A diet-wide Mendelian randomization analysis: causal effects of dietary habits on type 2 diabetes.

Background: Traditional clinical studies have indicated a link between certain food intakes and type 2 diabetes (T2D), but the causal relationships between different dietary habits and T2D remain unknown. Using Mendelian randomization (MR) approaches, we investigated the potential causal association between dietary habits and T2D risk. Methods: We collected publicly available genome-wide association studies' summary statistics for 18 dietary habits from the UK Biobank and T2D data from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium. We applied the inverse variance weighted (IVW) method, supplemented with the MR-Egger method, weighted median method (WMM), simple method, weighted mode, MR-Egger regression, and the MR pleiotropy residual sum and outlier test to determine whether a particular diet was causal for T2D. Results: Reliable and robust MR estimates demonstrated that poultry intake has a causal effect on a higher risk of T2D (IVW: OR 6.30, 95% CI 3.573-11.11, p = 2.02e - 10; WMM: OR 5.479, 95% CI 0.2758-10.88, p = 1.19e - 06). Conversely, dried fruit intake (IVW: OR 0.380, 95% CI 0.237-0.608, p = 5.57e - 05; WMM: OR 0.450, 95% CI 0.321-0.630, p = 3.33e - 06) and cereal intake (IVW: OR 0.455, 95% CI 0.317-0.653, p = 1.924e - 05; WMM: OR 0.513, 95% CI 0.379-0.694, p = 1.514e - 05) were causally associated with T2D as protective factors. Sensitivity analyses confirmed the reliability and robustness of these findings. Discussion: Our study established the causal effects of poultry intake, dried fruit intake, and cereal intake on T2D, identifying poultry intake as a risk factor and the other two as protective factors. Further research into potential mechanisms is required to validate these novel findings.

Changes in the Antimicrobial Resistance and Bacterial Epidemiology of Moraxella catarrhalis from Pediatric Community-Acquired Pneumonia Patients During the COVID-19 Pandemic: A 5-Year Study at a Tertiary Hospital of Southwest China.

This study aimed to assess the impact of the COVID-19 pandemic on Moraxella catarrhalis infections in pediatric patients hospitalized with community-acquired pneumonia (CAP). The epidemiological features and antimicrobial resistance (AMR) patterns of M. catarrhalis were compared between the pre-pandemic period (2018-2019) and during the pandemic (2020-2022). The results revealed a marked increase in the positivity rate of M. catarrhalis in 2020 and 2021 compared with the pre-pandemic years. The median age of the patients increased significantly in 2021 and 2022, while the proportion of male patients decreased substantially from 2019 to 2021. In addition, there were notable changes in the co-infections of Haemophilus influenzae, parainfluenza virus, and respiratory syncytial virus during the COVID-19 pandemic. The AMR profile of M. catarrhalis also changed significantly, showing increased resistance to ampicillin, but decreased resistance to trimethoprim-sulfamethoxazole and ofloxacin, and a lower proportion of multidrug-resistant isolates. Notably, ampicillin resistance increased among ß-lactamase-producing isolates. Before the pandemic, the number and detection rate of isolates, along with resistance to ampicillin and trimethoprim-sulfamethoxazole, were seasonally distributed, peaking in autumn and winter. However, coinciding with local COVID-19 outbreaks, these indices sharply fell in February 2020, and the number of isolates did not recover during the autumn and winter of 2022. These findings indicate that the COVID-19 pandemic has significantly altered the infection landscape of M. catarrhalis in pediatric CAP patients, as evidenced by shifts in the detection rate, demographic characteristics, respiratory co-infections, AMR profiles, and seasonal patterns.

p110CUX1 promotes acute myeloid leukemia progression via regulating pyridoxal phosphatase expression and activating PI3K/AKT/mTOR signaling pathway.

