Cabozantinib promotes erythroid differentiation in K562 erythroleukemia cells through global changes in gene expression and JNK activation.

Cabozantinib is a potent tyrosine kinase inhibitor with multiple targets including MET, VEGFR2, RET, KIT, and FLT3. Cabozantinib is widely used for the treatment of medullary thyroid cancer and renal cell carcinoma. We recently suggested cabozantinib as a potential therapeutic alternative for acute myeloid leukemia (AML) patients with FLT3-internal tandem duplication (FLT3-ITD). Here, we report that cabozantinib can promote differentiation in erythroid leukemia cells. We found that K562 erythroid leukemia cells treated with 1 µM cabozantinib for 72 h underwent erythroid lineage differentiation. Transcriptomic analysis revealed that various pathways associated with heme biosynthesis, hemoglobin production, and GATA1 targets were upregulated, whereas cell survival pathways were downregulated. Further examination revealed that cabozantinib-induced erythroid differentiation is at least in part regulated by JNK activation and phosphorylation. Levels of phosphorylated BCR-ABL, AKT, STAT5, ERK, and p38 also decreased following cabozantinib treatment. Therefore, we indicate that cabozantinib has dual functions. First, it induces K562 cell differentiation toward the erythroid lineage by upregulating heme biosynthesis, globin synthesis, and erythroid-associated reactions. Second, cabozantinib inhibits K562 cell proliferation by inhibiting the phosphorylation of BCR-ABL and the downstream MAPK, PI3K-AKT, and JAK-STAT signaling pathways.

Change in Urine Albumin-to-Creatinine Ratio and Risk of Diabetic Peripheral Neuropathy in Type 2 Diabetes: A Retrospective Cohort Study.

PURPOSE: This study aimed to assess association between change in urine albumin-to-creatinine ratio (UACR) and the risk of diabetic peripheral neuropathy (DPN) in type 2 diabetes mellitus. PATIENTS AND METHODS: A retrospective study was performed, which included 185 individuals with type 2 diabetes. At baseline, and at two-year follow-up, we collected basic data, recorded symptoms and signs of DPN, measured biochemical indicators, composite motor nerve conduction velocity (composite MCV), and composite sensory nerve conduction velocity (composite SCV). RESULTS: Changes of composite SCV, MCV and TCSS among different changes in UACR in patients without DPN and with DPN were not significantly different. An increase in UACR ≥30% (OR 3.059, 95%; CI: 1.012-9.249) suggested a risk for new-onset DPN. Based on ROC curve analysis, the areas under the curve were 0.654 ± 0.066 for change of UACR levels in non-DPN patients. CONCLUSION: Change in UACR and NCV was not related in patients without DPN and with DPN; change in UACR ≥30% suggested a risk for new-onset DPN.

A general strategy for diverse syntheses of anhydrolandomycinone, tetrangulol, and landomycinone.

A general synthetic strategy based on a protecting group-promoted CH arylation method was developed for total syntheses of anhydrolandomycinone (1), tetrangulol (2), and landomycinone (3) from the same set of starting materials.

Differential responses of soil nematode community to pig manure application levels in Ferric Acrisols.

Excessive pig manure application probably degrades arable soil quality in some intensive pig farming areas. The responses of the nematode community to dosages of pig manure were investigated in Ferric Acrisols under 3-season peanut monoculture. Varying dosages of manure (1.75, 3.5, 7, 14 and 28 t·ha-1·yr-1) in combination with chemical fertilizer were applied to field plots, and chemical fertilizer alone was also applied as a control. With increasing manure application, the abundance of bacterivores and omnivores-predators increased, the abundance of plant parasites decreased, and fungivores abundance exhibited hump-shaped variation. Simpson diversity index and plant parasite index/maturity index of the nematode communities increased to a maximum level at a manure application rate of 3.5 t·ha-1·yr-1 and then sharply decreased. The changes in the soil nematode community were further determined to be correlated with chemical properties; available phosphorus had the strongest quadratic correlation with the two indices, implying that available phosphorus had a better indicative effect than other soil properties to nematode community. Available phosphorus in soil was deduced from 49 to 64 mg·kg-1 with the best nematode communities. Our results emphasized the importance of regular applications of manure in agriculture field to balance nematode diversity and build healthy agro-ecosystems.