Blood
0006-4971
Cơ quản chủ quản: Elsevier BV , AMER SOC HEMATOLOGY
Lĩnh vực:
BiochemistryHematologyCell BiologyImmunology
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Transplantation and gene transfer of the human glucocerebrosidase gene into immunoselected primate CD34+Thy-1+ cells Abstract
In an attempt to improve our gene transfer efficiency into hematopoietic stem cells and to evaluate the capacity of immunoselected CD34+Thy-1+(CDw90) cells to reconstitute hematopoiesis following myeloablation, bone marrow (BM) transplantation was performed using autologous, immunoselected CD34+Thy-1+ cells in rhesus macaques. BM samples were positively selected for cells that express CD34, further subdivided using high gradient immunomagnetic selection for cells that express Thy-1, and transduced using a 7-day supernatant transduction protocol with a replication-defective retroviral vector that contained the human glucocerebrosidase (GC) gene. Circulating leukocytes were evaluated using a semiquantitative polymerase chain reaction (PCR) assay for the human GC gene, with the longest surviving animal evaluated at day 558. Provirus was detected at all time points in both CD20+ B cells and CD2+ dim T cells, but long-term gene transfer was not observed in the granulocyte population. The CD2+ dim population was phenotypically identified as being CD8+ natural killer cells. By day 302 and day 330, both the CD2+ bright and dim cell populations and sorted CD4+ and CD8+ cells had detectable provirus. Vector-derived GC mRNA was detected by reverse transcriptase (RT)-PCR analysis as far out as day 588. Thus, CD34+Thy-1+ cells isolated using high gradient magnetic separation techniques can engraft, be transduced with a replication-defective retroviral vector, and contribute to CD20+ B lymphocytes, CD8+ T lymphocytes, and CD4+ T lymphocytes; making them a suitable cell population to target for gene therapies involving lymphocytes.
Tập 88 - Trang 4166-4172 - 1996
What Predicts Adrenal Insufficiency in Patients with Thalassemia Major? Abstract
Abstract 5299
Background:
Thalassemia is one of the most common genetic blood disorders worldwide. With recent improvements in medical therapy, patients with transfusion-dependent thalassemia, i.e., thalassemia major, are living longer. As a result, there is a greater need to address endocrine complications related to chronic iron overload. Adrenal insufficiency (AI), in particular, is important to identify because therapies are available and can be life-saving.
Objectives:
The objectives of this study are to determine the prevalence of AI in our population of subjects with thalassemia major; to identify risk factors that predict AI in these individuals; and to localize the origin of the AI within the hypothalamic-pituitary-adrenal (HPA) axis.
Methods:
This is a prospective study of individuals with thalassemia major with an enrollment goal of 30 subjects. All subjects enrolled were initially tested for AI using a glucagon stimulation test. Those found to have AI (stimulated cortisol <18 mcg/dL) subsequently underwent an ovine corticotrophin-releasing hormone (oCRH) stimulation test for confirmatory purposes and to define the physiological basis for the AI.
Results:
Eleven subjects (8 - 29 years old, 6 female) have been enrolled to date. In our population of patients with TM, the prevalence of AI was 55%. There was no correlation between age, number of years transfused, or ferritin levels and AI. All male patients failed the glucagon stimulation test, whereas 5 of 6 females passed the glucagon stimulation test, p = 0.0024. There was no correlation between 8 AM ACTH levels and 8 AM cortisol levels. There was a significant correlation (p = 0.025) between 8 AM cortisol level and peak cortisol level following glucagon stimulation testing. Of the six subjects with AI, two subjects subsequently failed the oCRH stimulation test (peak cortisol < 21.9 mcg/dL). In these two subjects, peak oCRH ACTH levels were elevated, 144 and 164 pg/mL, respectively, suggesting primary adrenal insufficiency.
Conclusions:
We conclude that 8 AM cortisol level is a good predictor of adrenal insufficiency in our population, and can potentially be used as a simple screening test for AI with a strong negative predictive value. There appears to be a male predominance of AI in our population. This may indicate a protective role of female sex in this population. Two subjects had classic primary AI with robust ACTH levels in the face of inadequate cortisol production following oCRH testing. Four subjects (all males) who failed the glucagon stimulation test subsequently demonstrated normal ACTH and cortisol response to oCRH, indicating a possible hypothalamic origin to their AI. This dysfunction is likely independent of iron overload and warrants further investigation. Alternatively, these subjects may have impaired sympathetic nervous system function leading to hypoglycemic unawareness. Both outcomes are novel to the field and of medical significance.