As an evolutionarily conserved transcription factor, Cut-like homeobox 1 (CUX1) plays crucial roles in embryonic and nervous system development, cell differentiation, and DNA damage repair. One of its major isoforms, p110CUX1, exhibits stable DNA binding capabilities and contributes to the regulation of cell cycle progression, proliferation, migration, and invasion. While p110CUX1 has been implicated in the progression of various malignant tumors, its involvement in acute myeloid leukemia (AML) remains uncertain. This study aims to elucidate the role of p110CUX1 in AML. Our findings reveal heightened expression levels of both p110CUX1 and pyridoxal phosphatase (PDXP) in AML cell lines. Overexpression of p110CUX1 promotes AML cell proliferation while inhibiting apoptosis and differentiation, whereas knockdown of PDXP yields contrasting effects. Mechanistically, p110CUX1 appears to facilitate AML development by upregulating PDXP expression and activating the PI3K/AKT/mTOR signaling pathway. Animal experimental corroborate the pro-AML effect of p110CUX1. These results provide experimental evidence supporting the involvement of the p110CUX1-PDXP-PI3K/AKT/mTOR axis in AML progression. Hence, targeting p110CUX1 may hold promise as a therapeutic strategy for AML.

The impact of the COVID-19 pandemic on Staphylococcus aureus infections in pediatric patients admitted with community acquired pneumonia.

The COVID-19 pandemic has significantly transformed the infection spectrum of various pathogens. This study aimed to evaluate the impact of the COVID-19 pandemic on Staphylococcus aureus (S. aureus) infections among pediatric patients with community acquired pneumonia (CAP). We retrospectively reviewed pediatric CAP admissions before (from 2018 to 2019) and during (from 2020 to 2022) the COVID-19 pandemic. The epidemiology and antimicrobial resistance (AMR) profiles of S. aureus isolates were examined to assess the pandemic's effect. As a result, a total of 399 pediatric CAP patients with S. aureus infections were included. The positivity rate, gender, and age distribution of patients were similar across both periods. There was a marked reduction in respiratory co-infections with Haemophilus influenzae (H. influenzae) during the COVID-19 pandemic, compared to 2019. Additionally, there were significant changes in the resistance profiles of S. aureus isolates to various antibiotics. Resistance to oxacillin and tetracycline increased, whereas resistance to penicillin, gentamicin, and quinolones decreased. Notably, resistance to erythromycin significantly decreased in methicillin-resistant S. aureus (MRSA) strains. The number of S. aureus isolates, the proportion of viral co-infections, and the number of resistant strains typically peaked seasonally, primarily in the first or fourth quarters of 2018, 2019, and 2021. However, shifts in these patterns were noted in the first quarter of 2020 and the fourth quarter of 2022. These findings reveal that the COVID-19 pandemic has significantly altered the infection dynamics of S. aureus among pediatric CAP patients, as evidenced by changes in respiratory co-infections, AMR patterns, and seasonal trends.

Changes in the epidemiology and antimicrobial resistance patterns of Streptococcus pneumoniae from pediatric community acquired pneumonia patients attended in a Chinese hospital during the COVID-19 pandemic.

PURPOSE: The COVID-19 pandemic has altered the infection dynamics of numerous pathogens. This study aimed to elucidate its impact on Streptococcus pneumoniae (S. pneumoniae) infections in children with community acquired pneumonia (CAP). METHODS: A retrospective analysis was conducted in pediatric CAP patients admitted before (2018-2019) and during (2020-2022) the COVID-19 pandemic. The epidemiology and antimicrobial resistance (AMR) patterns of S. pneumoniae were compared to reveal the impact of the pandemic. RESULTS: A total of 968 S. pneumoniae-associated pediatric CAP patients were enrolled. Although the positivity rate and gender of patients were stable across both periods, the age notably increased in 2021 and 2022. Additionally, significant changes were observed in the co-infections with several pathogens and the resistance rates to certain antibiotics during the COVID-19 pandemic. The resistance rate to clindamycin and quinupristin-dalfopristin increased, whereas the resistance rate to tetracycline, trimethoprim-sulfamethoxazole, telithromycin, and proportion of multi-drug resistant isolates decreased. The number of S. pneumoniae strains and resistant isolates exhibited similar seasonal patterns in 2018 and 2019, peaking in November or December with another minor peak in March or April. During the COVID-19 pandemic, there was a sharp decrease in February 2020 and no resurgence was observed at the end of 2022. Additionally, the minor peak was absent in 2020 and shifted to other months in 2021 and 2022. CONCLUSIONS: The COVID-19 pandemic has markedly altered the infection spectrum of S. pneumoniae in pediatric CAP patients, as evidenced by shifts in the age of patients, respiratory co-infections, AMR patterns, and seasonal trends.

