype and is shown in the figure. As can be seen, patients with an A allele had a higher δHbF (12.1%) as opposed to those with the wild type (G/G), which was at 10.6%. Those homozygous for the minor allele (A/A) showed a 10.8% increase in HbF in response to HU therapy. These results are suggestive of a higher HbF response to HU when an A allele is present at this position. The number of homozygous for the minor allele are too small to reach a definite conclusion. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 6
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 3571-3571
    Abstract: Chronic inflammation is a well-established feature of sickle cell disease (SCD) even at steady state, and the degree of inflammation tends to correlate with disease severity. Elevated neutrophil count, as a reflection of the overall inflammatory state, has emerged as an indicator of poor prognosis and has been associated with adverse outcomes including stroke and early mortality. To further delineate the role of neutrophils in the pathogenesis of various complications and in overall disease severity in SCD, we analyzed the gene expression profiles of neutrophils from 5 patients with "severe" disease ( 〉 3 vaso-occlusive episodes [VOE] per year), 5 patients with "mild" disease ( 〈 3 VOE/year) and compared these to each other and to the gene expression profiles of neutrophils from 5 age and sex matched, healthy, non-sickle cell, African-American individuals. Granulocytes were separated from freshly collected venous blood using Histopaque (Sigma diagnostic) density gradient separation. Total RNA was extracted immediately after cell separation by using Rneasy Mini Kit (Qiagen). 2 micrograms of total RNA was converted to double stranded cDNA (ds-cDNA) by using SuperScript Choice System (Invitrogen). In vitro transcription was performed on the ds-cDNA using Enzo RNA transcript labelling kit. After the fragmentation, labeled RNA was hybridized to a set of oligonucleotide arrays (HG U133A, Affymetrix, Santa Clara, CA) and the data was analysed with the Microarray suite 5.0 software (Affymetrix). Out of the differentially expressed genes (314 genes for severe vs. control, 718 genes for mild vs control), those with greater than two fold expression were analysed with the geneMAPP software for localization into biological pathways. In general, a larger number of genes were differentially expressed between "mild" patients vs. control, compared to that between "severe" vs "mild" patients. Genes related to cellular proliferation, growth and maintenance, DNA repair, DNA replication, and cell cycle progression were expressed at significantly higher levels in SCD patients compared to controls. The most impressive finding was the significantly higher expression of genes leading to NFkB activation and inhibition of apoptosis: IAP-1 (increased 6.7 fold and 4.7 fold in mild and severe patients respectively), IkB (decreased 0.14 fold and 0.3 fold), Apaf-1 (decreased 0.4 fold in mild), and c-jun (decreased 0.4 fold in severe); Traf-2 (TNF receptor associated factor-2; increased 3.5 fold and 2 fold); genes in the MAPK signalling pathway: ERK-2 (increased 3.5 fold and 2-fold), MAP2K3 (increased 3.5 fold and 2 fold). These data show that neutrophils in SCD patients are activated with higher expression of genes in the TNF, MAPK, and NFkB pathways consistent with an inflammatory state. Delayed or inhibited apoptosis of neutrophils further maintains this inflammatory state even during the so-called "steady state" of the disease. We conclude that the analyses of gene expression in neutrophils can be a useful tool in identifying pathways and genes that distinguish SCD patients from controls and in differentiating mild and severe phenotypes.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
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  • 7
    In: Blood Cells, Molecules, and Diseases, Elsevier BV, Vol. 47, No. 4 ( 2011-12), p. 235-242
    Type of Medium: Online Resource
    ISSN: 1079-9796
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2011
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  • 8
    In: The Lancet, Elsevier BV, Vol. 401, No. 10387 ( 2023-05), p. 1499-1507
    Type of Medium: Online Resource
    ISSN: 0140-6736
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    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
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  • 9
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 4423-4423
    Abstract: Abstract 4423 Considerable variation is observed in BCR-ABL analysis by qPCR making it difficult to compare inter-laboratory results in monitoring therapy of CML. Many factors contribute to the variation (primers, probes, and standards). The combination of two primers plus a probe and b3a2 plasmid standard from the European Against Cancer (EAC) program is widely accepted to quantitate two major types of p210, b3a2 and b2a2. Since the amplicon size and sequences are different between b3a2 and b2a2, we used EAC primers plus probe with b3a2 and b2a2 standards to quantitate b3a2 and b2a2 respectively. It was found that with well determined copy numbers (CN) of both types of standards, the Ct (threshold cycle) values of b2a2 standards are smaller than b3a2 standards at each concentration point especially at lower CN (30000 CN, 0.26 cycle earlier; 300 CN, 0.42 cycle earlier; 30 CN, 0.56 cycle earlier