No abstract

While the aberrant translocation of the mixed-lineage leukemia (MLL) gene drives pathogenesis of acute myeloid leukemia (AML), it represents an independent predictor for poor prognosis of adult AML patients. Thus, small molecule inhibitors targeting menin-MLL fusion protein interaction have been emerging for the treatment of MLL-rearranged AML. As both inhibitors of histone deacetylase (HDAC) and menin-MLL interaction target the transcription-regulatory machinery involving epigenetic regulation of chromatin remodeling that governs the expression of genes involved in tumorigenesis, we hypothesized that these two classes of agents might interact to kill MLL-rearranged (MLL-r) AML cells. Here, we report that the combination treatment with subtoxic doses of the HDAC inhibitor chidamide and the menin-MLL interaction inhibitor MI-3 displayed a highly synergistic anti-tumor activity against human MLL-r AML cells in vitro and in vivo, but not those without this genetic aberration. Mechanistically, co-exposure to chidamide and MI-3 led to robust apoptosis in MLL-r AML cells, in association with loss of mitochondrial membrane potential and a sharp increase in ROS generation. Combined treatment also disrupted DNA damage checkpoint at the level of CHK1 and CHK2 kinases, rather than their upstream kinases (ATR and ATM), as well as DNA repair likely via homologous recombination (HR), but not non-homologous end joining (NHEJ). Genome-wide RNAseq revealed gene expression alterations involving several potential signaling pathways (e.g., cell cycle, DNA repair, MAPK, NF-κB) that might account for or contribute to the mechanisms of action underlying anti-leukemia activity of chidamide and MI-3 as a single agent and particularly in combination in MLL-r AML. Collectively, these findings provide a preclinical basis for further clinical investigation of this novel targeted strategy combining HDAC and Menin-MLL interaction inhibitors to improve therapeutic outcomes in a subset of patients with poor-prognostic MLL-r leukemia.

Vaccination is critical for controlling the COVID-19 pandemic. However, the progress of COVID-19 vaccination varies from different countries, and global vaccine inequity has been a worldwide public health issue. This study collected data from the Our World in Data COVID-19 vaccination data set between 13 December 2020 and 1 January 2022. The measurement reflecting the pandemic situation included New cases, New deaths, Hospital patients, ICU patients, and the Reproduction rate. Indicators for measuring the vaccination coverage included Total vaccinations per hundred and People vaccinated per hundred. The Human Development Index (HDI) measured the country’s development level. Findings indicated that countries with higher HDI have more adequate vaccine resources, and global vaccine inequity exists. The study also found that vaccination significantly mitigates the pandemic, and reaching 70% immunization coverage can further control the epidemic. In addition, the emergence of Omicron variants makes the COVID-19 epidemic situation even worse, suggesting the importance and necessity of addressing vaccine inequity. The globe will face a greater challenge in controlling the pandemic if lower-vaccinated countries do not increase their vaccination coverage. Addressing the issue of vaccine inequity needs the cooperation of HIC, LMIC, public health departments, and vaccine producers. Moreover, the media has to contribute to effective public health communication by raising public perceptions of the COVID-19 pandemic, vaccination, and vaccine inequity.

Aims Chronic heart failure (CHF) is often a common comorbidity in critically ill patients admitted to the intensive care unit (ICU) and carries an extremely poor prognosis. The study aimed to investigate the relationship between the blood urea nitrogen to serum albumin ratio (BAR) and the prognosis of patients with CHF admitted to the ICU. Methods and resultsThis retrospective cohort study included 1545 critically ill patients with CHF as a diagnosed comorbidity admitted to the ICU deposited in the MIMIC-III database, of whom 90 day all-cause mortality was 27.6% (n = 427) and in-hospital mortality was 17.3% (n = 267). The results of multiple logistic regression analysis indicated that BAR is an independent risk factor for in-hospital mortality in critically ill patients with CHF [compared with BAR ≤ 0.83; 0.83