Impact of the COVID-19 pandemic on Haemophilus influenzae infections in pediatric patients hospitalized with community acquired pneumonia.

The COVID-19 pandemic has altered the infection landscape for many pathogens. This retrospective study aimed to compare Haemophilus influenzae (H. influenzae) infections in pediatric CAP patients hospitalized before (2018-2019) and during (2020-2022) the COVID-19 pandemic. We analyzed the clinical epidemiology and antimicrobial resistance (AMR) patterns of H. influenzae from a tertiary hospital in southwest China. A total of 986 pediatric CAP patients with H. influenzae-associated infections were included. Compared to 2018, the positivity rate increased in 2019 but dropped significantly in 2020. Although it rose in the following 2 years, the rate in 2022 remained significantly lower than in 2019. Patients' age during the pandemic was significantly higher than in 2018 and 2019, while gender composition remained similar across both periods. Notably, there were significant changes in co-infections with several respiratory pathogens during the pandemic. Resistance rates of H. influenzae isolates to antibiotics varied, with the highest resistance observed for ampicillin (85.9%) and the lowest for cefotaxime (0.0%). Resistance profiles to various antibiotics underwent dramatic changes during the COVID-19 pandemic. Resistance to amoxicillin-clavulanate, cefaclor, cefuroxime, trimethoprim-sulfamethoxazole, and the proportion of multi-drug resistant (MDR) isolates significantly decreased. Additionally, MDR isolates, alongside isolates resistant to specific drugs, were notably prevalent in ampicillin-resistant and ß-lactamase-positive isolates. The number of pediatric CAP patients, H. influenzae infections, and isolates resistant to certain antibiotics exhibited seasonal patterns, peaking in the winter of 2018 and 2019. During the COVID-19 pandemic, sharp decreases were observed in February 2020, and there was no resurgence in December 2022. These findings indicate that the COVID-19 pandemic has significantly altered the infection spectrum of H. influenzae in pediatric CAP patients, as evidenced by shifts in positivity rate, demographic characteristics, respiratory co-infections, AMR patterns, and seasonal trends.

Lysosome-related genes predict acute myeloid leukemia prognosis and response to immunotherapy.

Background: Acute myeloid leukemia (AML) is a highly aggressive and pathogenic hematologic malignancy with consistently high mortality. Lysosomes are organelles involved in cell growth and metabolism that fuse to form specialized Auer rods in AML, and their role in AML has not been elucidated. This study aimed to identify AML subtypes centered on lysosome-related genes and to construct a prognostic model to guide individualized treatment of AML. Methods: Gene expression data and clinical data from AML patients were downloaded from two high-throughput sequencing platforms. The 191 lysosomal signature genes were obtained from the database MsigDB. Lysosomal clusters were identified by unsupervised consensus clustering. The differences in molecular expression, biological processes, and the immune microenvironment among lysosomal clusters were subsequently analyzed. Based on the molecular expression differences between lysosomal clusters, lysosomal-related genes affecting AML prognosis were screened by univariate cox regression and multivariate cox regression analyses. Algorithms for LASSO regression analyses were employed to construct prognostic models. The risk factor distribution, KM survival curve, was applied to evaluate the survival distribution of the model. Time-dependent ROC curves, nomograms and calibration curves were used to evaluate the predictive performance of the prognostic models. TIDE scores and drug sensitivity analyses were used to explore the implication of the model for AML treatment. Results: Our study identified two lysosomal clusters, cluster1 has longer survival time and stronger immune infiltration compared to cluster2. The differences in biological processes between the two lysosomal clusters are mainly manifested in the lysosomes, vesicles, immune cell function, and apoptosis. The prognostic model consisting of six prognosis-related genes was constructed. The prognostic model showed good predictive performance in all three data sets. Patients in the low-risk group survived significantly longer than those in the high-risk group and had higher immune infiltration and stronger response to immunotherapy. Patients in the high-risk group showed greater sensitivity to cytarabine, imatinib, and bortezomib, but lower sensitivity to ATRA compared to low -risk patients. Conclusion: Our prognostic model based on lysosome-related genes can effectively predict the prognosis of AML patients and provide reference evidence for individualized immunotherapy and pharmacological chemotherapy for AML.

