Novel Oral Derivative UD-017, a Highly Selective CDK7 Inhibitor, Exhibits Anticancer Activity by Inducing Cell-Cycle Arrest and Apoptosis in Human Colorectal Cancer

Objective: This study aimed to investigate the anticancer profile of a new cyclin-dependent kinase 7 (CDK7) inhibitor, UD-017, by examining its mechanism of action using HCT-116 colorectal cancer cells. Methods: The anticancer properties of UD-017 were assessed using several assays, including in vitro kinase, proliferation, and apoptosis assays, western blot analysis, and an in vivo xenograft mouse model. Results: UD-017 significantly inhibited CDK7 activity (IC50 = 16 nM) with high selectivity in an in vitro kinase assay testing a panel of over 300 proteins and lipid kinases. UD-017 also inhibited the growth of HCT-116 cells (GI50 = 19 nM) and inhibited the phosphorylation of various downstream mediators of CDK7 signaling. In cell cycle and apoptosis assays using HCT-116 cells, UD-017 increased the number of cells in both G1 and G2/M phases and induced apoptosis. In vivo, UD-017 inhibited tumor growth in an HCT-116 xenograft mouse model by 33%, 64%, and 88% at doses of 25, 50, and 100 mg/kg, respectively, with clear dose-dependency. Co-administration of 5-FU and 50 mg/kg UD-017 had a strong synergistic effect, as reflected in the complete inhibition of tumor growth. Conclusion: CDK7 may play a major role in colorectal cancer growth by regulating the cell cycle and apoptosis. UD-017 is a promising candidate therapeutic agent for the treatment of cancer involving CDK7 signaling

Deposition of long-range transported particulate matter on the needle surfaces of Japanese cypress (Chamaecyparis obtusa) grown in Nagasaki located in the western region of Japan

To characterize the deposition of long-range transported particulate matter (PM) on the foliar surface of Japanese forest trees, we periodically collected the PM deposited on the needle surface of mature Japanese cypress (Chamaecyparis obtusa) grown in the mountainous area of Nagasaki located in the western region of Japan from 24 April to 30 October, 2017. Metal element compositions and concentration ratios along with the ratios of Pb isotopes in the PM were analyzed. The total amount of metal elements (Na, Mg, Al, K, Ca, V, Cr, Mn, Fe, Ni, Cu, Zn, As and Pb) on the needle surfaces was relatively low during summer and autumn but was high during the spring when there was high atmospheric concentration of PM with diameter less than 2.5 μm due to influence of outflow from Asian continent. The seasonal variations in the amounts of less-abundant metal elements (Al, V, Ni, Cu, Zn, As and Pb) exhibited similar trends. The Pb amount varied with Zn amount at a constant ratio of 0.4, which was close to the Pb /Zn ratio of PM in China. Most of the Pb isotope ratios ( 207 Pb/ 206 Pb and 208 Pb / 206 Pb) in the PM were close to those observed in the Chinese coal. Therefore, Pb on the needle could have originated from the coal combustion in China. The enrichment factor (EF) of Pb ranged from 650 to 2270, and was significantly correlated with the 207 Pb / 206 Pb ratios, suggesting that components having EFs of greater than 650 could have originated from anthropogenic source. The amount of Pb significantly correlated with that of Ni, Cu, Zn, and As, which showed EFs more than 650. These results indicate that the long-range transported PM, including Pb, Ni, Cu, Zn, and As, originated from the anthropogenic sources in China, and deposited on the needle of C. obtusa grown in Nagasaki

Development of a Prognostic Scoring System using MYC Expression and Soluble Interleukin Receptor -2 level for Diffuse Large B-cell Lymphoma

Background: Diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS), is the most frequent type of lymphoid neoplasm. Methods: We investigated the relationships between clinical factors of DLBCL-NOS and MYC immunohistochemistry (IHC) staining. Results: A total of 110 patients diagnosed with DLBCL-NOS from 2012 to 2020 at Tottori University Hospital and treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) chemotherapy were included. IHC staining of MYC in formalin-fixed, paraffin-embedded tumor specimens was performed, and ROC-curve analysis revealed the cut-off value of the MYC positive rate as 55%. The 2-year overall survival (OS) rates of the MYC-negative and -positive groups were 84.7% vs 57.7% (P = 0.0091), and the progression-free survival rates were 77.8% vs 54.7% (P = 0.016), respectively. Multivariate analysis for OS showed prognostic significance of MYC positivity [hazards ratio (HR): 2.496; P = 0.032], and serum levels of soluble interleukin-2 receptor (sIL-2R) > 2000 U/mL (HR: 3.950; P = 0.0019), as well as age > 75 (HR: 2.356; P = 0.068). The original scoring system was developed based on these findings. By assigning one point to each item, age (> 75), MYC positivity, and sIL-2R level (> 2000), all patients were classified into three risk categories: group 1 (0 points), group 2 (1 point), and group 3 (2–3 points). The 2-year survival rates were 100%, 83.0%, and 47.1% for the groups 1, 2, and 3, respectively (P < 0.0001). Conclusion: We suggest that a prognostic scoring system using MYC expression and soluble interleukin receptor -2 level is useful for the prediction of prognosis, contributing to further stratification in DLBCL-NOS