A new cyclin-dependent kinase-9 inhibitor A09-003 induces apoptosis in acute myeloid leukemia cells with reduction of myeloid cell leukemia sequence-1 protein.

Acute myeloid leukemia (AML) is the most common type of hematological disease in adults, and has a very poor outcome [1]. Based on its wide range of efficacy in AML models, a small-molecule inhibitor of the anti-apoptotic protein BCL-2, venetoclax (ABT-199/GDC-0199), was developed for clinical trials. However, venetoclax showed limited monotherapy activity [2]. The overexpression of myeloid cell leukemia sequence-1 protein (Mcl-1)-due to mutations in Fms-like tyrosine kinase 3 internal tandem duplication (FLT-3 ITD)-was considered to be the main reason for low efficacy of venetoclax in clinical trials [3-5]. To achieve venetoclax sensitization in AML, targeting CDK-9 with venetoclax is a promising therapeutic strategy. In this study, we developed A09-003 as a potent inhibitor of CDK-9, with an IC50 value of 16 nM. A09-003 inhibited cell proliferation in various leukemia cell lines. In particular, the proliferation inhibitory effect of A09-003 was most potent in MV4-11 and Molm-14 cells, harboring the FLT-3 ITD mutation with a high expression profile of Mcl-1. Marker analysis revealed that A09-003 reduced CDK-9 phosphorylation and reduced RNA polymerase II activity with decreased Mcl-1 expression. Finally, combining A09-003 with venetoclax induced apoptotic cell death in a synergistic manner. In summary, this study shows the potential of A09-003 in AML therapy.

Growth, puberty, and bone health in children and adolescents with inflammatory bowel disease.

BACKGROUND: Endocrine complications such as impaired growth, delayed puberty, and low bone mineral density (BMD) can be associated with inflammatory bowel disease (IBD) in children and adolescents. This study was performed to investigate the frequency, characteristics, and outcomes of endocrine complications of IBD in children and adolescents. METHODS: This study included 127 patients with IBD diagnosed before 18 years of age [117 with Crohn disease (CD) and 10 with ulcerative colitis (UC)]. Growth profiles, pubertal status, 25-hydroxyvitamin D3 [25(OH)D3] levels, and BMD were reviewed retrospectively. RESULTS: Short stature was observed in 14 of 127 (11.0 %) with a mean height-SDS of -2.31 ± 0.72. During a 2-year follow-up period, height-SDS did not significantly improve, while weight-SDS significantly improved. Among 109 patients who were older than 13 (girls) or 14 (boys) years of age during the study period, 11 patients (10.1 %) showed delayed puberty, which was associated with low weight-SDS. Vitamin D deficiency was documented in 81.7 % (94/115) with the average 25(OH)D3 level of 14.5 ± 7.0 ng/mL. Lumbar BMD Z-score was below - 2 SDS in 25 of 119 patients (21.0 %). Height-SDS, weight-SDS, and body mass index (BMI)-SDS were lower in patients with osteoporosis than those without osteoporosis. When pediatric CD activity index scores were high (≥ 30), weight-SDS, BMI-SDS, insulin-like growth factor 1 (IGF-1)-SDS, and testosterone levels were significantly decreased. CONCLUSIONS: Vitamin D deficiency and osteoporosis are common in pediatric IBD patients. As disease severity deteriorates, weight-SDS, IGF-1-SDS, and testosterone levels were decreased. Optimal pubertal development is necessary for bone health.

SERS Effect on Spin-Coated Seeding of Tilted Au-ZnO Nanorods for Low-Cost Diagnosis.

Uniformly parallel Au-coated ZnO nanorods have previously been shown to amplify local Raman signals, providing increased sensitivity to disease markers in the detection of inflammation and cancer. However, practical and cost-effective fabrication methods of substrates for surface-enhanced Raman spectroscopy (SERS) fail to produce highly uniform surfaces. Here, the feasibility of Raman enhancement on less-uniform substrates is assessed. ZnO nanorod structures were fabricated by hydrothermal synthesis, starting from spin-coated seed substrates. Following analysis, the nanostructures were coated with Au to create stochastically variant substrates. The non-uniformity of the fabricated Au-coated ZnO nanorod structures is confirmed morphologically by FE-SEM and structurally by X-ray diffraction, and characterized by the angular distributions of the nanorods. Monte Carlo finite element method simulations matching the measured angular distributions and separations predicted only moderate increases in the overall Raman enhancement with increasing uniformity. Highly variant substrates exhibited approximately 76% of the Raman enhancement of more uniform substrates in simulations and experiments. The findings suggest that, although highly inhomogeneous Au-coated ZnO nanorod substrates may not attain the same Raman enhancement as more uniform substrates, the relaxation of fabrication tolerances may be economically viable.