A GCH1 haplotype confers sex-specific susceptibility to pain crises and altered endothelial function in adults with sickle cell anemia.

GTP cyclohydrolase (GCH1) is rate limiting for tetrahydrobiopterin (BH4) synthesis, where BH4 is a cofactor for nitric oxide (NO) synthases and aromatic hydroxylases. GCH1 polymorphisms are implicated in the pathophysiology of pain, but have not been investigated in African populations. We examined GCH1 and pain in sickle cell anemia where GCH1 rs8007267 was a risk factor for pain crises in discovery (n = 228; odds ratio [OR] 2.26; P = 0.009) and replication (n = 513; OR 2.23; P = 0.004) cohorts. In vitro, cells from sickle cell anemia subjects homozygous for the risk allele produced higher BH4. In vivo physiological studies of traits likely to be modulated by GCH1 showed rs8007267 is associated with altered endothelial dependent blood flow in females with SCA (8.42% of variation; P = 0.002). The GCH1 pain association is attributable to an African haplotype with where its sickle cell anemia pain association is limited to females (OR 2.69; 95% CI 1.21-5.94; P = 0.01) and has the opposite directional association described in Europeans independent of global admixture. The presence of a GCH1 haplotype with high BH4 in populations of African ancestry could explain the association of rs8007267 with sickle cell anemia pain crises. The vascular effects of GCH1 and BH4 may also have broader implications for cardiovascular disease in populations of African ancestry.

8-azaadenosine and 8-chloroadenosine are not selective inhibitors of ADAR.

The RNA editing enzyme ADAR, is an attractive therapeutic target for multiple cancers. Through its deaminase activity, ADAR edits adenosine to inosine in dsRNAs. Loss of ADAR in some cancer cell lines causes activation of the type I interferon pathway and the PKR translational repressor, leading to inhibition of proliferation and stimulation of cell death. As such, inhibition of ADAR function is a viable therapeutic strategy for many cancers. However, there are no FDA approved inhibitors of ADAR. Two small molecules have been previously shown to inhibit ADAR or reduce its expression: 8-azaadenosine and 8-chloroadenosine. Here we show that neither molecule is a selective inhibitor of ADAR. Both 8-azaadenosine and 8-chloroadenosine show similar toxicity to ADAR-dependent and independent cancer cell lines. Furthermore, the toxicity of both small molecules is comparable between cell lines with either knockdown or overexpression of ADAR, and cells with unperturbed ADAR expression. Treatment with neither molecule causes activation of PKR. Finally, treatment with either molecule has no effect on A-to-I editing of multiple ADAR substrates. Together these data show that 8-azaadenosine and 8-chloroadenosine are not suitable small molecules for therapies that require selective inhibition of ADAR, and neither should be used in preclinical studies as ADAR inhibitors.

The Challenges of Daratumumab in Transfusion Medicine.

The field of transfusion medicine has evolved rapidly in recent years, but the central principle of transfusion is still simple, namely, the antigen-antibody interaction. Daratumumab (DARA), a monoclonal antibody (MoAb), was developed to treat relapsed/refractory multiple myeloma (RRMM). DARA works by targeting the CD38 portion of malignant cells; however, this drug attaches to the red blood cell (RBC) reagents used in blood banks, further complicating the antibody identification work-up. The AABB (formerly known as the American Association of Blood Banks) has issued a memorandum on how blood banks can effectively address panreactivity caused by DARA. Dithiothreitol (DTT), a common reagent in blood banks, has emerged as an inexpensive and practical way to dissolve panreactivity caused by DARA. However, DTT is known to destroy the Kell antigen blood group and other, less frequently encountered blood group antigens. Other promising alternative solutions, such as umbilical cord RBCs, screening cells, and neutralization, are not widely available yet. The exploration of these issues and options, in this review of the literature, is intended to guide blood bank technologists in dealing with panagglutination reactivity caused by DARA.

Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet's disease.

Behçet's disease is a genetically complex disease of unknown etiology characterized by recurrent inflammatory attacks affecting the orogenital mucosa, eyes and skin. We performed a genome-wide association study with 311,459 SNPs in 1,215 individuals with Behçet's disease (cases) and 1,278 healthy controls from Turkey. We confirmed the known association of Behçet's disease with HLA-B*51 and identified a second, independent association within the MHC Class I region. We also identified an association at IL10 (rs1518111, P = 1.88 x 10(-8)). Using a meta-analysis with an additional five cohorts from Turkey, the Middle East, Europe and Asia, comprising a total of 2,430 cases and 2,660 controls, we identified associations at IL10 (rs1518111, P = 3.54 x 10(-18), odds ratio = 1.45, 95% CI 1.34-1.58) and the IL23R-IL12RB2 locus (rs924080, P = 6.69 x 10(-9), OR = 1.28, 95% CI 1.18-1.39). The disease-associated IL10 variant (the rs1518111 A allele) was associated with diminished mRNA expression and low protein production.