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