p200CUX1-regulated BMP8B inhibits the progression of acute myeloid leukemia via the MAPK signaling pathway.

The full-length p200CUX1 protein encoded by the homology frame CUT-like protein (CUX1) plays an important role in tumors as a pro-oncogene or oncogene. However, its role and mechanism in acute myeloid leukemia remain unknown. p200CUX1 regulates several pathways, including the MAPK signaling pathway. Our data showed that p200CUX1 is lowly expressed in THP1 and U937 AML cell lines. Lentiviral overexpression of p200CUX1 reduced proliferation and promoted apoptosis and G0/G1 phase blockade, correlating with MAPK pathway suppression. Additionally, p200CUX1 regulated the expression of bone morphogenetic protein 8B (BMP8B), which is overexpressed in AML. Overexpression of p200CUX1 downregulated BMP8B expression and inhibited the MAPK pathway. Furthermore, BMP8B knockdown inhibited AML cell proliferation, enhanced apoptosis and the sensitivity of ATRA-induced cell differentiation, and blocked G0/G1 transition. Our findings demonstrate the pivotal function of the p200CUX1-BMP8B-MAPK axis in maintaining the viability of AML cells. Consequently, targeting p200CUX1 could represent a viable strategy in AML therapy.

Comparison of Mycoplasma pneumoniae infection in children admitted with community acquired pneumonia before and during the COVID-19 pandemic: a retrospective study at a tertiary hospital of southwest China.

PURPOSE: The COVID-19 pandemic has notably altered the infection dynamics of various pathogens. This study aimed to evaluate the pandemic's impact on the infection spectrum of Mycoplasma pneumoniae (M. pneumoniae) among children with community acquired pneumonia (CAP). METHODS: We enrolled pediatric CAP patients admitted to a tertiary hospital in southwest China to compare the prevalence and characteristics of M. pneumoniae infections before (2018-2019) and during (2020-2022) the COVID-19 pandemic. Detection of M. pneumoniae IgM antibodies in serum were conducted using either indirect immunofluorescence or passive agglutination methods. RESULTS: The study included 1505 M. pneumoniae-positive and 3160 M. pneumoniae-negative CAP patients. Notable findings were the higher age and frequency of pneumonia-associated symptoms in M. pneumoniae-positive patients, alongside a lower male proportion and fewer respiratory co-infections. The year 2019 saw a notable increase in M. pneumoniae infections compared to 2018, followed by a decline from 2020 to 2022. The COVID-19 pandemic period witnessed significant alterations in age distribution, male proportion, and co-infections with specific pathogens in both M. pneumoniae-positive and negative patients. The M. pneumoniae infections were predominantly seasonal, peaking in autumn and winter during 2018 and 2019. Although there was a sharp drop in February 2020, the infection still peaked in cold months of 2020 and 2021. However, the typical seasonal pattern was nearly absent in 2022. CONCLUSIONS: The COVID-19 pandemic has markedly changed the infection landscape of M. pneumoniae in pediatric CAP patients, with shifts observed in infection rates, demographic profiles, co-infections, and seasonal patterns.

A Mendelian randomization study: physical activities and chronic kidney disease.