compared to b3a2 standards from 32 experiments). In order to find out if these differences in Ct have any effect in quantitation of b2a2 samples, RNA samples pre-determined as b2a2 p210 were amplified and CN quantitated in the presence of b3a2 and b2a2 standards in the same qPCR plates. For b2a2 samples, a higher ratio of b2a2 to ABL using b3a2 standards was observed compared to the ratio using b2a2 standards (1.48 fold, p=0.0025, n=45). The data was further broken down into three International Scale (IS) ranges. For 〉 1–10% IS range, the ratio by b3a2 standard is 1.30±0.08 fold (n=12) compared to b2a2 standard. Similarly, for 〉 0.1–1% IS range, the ratio is 1.46±0.08 fold (n=12) and for ≤ 0.1% IS range, the ratio is 1.60±0.22 fold (n=21). Equal numbers of b3a2 and b2a2 RNA samples were analyzed by reference lab and GHSU lab to establish IS conversion factor (CF) for GHSU lab. There was a small difference between b3a2 and b2a2 CF when their own respective standards were used (0.67 for b3a2, 0.57 for b2a2). Therefore, a common CF of 0.62 can be generated for both types of p210. With application of common CF (0.62) to convert b3a2 and b2a2 raw ratios to IS, only 7% is under-estimated for b3a2 and 9% is over-estimated for b2a2. However, when b2a2 and b3a2 quantitation uses only b3a2 standard, there is a big difference in CF value (0.67 for b3a2 vs. 0.39 for b2a2), and a common CF (0.51) can be still generated when two types of BCR-ABL samples are mixed equally. The accuracy of results in IS were jeopardized if the labs used only b3a2 standard for both b3a2 and b2a2 quantitation. For example if this CF (0.51) is used to convert b3a2 and b2a2 raw ratios, 24% is under-estimated for b3a2 and 31% is over-estimated for b2a2. These variations may look small but may be exaggerated if the labs have big variations in their assay and do not have equal numbers of b3a2 and b2a2 to establish the CF. Further, data from recent survey results were compared to see if the labs using only b3a2 standards for both types of p210 have higher ratios for b2a2 BCR-ABL than the labs using two individual standards. The results of commercially available standards (b3a2 only) were compared with GHSU results, which uses both types of standards (b3a2 and b2a2) to evaluate CN's of respective fusion gene. In one survey with b3a2 RNA, the means of original raw ratio and ratio in IS by using the commercial reagent were very similar to the results by GHSU using b3a2 results (1.13 - raw ratio; 1.34 - IS between two). In two other surveys where b2a2 RNA was used, the means of raw ratio in samples analyzed using commercial reagent (b3a2 Standards) were 1.46 and 1.48 fold, compared to means of same samples analyzed by GHSU using b2a2 standards. Similarly, 1.59 and 1.76 fold difference is observed between samples using commercial standards (b3a2) and GHSU standards (b2a2) in the second survey. Moreover the ratios in IS reported in the second survey by commercial reagent were 1.85 fold and 2.23 fold of GHSU results. These findings suggest that there is a statistically significant over-estimation of b2a2 to control gene ratio, especially at MMR range, when b3a2 standards are used for b2a2 analysis. This may be one of the important factors that contribute to the considerable variation in BCR-ABL analysis. The phenomenon may be explained by the sequences or structure of an extra exon in b3a2 that is missing in the b2a2 fusion gene, and this may result in the different amplification rates of two types of p210. It is suggested that in order to quantitate the ratio of b3a2 and b2a2 accurately, their own standards should be used in qPCR analysis. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 10
    In: British Journal of Haematology, Wiley, Vol. 189, No. 6 ( 2020-06), p. 1204-1209
    Abstract: Sickle cell disease (SCD) has a distinct pattern of transfusional iron overload (IO) when compared to transfusion‐dependent β‐thalassaemia major (TDT). We conducted a single institution prospective study to evaluate plasma biomarkers of iron regulation and inflammation in patients with SCD with IO (SCD IO cases, n  = 22) and without IO (SCD non‐IO cases, n  = 11), and non‐SCD controls ( n  = 13). Hepcidin was found to be inappropriately low, as evidenced by a significantly higher median hepcidin/ferritin ratio in non‐SCD controls compared to SCD IO cases (0·3 vs. 0·02, P   〈  0·0001) and SCD non‐IO cases (0·3 vs. 0·02, P   〈  0·0001), suggesting that certain inhibitory mechanism (s) work to suppress hepcidin in SCD. As opposed to the SCD non‐IO state, where hepcidin shows a strong significant positive correlation with ferritin (Spearman ρ = 0·7, P  = 0·02), this correlation was lost when IO occurs (Spearman ρ = −0·2, P  = 0·4). Although a direct non‐linear correlation between erythroferrone (ERFE) and hepcidin did not reach statistical significance both in the IO (Spearman ρ = −0·4, P  = 0·08) and non‐IO state (Spearman ρ = −0·6, P  = 0·07), patients with highest ERFE had low hepcidin levels, suggesting that ERFE contributes to hepcidin regulation in some patients. Our results suggest a multifactorial mechanism of hepcidin regulation in SCD.
    Type of Medium: Online Resource
    ISSN: 0007-1048 , 1365-2141
    URL: Issue
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    Language: English
    Publisher: Wiley
    Publication Date: 2020
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