TP53 suppression promotes erythropoiesis in del(5q) MDS, suggesting a targeted therapeutic strategy in lenalidomide-resistant patients.

Stabilization of p53 in erythroid precursors in response to nucleosomal stress underlies the hypoplastic anemia in myelodysplastic syndromes (MDS) with chromosome 5q deletion [del(5q)]. We investigated whether cenersen, a clinically active 20-mer antisense oligonucleotide complementary to TP53 exon10, could suppress p53 expression and restore erythropoiesis in del(5q) MDS. Cenersen treatment of ribosomal protein S-14-deficient erythroblasts significantly reduced cellular p53 and p53-up-regulated modulator of apoptosis expression compared with controls, accompanied by a significant reduction in apoptosis and increased cell proliferation. In a two-stage erythroid differentiation assay, cenersen significantly suppressed nuclear p53 in bone marrow CD34+ cells isolated from patients with del(5q) MDS, whereas erythroid burst recovery increased proportionally to the magnitude of p53 suppression without evidence of del(5q) clonal suppression (r = -0.6; P = 0.005). To explore the effect of p53 suppression on erythropoiesis in vivo, dexamethasone, a glucocorticoid receptor-dependent p53 antagonist, was added to lenalidomide treatment in eight lower-risk, transfusion-dependent, del(5q) MDS patients with acquired drug resistance. Transfusion independence was restored in five patients accompanied by expansion of erythroid precursors and decreased cellular p53 expression. We conclude that targeted suppression of p53 could support effective erythropoiesis in lenalidomide-resistant del(5q) MDS.

Impacts of Independence Day fireworks on pollution levels of atmospheric polycyclic aromatic hydrocarbons (PAHs) in the U.S.

Fireworks on Independence Day have been identified as a nationwide but short-term source of particulate matter in the U.S. No study has specifically examined their impacts on ambient polycyclic aromatic hydrocarbons (PAHs). Based on data between 1990 and 2019 in the Air Quality System, we identified 76 unique events that had PAH measurements on both July 4th days and control days (within 15 days before and after July 4th). We compared concentrations and diagnostic ratios of 16 priority PAHs between event and control days using Wilcoxon signed-rank tests and multivariable regressions. A local PAH monitoring campaign was conducted at eight sites in Memphis, Tennessee, to obtain a close observation of PAH changes. The national geometric mean (GM) concentrations of summed 16 PAHs (ΣPAHs) were similar between event and control days (48.1 ng/m3 vs. 52.8 ng/m3, p = 0.98). About a quarter of events had elevated PAH concentrations compared with control days. Higher diagnostic ratios were found on event days, suggesting more contributions from fireworks sources. PAHs on July 4th were unlikely to cause acute or chronic health effects. While the local monitoring showed a 15% increase of ΣPAHs on July 4th, the difference was not significant (p = 0.62). Elevated PAH concentrations occurred at sites near fireworks sources and without major traffics, but did not occur at those in remote areas or near major interstate highways. In conclusion, this study finds that Independence Day fireworks have negligible impacts on atmospheric PAHs at the national level, and are unlikely to pose significant health risks. The firework effect is localized within a limited geographic scale, suggesting potential needs for local monitoring and control programs.

D-dimer assay to exclude pulmonary embolism in high-risk oncologic population: correlation with CT pulmonary angiography in an urgent care setting.

PURPOSE: To prospectively evaluate (a) the diagnostic performance of D-dimer assay for pulmonary embolism (PE) in an oncologic population by using computed tomographic (CT) pulmonary angiography as the reference standard, (b) the association between PE location and assay sensitivity, and (c) the association between assay results and clinical factors that raise suspicion of PE. MATERIALS AND METHODS: This HIPAA-compliant study had institutional review board approval; informed consent was obtained. Five hundred thirty-one consecutive patients were clinically suspected of having PE; 201 were enrolled (72 men, 129 women; median age, 61 years) and underwent CT pulmonary angiography and D-dimer assay. Relevant clinical history, symptoms, and signs were recorded. CT images were interpreted, and the location of emboli was recorded. The negative predictive value (NPV), positive predictive value (PPV), sensitivity, specificity, and diagnostic likelihood ratios of the D-dimer assay results were calculated. RESULTS: Forty-three patients (21%) had pulmonary emboli at CT. D-Dimer results were positive in 171 patents (85%). The NPV and sensitivity were 97% and 98%, respectively. The specificity and PPV were 18% and 25%, respectively. No association was shown between clinical history, symptoms, or signs and NPV, PPV, sensitivity, or specificity or between location of PE and sensitivity. CONCLUSION: D-Dimer results have high NPV and sensitivity for PE in oncologic patients and, if negative, can be used to exclude PE in this population. Combining the assay with clinical symptoms and signs did not substantially change NPV, PPV, sensitivity, or specificity.

Paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal stem cell disorder resulting from a somatic mutation in the hematopoietic stem cell. It is characterized by intravascular hemolysis, cytopenias, frequent infections, bone marrow hypoplasia, and a high incidence of life-threatening venous thrombosis. An absent glycosylphosphatidylinositol (GPI)-anchored receptor prevents several proteins from binding to the erythrocyte membrane. These include the complement-regulatory proteins, CD55 and CD59, whose absence results in enhanced complement-mediated lysis. Patients present with anemia and hemoglobinuria. Laboratory diagnosis includes the sucrose hemolysis test, Ham acid hemolysis test, and fluorescent-activated cell analysis. There is considerable overlap between PNH, aplastic anemia, and myelodysplastic syndrome and some cases evolve into acute leukemia. Treatment is mainly supportive consisting of transfusion therapy, anticoagulation, and antibiotic therapy. Hematopoietic stem cell transplantation may be curative.

Performance of a new, rapid, automated immunoassay for the detection of anti-platelet factor 4/heparin complex antibodies.

Heparin-induced thrombocytopenia (HIT) is a life-threatening adverse reaction to heparin that must be identified quickly to determine appropriate anticoagulant therapy strategies. The most common antibodies involved in HIT are directed against platelet factor 4/heparin (PF4/H) complexes. Many methods for anti-PF4/H detection exist such as enzyme immunoassays (EIAs), which have been shown to exhibit high-negative predictive value allowing for the exclusion of HIT in the majority of suspected patients; however, most EIAs are performed in a batch mode, thereby delaying results to the physician. HemosIL HIT-Ab(PF4-H) is a new, rapid method for the detection of total immunoglobulin against PF4/H complexes on ACL TOP Family systems. The assay was evaluated in a multicentre study at three sites with 414 HIT-suspected patients. Using a cut-off value of 1.0 U/ml for HemosIL HIT-Ab(PF4-H), the new test was compared with Asserachrom HPIA. Results showed a co-positivity of 60.2% [95% confidence interval (CI) 48.9-70.8], co-negativity of 94.6% (95% CI 91.5-96.7), and overall agreement of 87.7% (95% CI 84.1-90.7). These results are comparable to other PF4/H antibody assays available; with the added benefit of full automation and on-demand testing which provides results at the critical moment when physicians are required to make clinical decisions regarding anticoagulant therapy.