Increasing evidence has shown that physical activity is related to a lower risk of chronic kidney disease (CKD), thus indicating a potential target for prevention. However, the causality is not clear; specifically, physical activity may protect against CKD, and CKD may lead to a reduction in physical activity. Our study examined the potential bidirectional relationship between physical activity and CKD by using a genetically informed method. Genome-wide association studies from the UK Biobank baseline data were used for physical activity phenotypes and included 460,376 participants. For kidney function (estimated Glomerular Filtration Rate (eGFR) and CKD, with eGFR < 60 mL/min/1.73 m2), CKDGen Consortium data were used, which included 480,698 CKD participants of European ancestry. Mendelian randomization (MR) analysis was used to determine the causal relationship between physical activities and kidney function. Two-sample MR genetically predicted that heavy DIY (do it yourself) (e.g., weeding, lawn mowing, carpentry, and digging) decreased the risk of CKD (odds ratio [OR] = 0.287, 95% CI = 0.117-0.705, p = 0.0065) and improved the level of eGFR (ß = 0.036, 95% CI = 0.005-0.067, p = 0.021). The bidirectional MR showed no reverse causality. It is worth noting that other physical activities, such as walking for pleasure, strenuous sports, light DIY (e.g., pruning and watering the lawn), and other exercises (e.g., swimming, cycling, keeping fit, and bowling), were not significantly correlated with CKD and eGFR. This study used genetic data to provide reliable and robust causal evidence that heavy physical activity (e.g., weeding, lawn mowing, carpentry, and digging) can protect kidney function and further lower the risk of CKD.

Ultrasensitive detection of genetic variation based on dual signal amplification assisted by isothermal amplification and cobalt oxyhydroxide nanosheets/quantum dots.

PML/RARα fusion gene (P/R) is the characteristic signature genetic variation of acute promyelocytic leukemia (APL). Here, by integrating triple-stranded DNA hybridization-triggered strand displacement amplification (tri-HT SDA) and cobalt oxyhydroxide nanosheets/quantum dots (CoOOH/QD)-based amplification, we constructed a novel biosensor of easy-operating, time-saving and high sensitivity for detecting P/R to meet clinical needs. Owing to the specific recognition and efficient amplification of tri-HT SDA as well as impressive anti-interference and considerable amplification of CoOOH/QD, this biosensor demonstrated a wide dynamic range (10 fM to 10 nM) with a low limit of detection (5.50 fM) in P/R detection. Additionally, this biosensor could detect P/R spiked into human serum with good recoveries and relative standard deviation (RSD), thus potentially exhibiting ultrasensitive and specific nuclear acid sequence detection ability in clinical diagnosis owing to combing isothermal amplification and nanomaterials.

HDAC11 mediates the ubiquitin-dependent degradation of p53 and inhibits the anti-leukemia effect of PD0166285.

Cytarabine-resistant acute myeloid leukemia (AML) is a common phenomenon, necessitating the search for new chemotherapeutics. WEE1 participates in cell cycle checkpoint signaling and inhibitors targeting WEE1 (WEE1i) constitute a potential novel strategy for AML treatment. HDAC (histone deacetylase) inhibitors have been shown to enhance the anti-tumor effects of WEE1i but molecular mechanisms of HDAC remain poorly characterized. In this study, the WEE1 inhibitor PD0166285 showed a relatively good anti-leukemia effect. Notably, PD0166285 can arise the expression of HDAC11 which was negatively correlated with survival of AML patients. Moreover, HDAC11 can reduced the anti-tumor effect of PD0166285 through an effect on p53 stability and the changes in phosphorylation levels of MAPK pathways. Overall, the cell cycle inhibitor, PD0166285, is a potential chemotherapeutic drug for AML. These fundings contribute to a functional understanding of HDAC11 in AML.

Global and local fat effects on bone mass and quality in obesity.