Disclosures:
Geffner: Daiichi- Sankyo: Steering Committee for Clinical Trial; Eli Lilly, Inc.: Research Contract; Endo Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ipsen: Data Safety Monitoring Board and Research Contract; Novo Nordisk: Research Funding; Pfizer, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding.
Tập 118 - Trang 5299 - 2011
Coagulation Factor Activity Level and Clinical Bleeding Severity in Rare Bleeding Disorders: Results From the European Network of Rare Bleeding Disorders (EN-RBD), Abstract
Abstract 3312
The European Network of Rare Bleeding Disorders (EN-RBD) was established to bridge the gap between knowledge and practice in the care of patients with RBDs (rare bleeding disorders frequency <1/0.5-2M). The aim of this first report was to explore the relationship between the coagulation factor activity levels and clinical bleeding severity in patients with RBDs. A total of 592 records on patients with RBDs were cross-sectionally collected over a period of three years. Data on clinical bleeding episodes were available for 495 patients and were classified into four categories according to severity. The mean age of patients was 31 years (range, 7 months-95 years), with 51% being females. On linear regression analysis, there was a strong association between coagulation factor activity level and clinical bleeding severity for fibrinogen, factor (F)FX, FXIII, and combined FV and FVIII deficiencies. A weaker association was present for FV and FVII deficiencies. There was no association between coagulation factor activity level and clinical bleeding severity for FXI. It is of clinical relevance to identify levels that are not associated with spontaneous major bleeding, which was done by constructing receiver operating characteristic curves. These levels were highest for FXIII deficiency (25 U/dl), followed by FV+VII (15 U/dl), FVII (15 U/dl), FX (5 U/dl), and FV (1 U/dl) deficiencies. For fibrinogen deficiency, a factor activity level of 20 mg/dl is needed to ensure absence of major spontaneous bleeding. There is a clear relation between coagulation factor activity level and clinical bleeding severity in RBDs, which is different for the missing clotting factor.
Disclosures:
Peyvandi: NovoNordisk, CSL Behring: Honoraria. Bidlingmaier:CSL Behring, Bayer Schering: Research Funding; CSL Behring, NovoNordisk, Pfizer, Bayer Schering: Membership on an entity's Board of Directors or advisory committees; Baxter, Biotest, CSL Behring, NovoNordisk, Pfizer, Bayer Schering: Honoraria. Schved:LFB, CSL Behring, Novonordisk, Bayer Schering: Research Funding.
Tập 118 - Trang 3312 - 2011
Identification of Subtype-Specific Genomic Alterations of Acute and Lymphoma Types of Adult T-Cell Leukemia/Lymphoma. Abstract
Background: Adult T cell leukemia/lymphoma (ATLL) is a human T-lymphotropic virus type-I mediated neoplasm and four major clinical subtypes are recognized; i.e., smoldering, chronic, lymphoma and acute types. Among these subtypes, acute and lymphoma types are fetal disease with poor prognosis. Although these two subtypes represent different clinical features, detailed analysis for genomic/genetic differences has not been sufficiently investigated.
Purpose: To investigate genomic aberrations of these subtypes, we performed array-based comparative genomic hybridization (array CGH: 2308 BAC clones spotted in duplicate) for 66 cases of ATLL (17 cases of acute and 49 cases of lymphoma subtypes). To determine target genes in recurrently amplified regions, quantitative real-time PCR (RQ-PCR) was conducted.
Results: Array CGH: Comparison of genome profiles revealed that lymphoma type shows more frequent gain and loss than those of acute type. The numbers of respective genomic gain and loss regions of lymphoma type were 9.7 and 9.8 on average. The numbers of genomic gain and loss regions of acute type were 4.2 and 4.5 on average. Gain of 1q, 2p, 4q, 7p and 7q, and loss of 10p, 13q, 16q and 18p were characteristic to lymphoma type whereas gain of 3p and 3q was specific to acute type. Recurrent high-level amplifications were found at 1p35, 6p25, 7p22.2, 7q21–q22, 7q31–q36 and 14q32 in lymphoma type. However, such genomic amplifications were not found in acute type.
RQ-PCR: CARMA1 (7p22 locus), which encodes signaling proteins associated with development of B and T cells, was a possible target of the 7p22 amplification in lymphoma type. The extremely higher expression of BCL11B (14q32 locus) which is a key regulator of both differentiation and survival during thymocyte development, was found in acute type irrespective of the 14q32 amplification. However, no overexpression of BCL11B was found in lymphoma type with high copy number gain, indicating that BCL11B is not the target gene for 14q32 amplification in the lymphoma type.
