In sickle cell disease transfusions improve blood flow by reducing the proportion of red cells capable of forming sickle hemoglobin polymer. This limits hemolysis and the endothelial damage that result from high proportions of sickle polymer-containing red cells. Additionally, transfusions are used to increase blood oxygen carrying capacity in sickle cell patients with severe chronic anemia or with severe anemic episodes. Transfusion is well-defined as prophylaxis (stroke) and as therapy (acute chest syndrome and stroke) for major complications of sickle cell disease and has been instituted, based on less conclusive data, for a range of additional complications, such as priapism, vaso-occlusive crises, leg ulcers, pulmonary hypertension, and during complicated pregnancies. The major and unavoidable complication of transfusions in sickle cell disease is iron overload. This paper provides an overview of normal iron metabolism, iron overload in transfused patients with sickle cell disease, patterns of end organ damage, diagnosis, treatment, and prevention of iron overload.
Epstein-Barr virus (EBV) is associated with a number of diseases, including malignancies. Currently, it is not known whether patients with different EBV-associated diseases have different methylation profiles of circulating EBV DNA. Through whole-genome methylation analysis of plasma samples from patients with nasopharyngeal carcinoma (NPC), EBV-associated lymphoma and infectious mononucleosis, we demonstrate that EBV DNA methylation profiles exhibit a disease-associated pattern. This observation implies a significant potential for the development of methylation analysis of plasma EBV DNA for NPC diagnostics. We further analyse the plasma EBV DNA methylome of NPC and non-NPC subjects from a prospective screening cohort. Plasma EBV DNA fragments demonstrate differential methylation patterns between NPC and non-NPC subjects. Combining such differential methylation patterns with the fractional concentration (count) and size of plasma EBV DNA, population screening of NPC is performed with an improved positive predictive value of 35.1%, compared to a count- and size-based only protocol.
Acute promyelocytic leukemia (APL) is characterized by the promyelocytic leukemia-retinoic acid receptor a (PML-RARA) fusion. In rare instances, RARA is fused to other partners, which dictate sensitivity to targeted therapies. Chen et al previously reported in Blood a novel TBLR1-RARA fusion, which is all-trans-retinoic acid (ATRA)-insensitive in vivo, in a t(3;17)(q26;q21)-harboring APL. 1,2 Here, we report another new RARA fusion resulting from the same translocation in a variant APL patient.The patient was a 36-year-old man who presented with fatigue, dyspnea, and easy bruising for 2 weeks. Complete blood count revealed a hemoglobin level of 5.4 g/dL, platelet count of 41 3 10 9 /L, and white blood cell count of 3.6 3 10 9 /L with 60% hypergranular blasts. Clotting profile showed a decreased fibrinogen level and prolonged prothrombin time but normal activated partial thromboplastin time. Bone marrow (BM) examination showed 68% of blasts with morphology similar to those in peripheral smear ( Figure 1A). The blasts were positive for myeloperoxidase, CD13, CD15, CD33, and CD117 but negative for CD34 and HLA-DR by flow cytometry. A diagnosis of APL was suggested and ATRA (45 mg/m 2 per day) was initiated while awaiting molecular findings. On day 4 of ATRA therapy, the patient developed differentiation syndrome (DS) with fluid retention and pleural effusions. Steroids and diuretics were started, and the 7 1 3 induction chemotherapy was commenced with cytarabine (200 mg/m 2 ) and daunorubicin (60 mg/m 2 ). A morphological complete remission was confirmed at day 30. Figure 1B-C) but the expected TBLR1-RARA fusion previously identified in t(3;17) was absent. No mutations in FLT3, NPM1, CEBPA, DNMT3A, RUNX1, K/NRAS, WT1, or IDH1/2 were detected. Using 59-rapid amplification of complementary DNA ends, we found that RARA was fused to another 3q26 gene called fibronectin type III (FN3) domain containing 3B (FNDC3B) in our patient. Subsequent RT-PCR confirmed the fusion between exon 24 of FNDC3B and exon 3 of RARA ( Figure 1D), which is involved in all other RARA fusions. FNDC3B was originally identified as an adipocyte differentiation factor.3 It contains 9 FN3 domains, which are implicated in protein interactions. The full-length FNDC3B-RARA transcript is predicted to encode a 1461-amino acid protein, containing 8 FN3 domains of FNDC3B as well as the DNA-binding and ligand-binding domain of RARA ( Figure 1E). Two reciprocal RARA-FNDC3B transcripts were also detected. The major transcript involves an in-frame fusion between RARA exon 2 and FNDC3B exon 25, whereas the minor transcript involves an out-offrame fusion between the same RARA exon and FNDC3B exon 26 ( Figure 1D). These transcripts are expected to generate 205-and 111-amino acid proteins, respectively ( Figure 1E). Both FNDC3B-RARA and RARA-FNDC3B fusions were undetected after the patient
The purpose of this study was to compare a novel bone marrow device with the standard marrow needle in a prospective, randomized study in a teaching hospital employing hematologists-in-training. The new device, the OnControl Bone Marrow (OBM) Biopsy System, utilizes a battery-powered drill to insert the needle. Fifty-four bone marrows (27 standard and 27 OBM) were performed by 11 fellows under the observation and supervision of 3 attending hematologists and 1 research technologist. The primary endpoint of the study, the mean length of the marrow biopsy specimens, a surrogate for marrow quality, was determined by a pathologist in a blinded manner. The mean length of the marrow biopsy specimens was significantly longer (56%) for the OBM group (15.3 mm) than for the standard bone marrow (SBM) group (9.8 mm), P<0.003. An objectively determined secondary endpoint; mean procedure time, skin-to-skin; also favored the OBM group (175 s) versus the SBM group (292 s), P<0.007. Several subjective secondary endpoints also favored the OBM group. Only minor adverse events were encountered in the OBM and SBM study groups. It was concluded that bone marrow procedures (BMPs) performed by hematologists-in-training were significantly faster and superior in quality when performed with the OBM compared to the SBM. These data suggest that the OBM may be considered a new standard of care for adult hematology patients. OBM also appears to be a superior method for training hematology fellows.