Aims: The aim of this study was to investigate the global and local impact of fat on bone in obesity by using the diet-induced obese (DIO) mouse model. Methods: In this study, we generated a diet-induced mouse model of obesity to conduct lipidomic and 3D imaging assessments of bone marrow fat, and evaluated the correlated bone adaptation indices and bone mechanical properties. Results: Our results indicated that bone mass was reduced and bone mechanical properties were impaired in DIO mice. Lipidomic sequencing and bioinformatic analysis identified 373 differential lipids, 176 of which were upregulated and 197 downregulated. Functional enrichment analysis revealed a significant downregulation of the pathways: fat digestion and absorption (ko04975) and lipolysis regulation in adipocytes (ko04923) in DIO mice, leading to local fat accumulation. The use of 3D imaging confirmed the increase in fat accumulation within the bone marrow cavity of obese mice. Conclusion: Our study sheds light on the intricate interplay between fat and bone, and provides a non-toxic and non-invasive method for measuring marrow adipose tissue.

Enzyme-free dual amplification biosensor based on functional nucleic acid and CDs/CoOOH for detection of leukemia fusion gene.

Acute promyelocytic leukemia (APL) is an acute myeloid leukemia (AML) with a specific fusion gene target, PML/RARα fusion gene (PML/RARα), which is formed by the translocation of chromosomes 15 and 17. Detection of PML/RARα is the most reliable parameter for the diagnosis, treatment adjustment, efficacy evaluation, prognosis analysis and relapse prediction of APL. In this study, a novel biosensor was constructed for rapid enzyme-free detection of PML/RARα using DNAzyme and carbon dots/cobalt oxhydroxide nanosheet complexs (CDs/CoOOH). In the detection system, the separated DNAzymes could specifically recognize and bind together by the PML/RARα to form a complete DNAzyme for shearing hairpin probe (HP), then generated trigger, which was the first signal amplification. Then, trigger could hybridize with the capture probe (CP) anchored to streptavidin (SA) modified microplate as well as fluorescence quenching signal probe (SP@CDs/CoOOH). Finally, ascorbic acid (AA) was added to decompose CoOOH and the fluorescence of CDs was released, which was the second signal amplification. Through the dual signal amplification of DNAzyme and CDs/CoOOH, PML/RARα could be detected quickly and sensitively, which overcame the limitation of protein enzyme in traditional fluorescence methods, showing potential clinical application value in the diagnosis and treatment of leukemia.

MiR-454-3p promotes apoptosis and autophagy of AML cells by targeting ZEB2 and regulating AKT/mTOR pathway.

BACKGROUND: miR-454-3p is considered to have a crucial role in cancer progression, but the potential involvement in acute myeloid leukemia (AML) remains unclear. METHODS: Expression of miR-454-3p and ZEB2 mRNA and protein were quantified in AML cell lines. Cells were transfected with miR-454-3p inhibitor or mimic and cell growth was assessed by colony formation and CCK-8 assays and the cell cycle, apoptosis and autophagy were investigated by Western blotting, flow cytometry, immunofluorescence and 3-methyladenine (3-MA) treatment. RESULTS: miR-454-3p expression was attenuated in AML cells. miR-454-3p overexpression attenuated cell growth and stimulated cell cycle arrest, apoptosis and autophagy. Dual-luciferase reporter assays and bioinformatics analysis showed that AML progression was inhibited when miR-454-3p regulated ZEB2, an effect confirmed by rescue assays. 3-MA reduced the autophagy-inducing effect of ZEB2 knockdown and indicated that autophagy induced apoptosis. miR-454-3p downregulated p-mTOR/p-AKT levels in AML cells. CONCLUSION: The novel role of miR-454-3p as a tumor inhibitor in AML via regulation of the ZEB2/AKT/mTOR axis was demonstrated, indicating miR-454-3p as a potential new molecular target for AML.

Polymorphism in genes encoding two fatty acid binding proteins increases risk of ischemic stroke in a Chinese Han population.

