Cytogenetic abnormalities in NPM1-mutated acute myeloid leukemia.

NPM1mut acute myeloid leukemia (AML) has been identified as a distinct entity of myeloid neoplasms according to the 2017 European LeukemiaNet (ELN) guidelines. It confers a favorable prognosis regardless of cytogenetic abnormalities. We evaluated 418 newly diagnosed AML patients to test the validity of this hypothesis. Seventy-four patients with NPM1mut AML showed a good response to induction and a relatively favorable prognosis. Abnormal karyotypes were observed in 15 patients. Chromosomal abnormalities were significantly associated with a worse prognosis in NPM1mut AML patients (5-year overall survival (OS): 38.9 ± 12.9%, p = .037; event-free survival (EFS): 33.3 ± 12.2%, p = .043, respectively). Four patients with abnormal karyotypes who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT) during CR1 had longer survival than those who received chemotherapy only. Multivariable analysis revealed abnormal karyotypes independently predicted OS and EFS among NPM1mut AML patients. In summary, cytogenetic abnormalities are strong prognostic indicators in NPM1mut AML. Therefore, they should be classified accordingly, and alloHSCT should be performed on selected patients during CR1.

Glutamine synthetase facilitates cancer cells to recover from irradiation-induced G2/M arrest.

Resistance to radiation of cancer cells can be either intrinsic or acquired, leading to treatment failure. In response to DNA damage caused by IR, cancer cells are arrested in cell cycle showing limited proliferation and increased apoptosis. However, radiation-resistant cells are able to overcome the cell cycle block and proceed to proliferation, for which the detailed mechanism remains to be elucidated. In the present study, we showed that radioresistant cells exhibited a recoverable G2/M phase during prolonged cell cycle and manifested lower apoptosis rate and more colony formation. RNA-seq analysis revealed that glutamine synthetase (GS, GLUL) gene was highly expressed in radioresistant cancer cells in comparison with the parental cells, which was in accordance with the G2/M arrest after ionizing radiation. Knocking out of GS in radioresistant cells resulted in a delayed G2/M recovery and lowered proliferation rate after ionizing radiation treatment, which was accompanied with increased inhibitory phosphorylation of CDK1 at Y15 and downregulated Cdc25B, a dual specific phosphatase of CDK1. Moreover, there was an enhanced complex formation of CDK1 and Cyclin B1 when the cells were rescued by re-introducing GS. In vivo, knocking down of GS significantly sensitized CNE2-R xenografts to RT in mice. In this study, we demonstrate a novel role of glutamine synthetase independent of metabolic function in promoting recovery from G2/M arrest caused by ionizing radiation, thus, causing cancer cell resistance to radiotherapy.

Glutamine Synthetase Promotes Radiation Resistance via Facilitating Nucleotide Metabolism and Subsequent DNA Damage Repair.

Radiation resistance is a critical problem in radiotherapy for cancer. Radiation kills tumor cells mainly through causing DNA damage. Thus, efficiency of DNA damage repair is one of the most important factors that limits radiotherapy efficacy. Glutamine physiologically functions to generate protein and nucleotides. Here, we study the impact of glutamine metabolism on cancer therapeutic responses, in particular under irradiation-induced stress. We show that radiation-resistant cells possessed low glycolysis, mitochondrial respiration, and TCA cycle but high glutamine anabolism. Transcriptome analyses revealed that glutamine synthetase (GS), an enzyme catalyzing glutamate and ammonia to glutamine, was responsible for the metabolic alteration. ChIP and luciferase reporter assays revealed that GS could be transcriptionally regulated by STAT5. Knockdown of GS delayed DNA repair, weakened nucleotide metabolism, and enhanced radiosensitivity both in vitro and in vivo. Our data show that GS links glutamine metabolism to radiotherapy response through fueling nucleotide synthesis and accelerating DNA repair.

Adsorption of Cd(II), Cu(II) and Ni(II) ions by cross-linking chitosan/rectorite nano-hybrid composite microspheres.

Chitosan/rectorie (CTS/REC) nano-hybrid composite microsphere was prepared by changing the proportion of CTS/REC with 2:1, 3:1 and 4:1. Compared with the pure cross-linking chitosan microsphere, the nano-hybrid composite microsphere was proved to have better sorption capacity of Cd(II), Cu(II) and Ni(II), especially 2:1(CTS/REC-1). The adsorption behavior of the microsphere of Cd(II), Cu(II) and Ni(II) was investigated in single and binary metal systems. In single system, the equilibrium studies showed that the adsorption of Cd(II), Cu(II) and Ni(II) followed the Langmuir model and the pseudo-second-order kinetic model. The negative values of (ΔG) suggested that the adsorption process was spontaneous. In binary system, the combined action of the metals was found to be antagonistic and the metal sorption followed the order of Cu(II)>Cd(II)>Ni(II). The regeneration studies indicated that EDTA desorbed Cd(II), Cu(II) and Ni(II) from cross-linking microspheres better than HCl. The FT-IR and XPS spectra showed that coordination bonds were formed between Cd(II), Cu(II) and Ni(II) and the nitrogen atoms of cross-linking CTS/REC nano-hybrid composite microspheres.

Chitosan/organic rectorite composite for the magnetic uptake of methylene blue and methyl orange.

In this study, magnetic particles were prepared using organic rectorite as a carrier, and then a novel magnetic adsorbent named chitosan/organic rectorite-Fe3O4 intercalated composite microspheres (CS/Mt-OREC microspheres) was synthesized. The microspheres were characterized by XRD, FT-IR, TEM, SEM and VSM. The effects of adsorbent dosage, initial pH, contact time, temperatures, initial concentrations of methylene blue (MB) and methyl orange (MO) were studied. The adsorption process followed the pseudo-second-order kinetics, and the intra-particle diffusion was one but not the only rate-limiting step. The adsorption equilibrium data can be well described by Langmuir model. Thermodynamic parameters such as ΔG, ΔH, and ΔS were estimated to understand the adsorption mechanism of dyes. Moreover, CS/Mt-OREC microspheres were successfully regenerated using NaOH and HCl, and could be easily separated from aqueous solution in magnetic field.