Abemaciclib drives the therapeutic differentiation of acute myeloid leukaemia stem cells.

Self-renewal and differentiation arrest are two features of leukaemia stem cells (LSCs) responsible for the high relapse rate of acute myeloid leukaemia (AML). To screen drugs to overcome differentiation blockade for AML, we conducted screening of 2040 small molecules from a library of United States Food and Drug Administration-approved drugs and found that the cyclin-dependent kinase (CDK)4/6 inhibitor, abemaciclib, exerts high anti-leukaemic activity. Abemaciclib significantly suppressed proliferation and promoted the differentiation of LSCs in vitro. Abemaciclib also efficiently induced differentiation and impaired self-renewal of LSCs, thus reducing the leukaemic cell burden and improving survival in various preclinical animal models, including patient-derived xenografts. Importantly, abemaciclib strongly enhanced anti-tumour effects in combination with venetoclax, a B-cell lymphoma 2 (Bcl-2) inhibitor. This treatment combination led to a marked decrease in LSC-enriched populations and resulted in a synergistic anti-leukaemic effect. Target screening revealed that in addition to CDK4/6, abemaciclib bound to and inhibited CDK9, consequently attenuating the protein levels of global p-Ser2 RNA Polymerase II (Pol II) carboxy terminal domain (CTD), Myc, Bcl-2, and myeloid cell leukaemia-1 (Mcl-1), which was important for the anti-AML effect of abemaciclib. Collectively, these data provide a strong rationale for the clinical evaluation of abemaciclib to induce LSC differentiation and treat highly aggressive AML as well as other advanced haematological malignancies.

Characteristics and model of sludge adhesion during thermal drying.

During sludge thermal drying, the sludge adhered on the heated surface of drying equipments may affect drying efficiency. Sludge thermal drying experiments were conducted to investigate the effect of different drying conditions on sludge adhesion. The mass of sludge adhered on the heated surface (dryer wall) reached the maximum when sludge water content was about 60%. A high drying temperature would result in more sludge adhered on the heated surface in the temperature range of 80-160 degrees C. The convection heating and rougher surface would also lead to more sludge adhered on the heated surface. The relation between the maximum mass of adherent sludge and drying temperatures could be described by an exponential equation.

Alkaline post-treatment for improved sludge anaerobic digestion.

Alkaline post-treatment was tested in order to improve sludge anaerobic digestion. Between the 8th and the 12th hour of a 24-h digestion cycle, 5% of sludge was extracted from a semi-continuous digester with a sludge retention time of 20 days. The sludge was then disintegrated with 0.1 mol/L NaOH and returned to the digester after neutralization. The results showed that alkaline post-treatment increased the level of soluble organic substances in the extracted sludge, particularly of volatile fatty acids and polysaccharides. This process resulted in a 33% enhancement of biogas production in comparison with the control. When the ratio of the recycled sludge was further increased to 10% or 15%, the increment of biogas yield was reduced, due to excessive inactivation of anaerobic bacteria in the digester. Alkaline post-treatment had a minimal impact on the dewaterability of digested sludge.

Optimized alkaline pretreatment of sludge before anaerobic digestion.

NaOH was used to disintegrate a mixture composed mainly of primary sludge with biofilm sludge before anaerobic digestion in batch experiments. NaOH pretreatment dissolved some organic substances, and the optimum dose was 0.1mol/L. After the alkali-treated sludge was fed into the digesters, the higher pH delayed the start of digestion and reduced the biogas production during the initial stage, although the system recovered after a lag phase when the dose was lower than 0.04mol/L. Acid conditioning was necessary, but the increased salinity also impacted on the digestion efficiency. For sludge pretreatment, the optimum NaOH dose was 0.1mol/L, and the initial pH of the batch digesters needs to be controlled at less than eight. Under optimized conditions, the organic degradation rate was 38.3% and the biogas yield was 0.65L/g volatile suspended solid (VSS), whereas these values for the control were 30.3% and 0.64L/g VSS, respectively.