Background: Dyslipidemia is an independent predictor of ischemic stroke (IS). Genetic variations in lipid-metabolism related genes may increase the risk of IS. Fatty acid-binding protein 1 (FABP1) and fatty acid-binding protein 2 (FABP2) are lipid chaperones responsible for lipid transport and metabolism. The present study aimed to determine the association between FABP1 or FABP2 and ischemic stroke. Methods: A total of 251 participants were recruited composed of 138 patients with ischemic stroke and 113 healthy subjects. DNA was extracted from peripheral blood samples. The rs2241883 polymorphism in FABP1 and rs1799883 polymorphism in FABP2 were genotyped using polymerase chain reaction-restriction fragment length polymorphism. Generalized multifactor dimensionality reduction (GMDR) was used to find out the interaction combinations between two SNPs and environmental factors. Results: The GA genotype of FABP2 rs1799883 increased susceptibility to ischemic stroke under overdominant inheritance model (p = 0.042). After adjusting for the risk factors of IS, it was associated with a significantly higher risk of IS in the codominant inheritance model (adjust OR = 3.431, 95%CI = 1.060-11.103, p = 0.04). The interactions of FABP1 rs2241883 and FABP2 rs1799883 were not associated with IS risk (p = 0.172). Moreover, interaction analysis of two genes (rs1799883 and rs2241883) and two environmental factors (smoking and alcohol consumption) was associated with an increased risk of IS (p = 0.011). Conclusion: The GA genotype of FABP2 rs1799883, interactions between rs1799883, rs2241883 and smoking and alcohol consumption were associated with IS risk in Chinese Han populations.

ZNF460-regulated COMMD7 Promotes Acute Myeloid Leukemia Proliferation Via the NF-κB Signaling Pathway.

Acute myeloid leukemia (AML) is a malignancy of the hematological system, for which there remains an urgent need for new therapeutic and diagnostic targets. COMM domain containing 7 (COMMD7) is a recently-identified oncogene linked to poor prognosis in AML. COMMD7 regulates multiple signaling pathways, including nuclear factor-kappa B (NF-κB) signaling. Here, we report that COMMD7 is highly expressed in the AML cell lines KG1a and U937 and that its inhibition by shRNA reduced proliferation, promoted apoptosis and facilitated cell cycle arrest in the G2/M phase in relation to depression of the NF-κB pathway. Furthermore, zinc finger protein 460 (ZNF460) is overexpressed in AML and regulates COMMD7. We found that knockdown of ZNF460 downregulated the expression of COMMD7 while the NF-κB pathway was also inhibited. In addition, we noticed that knockdown of ZNF460 reduced proliferation and increased apoptosis rate of AML cells and that the cell cycle was blocked in the G2/M phase. In brief, our results revealed a critical effect of the ZNF460-COMMD7-NF-κB axis for the proliferation of AML cells. Therefore, COMMD7 may be a possible therapeutic target for AML.

Downregulation of Polo-like kinase 4 induces cell apoptosis and G2/M arrest in acute myeloid leukemia.

BACKGROUND: Polo-like kinase 4 (PLK4) is a crucial regulator for centriole replication and is reported to be aberrantly expressed in various cancers, where it participates to tumorigenesis. However, PLK4 effect in acute myeloid leukemia (AML), is still uncertain. This study investigates the function of PLK4 in AML. METHODS: Quantitative real-time PCR was used to measure the level of PLK4. Centrinone, a selective PLK4 small molecule inhibitor, was used for PLK4 inhibition and explore its effect in AML cells. The cell growth was detected by the CCK8, while the cell cycle and apoptosis were assessed by flow cytometry. The level of proteins associated with apoptosis, cell cycle and endoplasmic reticulum (ER) stress were analyzed by western blotting. RESULTS: PLK4 was overexpressed in AML cells. PLK4 knockdown or its specific inhibition by centrinone induced G2/M phase arrest via suppressing the expression of cyclin B1 and Cdc2 and promoting the level of proapoptotic proteins. Moreover, PLK4 targeting enhanced the level of proteins related to ER stress, such as GRP78, ATF4, ATF6, and CHOP. CONCLUSION: These findings demonstrated that targeting PLK4 can induce apoptosis, G2/M and ER stress in AML cells.