Conclusion: Array-CGH revealed that patterns of genomic aberrations between acute and lymphoma types were different. Quantitative gene expression analysis also implicated distinct mechanism of aberrant gene expressions between acute and lymphoma types. Combination of array-CGH and quantitative gene expression analysis provided evidence that the acute and lymphoma types are developed via distinct genomic/genetic pathways.
Tập 106 - Trang 4667 - 2005
Marrow versus peripheral blood for geno-identical allogeneic stem cell transplantation in acute myelocytic leukemia: influence of dose and stem cell source shows better outcome with rich marrow
Tập 102 - Trang 3043-3051 - 2003
Punch Biopsy Model To Evaluate the Impact of Anticoagulation or Antiplatelet Therapy-Induced Bleeding Episodes: Model Validation. Abstract
Background/Objective: Antiplatelet drugs and Vitamin-K antagonists are used to reduce thrombosis potential in patients with cardiovascular disease or with hypercoagulable disorders. Such treatments can impair platelet function and can lead to significant reduction in coagulation-related proteins with the resultant increased bleeding risk.1,2 The current study (Novo Nordisk F7HAEM-1825) was designed to evaluate the use of a new bleeding model for determining the effectiveness of haemostatic interventions to mitigate drug-induced bleeds. We sought to determine the feasibility of demonstrating measurable changes in punch biopsy-induced bleeding durations and bleeding volumes in healthy volunteers after receiving warfarin anti-coagulation therapy.
Methods: Healthy volunteers received two biopsies using a 5 mm punch biopsy tool with local anesthesia to the posterior thigh - one prior to warfarin administration (Biopsy 1), and a second post-warfarin administration after achieving an international normalized ratio (INR) of 2.5 (± 0.3) (Biopsy 2). Subjects were titrated with warfarin dosing to achieve a stable INR within the designated range (INR=2.5±0.3), at which time the second biopsy was performed. Bleed duration and bleed volumes were measured. Three data analysis methods were used: a generalized linear model with logarithmic link and gamma distribution, paired t-test on log-transformed data, and paired t-test on the original data.
Results: Twelve healthy subjects underwent the first baseline biopsy. One subject did not maintain an INR within the specified range, leaving 11 subjects assessed for the impact of warfarin on bleeding. Mean baseline and post-warfarin bleed durations and volumes are shown below.
Baseline (Biopsy 1) Mean Values Warfarin (Biopsy 2) Mean Values Day 1 INR Bleed Duration (min:sec) Blood Volume Loss (ml) Warfarin INR Bleed Duration (min: Sec) Blood Volume Loss (ml) Difference in bleed duration (min:sec) 1.08 12:43 2.34 2.48 20:36 3.83 7:53
All participants demonstrated increases in bleeding duration from Biopsy 2 compared to Biopsy 1. All participants demonstrated increases in bleeding duration from Biopsy 2 compared to Biopsy 1.
Changes in Bleeding Duration from Biopsy 1 (Baseline) to Biopsy 2 (Post Warfarin) All analysis methods demonstrated a mean increase in bleeding duration and blood volume loss by at least 60%, and all gave approximately the same estimate of the ratio Mean Bleeding duration at Biopsy 2/ Biopsy 1 (1.60–1.63) as well as approximately the same estimate of the ratio Mean Blood Loss at Biopsy 2/Biopsy 1 (1.64).
Conclusion: The method described here is a reproducible technique for evaluating the impact of anticoagulation products in altering bleed durations and volumes and may be useful for evaluating hemostatic agents to control anticoagulation-related bleeding. Additionally, this method may be useful for assessing anticoagulation reversal/mitigation strategies in clinically relevant hemorrhage.
Tập 110 - Trang 3157 - 2007
Interleukin-15 (IL-15) Induces NF-κB Activation and IL-8 Production in Human Neutrophils Abstract Interleukin-2 (IL-2) and IL-15 exert similar biological actions, which largely reflect the fact that their receptors share common β and γ subunits; in contrast, distinct subunits are required for high-affinity binding of either cytokine to a heterotrimeric receptor complex. Human neutrophils are known to express both the β and γ subunits of the IL-2/IL-15 receptor complex, and we now report that they also constitutively express messenger RNA transcripts encoding the IL-15 receptor chain, suggesting that they possess functional, heterotrimeric IL-15 receptors. Accordingly, we show that in neutrophils, IL-15 elicits several functional responses. In particular, neutrophils synthesize and release IL-8 in response to IL-15, but not to IL-2. Moreover, a nuclear factor-κB (NF-κB) DNA-binding activity was enhanced in nuclear extracts of IL-15–treated neutrophils, which could be supershifted by antibodies to p50 or RelA. Again, no detectable effect of IL-2 was observed on this response. In peripheral blood lymphocytes (PBL), however, both IL-2 and IL-15 were potent inducers of NF-κB activation. Conversely, neither IL-15 nor IL-2 elicited the formation of activator protein-1 (AP-1) DNA-binding complexes in neutrophils, even though both cytokines were found to activate these DNA-binding activities in PBL. Collectively, these observations establish neutrophils as a useful cellular model to discriminate between the actions of IL-15 and IL-2. More importantly, this is the first demonstration that IL-15 has the ability to induce NF-κB and AP-1 activation, which further emphasizes the potential relevance of this newly discovered cytokine to immune and inflammatory processes.