Nasopharyngeal carcinoma (NPC) of the undifferentiated subtype remains endemic in southern China, with a peak incidence in this region approaching 30 cases per 100,000 population per year. Despite advances in chemotherapy and radiation delivery techniques in localized disease, distant metastasis is still common and NPC remains the seventh leading cause of cancer death in the region. There is great need for early diagnosis, developing novel therapies, and identifying patients with localized disease at higher risk of future recurrence or metastasis to appropriately tailor their treatment and improve outcomes. Knowledge of the integral involvement of Epstein-Barr virus (EBV) in the pathogenesis of undifferentiated NPC has been of seminal importance in developing strategies to optimize disease management. The close association with EBV is being evaluated in multiple settings including screening of at-risk populations, disease prognostication, development of targeted therapies, optimizing adjuvant treatment, and early recurrence detection. These translational studies are likely to have an enormous effect on management of undifferentiated NPC and significantly improve the landscape of the disease in years to come.
BACKGROUND Cellular mitochondrial DNA (mtDNA) is organized as circular, covalently closed and double-stranded DNA. Studies have demonstrated the presence of short mtDNA fragments in plasma. It is not known whether circular mtDNA might concurrently exist with linear mtDNA in plasma. METHODS We elucidated the topology of plasma mtDNA using restriction enzyme BfaI cleavage signatures on mtDNA fragment ends to differentiate linear and circular mtDNA. mtDNA fragments with both ends carrying BfaI cleavage signatures were defined as circular-derived mtDNA, whereas those with no cleavage signature or with 1 cleavage signature were defined as linear-derived mtDNA. An independent assay using exonuclease V to remove linear DNA followed by restriction enzyme MspI digestion was used for confirming the conclusions based on BfaI cleavage analysis. We analyzed the presence of BfaI cleavage signatures on plasma DNA ends in nonhematopoietically and hematopoietically derived DNA molecules by sequencing plasma DNA of patients with liver transplantation and bone marrow transplantation. RESULTS Both linear and circular mtDNA coexisted in plasma. In patients with liver transplantation, donor-derived (i.e., liver) mtDNA molecules were mainly linear (median fraction, 91%; range, 75%–97%), whereas recipient-derived (i.e., hematopoietic) mtDNA molecules were mainly circular (median fraction, 88%; range, 77%–93%). The proportion of linear mtDNA was well correlated with liver DNA contribution in the plasma DNA pool (r = 0.83; P value = 0.0008). Consistent data were obtained from a bone marrow transplantation recipient in whom the donor-derived (i.e., hematopoietic) mtDNA molecules were predominantly circular. CONCLUSIONS Linear and circular mtDNA molecules coexist in plasma and may have different tissue origins.
Despite the fact that sickle cell anemia was one of the first diseases to have a demonstrated genetic etiology, to date there is still only one approved therapy for this disease. Recent increases in our understanding of the pathophysiology of the disease should translate into improved and more rapid development of newer therapies. This review will focus on the following current and potential therapeutic strategies to reduce the morbidity of sickle cell anemia. 1) Therapies such as decitabine, hydroxyurea, butyrate, lenalidomide and pomalidomide, which decrease the polymerization rate of HbS by increasing the concentration of Hb F; 2) Drugs that decrease relative intracellular HbS concentration by increasing total cell volume via inhibition of normal membrane ion exchange channels, such as KCL Cotransporter and Gardos Channels. These inhibitors include magnesium pidolate, imidazole antimycotics, arginine and Senicapoc; 3) Treatment of sickle cell vasoocclusion through inhibition of endothelial or cell surface adhesion molecules, such ICAM 4 and alpha(v)beta(3) integrins, by drugs related to the GPII(b)III(a) inhibitors or adhesion molecule modulators, and 4) Attempts to achieve vasodilation by nitric oxide and antioxidant therapy. This review will discuss the status of these emerging therapies in the treatment of sickle cell anemia.
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