DNMT3A R882H mutation promotes acute leukemic cell survival by regulating glycolysis through the NRF2/NQO1 axis.

BACKGROUND: Studies have confirmed that acute myeloid leukemia (AML) cells with DNA methyltransferase 3A Arg882His (DNMT3A R882H) mutation show an increased proliferation capability. However, the associated mechanism is still unclear. Glycolysis is involved in regulating malignant proliferation of cancer cell. Hence, we analyzed whether the DNMT3A R882H mutation interferes with glycolysis and thereby influences AML cell proliferation. METHODS: We generated AML cell line carrying a DNMT3A-R882H mutation and compared it with the wild type (DNMT3A-WT) with regard to glycolysis regulation. Moreover, we analyzed the cell line's proliferation and apoptosis by a CCK-8 assay, western blotting, and flow cytometry. The role of NRF2/NQO1 signaling in regulating glycolysis was investigated by NRF2-knockdown and Brusatol (specific inhibitor of NRF2) treatment. RESULTS: DNMT3A R882H cells had a higher glucose transport capacity compared to WT cells and their viability could be reduced by glucose deprivation. Moreover, daunorubicin had a slight inhibitory effect on glycolysis while glycolysis inhibition re-sensitized mutant cells to daunorubicin. Obviously, DNMT3A R882H mutation activated the NRF2/NQO1 pathway and enhanced the glycolytic activity in mutant cells. CONCLUSION: Taken together, these results suggest a novel mechanism by which a DNMT3A R882H mutation promotes glycolysis via activation of NRF2/NQO1 pathway. A parallel glycolysis inhibition adds to the anticancer effects of daunorubicin which might lead to a novel therapeutic approach for the treatment of AML patients carrying a DNMT3A R882H mutation.

DNMT3A R882H mutation drives daunorubicin resistance in acute myeloid leukemia via regulating NRF2/NQO1 pathway.

BACKGROUND: DNA methyltransferase 3A (DNMT3A) often mutate on arginine 882 (DNMT3AR882) in acute myeloid leukemia (AML). AML patients with DNMT3A R882 mutation are usually resistant to daunorubicin treatment; however, the associated mechanism is still unclear. Therefore, it is urgent to investigate daunorubicin resistance in AML patients with DNMT3A R882 mutant. METHOD: AML cell lines with DNMT3A-wild type (DNMT3A-WT), and DNMT3A-Arg882His (DNMT3A-R882H) mutation were constructed to investigate the role of DNMT3A R882H mutation on cell proliferation, apoptosis and cells' sensitivity to Danunorubin. Bioinformatics was used to analyze the role of nuclear factor-E2-related factor (NRF2) in AML patients with DNMT3A R882 mutation. The regulatory mechanism of DNMT3A R882H mutation on NRF2 was studied by Bisulfite Sequencing and CO-IP. NRF2 inhibitor Brusatol (Bru) was used to explore the role of NRF2 in  AML cells carried DNMT3A R882H mutation. RESULTS: AML cells with a DNMT3A R882H mutation showed high proliferative and anti-apoptotic activities. In addition, mutant cells were less sensitive to daunorubicin and had a higher NRF2 expression compared with those in WT cells. Furthermore, the NRF2/NQO1 pathway was activated in mutant cells in response to daunorubicin treatment. DNMT3A R882H mutation regulated the expression of NRF2 via influencing protein stability rather than decreasing methylation of NRF2 promoter. Also, NRF2/NQO1 pathway inhibition improved mutant cells' sensitivity to daunorubicin significantly. CONCLUSION: Our findings identified NRF2 as an important player in the regulation of cell apoptosis through which helps mediate chemoresistance to daunorubicin in AML cells with DNMT3A R882H mutation. Targeting NRF2 might be a novel therapeutic approach to treat AML patients with a DNMT3A R882H mutation. Video abstract.