Tập 92 Số 12 - Trang 4828-4835 - 1998
Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey Abstract Although activity that induced tumor regression was observed and termed tumor necrosis factor (TNF) as early as the 1960s, the true identity of TNF was not clear until 1984, when Aggarwal and coworkers reported, for the first time, the isolation of 2 cytotoxic factors: one, derived from macrophages (molecular mass 17 kDa), was named TNF, and the second, derived from lymphocytes (20 kDa), was named lymphotoxin. Because the 2 cytotoxic factors exhibited 50% amino acid sequence homology and bound to the same receptor, they came to be called TNF-α and TNF-β. Identification of the protein sequences led to cloning of their cDNA. Based on sequence homology to TNF-α, now a total of 19 members of the TNF superfamily have been identified, along with 29 interacting receptors, and several molecules that interact with the cytoplasmic domain of these receptors. The roles of the TNF superfamily in inflammation, apoptosis, proliferation, invasion, angiogenesis, metastasis, and morphogenesis have been documented. Their roles in immunologic, cardiovascular, neurologic, pulmonary, and metabolic diseases are becoming apparent. TNF superfamily members are active targets for drug development, as indicated by the recent approval and expanding market of TNF blockers used to treat rheumatoid arthritis, psoriasis, Crohns disease, and osteoporosis, with a total market of more than US $20 billion. As we learn more about this family, more therapeutics will probably emerge. In this review, we summarize the initial discovery of TNF-α, and the insights gained regarding the roles of this molecule and its related family members in normal physiology and disease.
Tập 119 Số 3 - Trang 651-665 - 2012
Combination Therapy of Deferasirox and Deferoxamine As Paregoric Treatment of Severe Iron Overload in Patients with Thalassemia Major Abstract
Abstract 5181
Background:
Despite the recent availability of multiple therapeutic options for chelation therapy, severe iron overload remains a significant cause of morbidity and mortality in a small group of patients with thalassemia major (TM). Every effort to induce negative iron balance for these patients is warranted. In this context, combination of deferasirox (DFX) and deferoxamine (DFO) may be of significant value. In this report, we present the paregoric use of DFX and DFO in severely iron overloaded thalassemic patients.
Patients and Methods:
Five patients (3 Males, 2 females) have been treated with DFX and DFO as a last rescue measure. In these patients previous combined treatment with DFO and DFP had failed. Informed consent and approval for the use of this schema as paregoric therapy was obtained by patients and hospital. The main inclusion criteria for this treatment were: LIC>30 mg/gr d. w. and T2* cardiac <10 msec. Treatment consisted of daily DFX at 30–40 mg/kg/day and DFO at 40–50 mg/kg/day for 3–6 days/week.
Results:
Patients' characteristics, results and toxicity are shown in table 1 and 2. Improvement in iron load status ranged widely during a follow-up from 1 to 3 yrs. LIC reduced in 4/5 patients, cardiac T2* increased in 3/5 patients, while LVEF showed no significant changes. Ferritin levels improved in 2/5 patients. Deterioration of safety parameters necessitated not to discontinue treatment.
Conclusions:
These data in the use of combination therapy of DFX and DFO suggest a potential modality of chelation therapy in severely iron overloaded patients. Response was variable and seemed not to be always related to compliance or the duration of treatment. Increase of serum creatinin and AST in all patients is a considerable problem in patients with persistent significant iron overload and already impaired hepatic and renal function, despite having been treated with different schema of iron chelation. Longer and cautious follow-up is needed to come to reliable conclusions.
Disclosures:
Ladis: Novartis: Consultancy, Honoraria, Research Funding; Apopharma: Consultancy, Honoraria, Research Funding. Kattamis:Apopharma: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau.
Tập 120 - Trang 5181 - 2012