Aging and comprehensive molecular profiling in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aging-related and heterogeneous hematopoietic malignancy. In this study, a total of 1,474 newly diagnosed AML patients with RNA sequencing data were enrolled, and targeted or whole exome sequencing data were obtained in 94% cases. The correlation of aging-related factors including age and clonal hematopoiesis (CH), gender, and genomic/transcriptomic profiles (gene fusions, genetic mutations, and gene expression networks or pathways) was systematically analyzed. Overall, AML patients aged 60 y and older showed an apparently dismal prognosis. Alongside age, the frequency of gene fusions defined in the World Health Organization classification decreased, while the positive rate of gene mutations, especially CH-related ones, increased. Additionally, the number of genetic mutations was higher in gene fusion-negative (GF-) patients than those with GF. Based on the status of CH- and myelodysplastic syndromes (MDS)-related mutations, three mutant subgroups were identified among the GF- AML cohort, namely, CH-AML, CH-MDS-AML, and other GF- AML. Notably, CH-MDS-AML demonstrated a predominance of elderly and male cases, cytopenia, and significantly adverse clinical outcomes. Besides, gene expression networks including HOXA/B, platelet factors, and inflammatory responses were most striking features associated with aging and poor prognosis in AML. Our work has thus unraveled the intricate regulatory circuitry of interactions among different age, gender, and molecular groups of AML.

Arsenic trioxide replacing or reducing chemotherapy in consolidation therapy for acute promyelocytic leukemia (APL2012 trial).

As all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are widely accepted in treating acute promyelocytic leukemia (APL), deescalating toxicity becomes a research hotspot. Here, we evaluated whether chemotherapy could be replaced or reduced by ATO in APL patients at different risks. After achieving complete remission with ATRA-ATO-based induction therapy, patients were randomized (1:1) into ATO and non-ATO groups for consolidation: ATRA-ATO versus ATRA-anthracycline for low-/intermediate-risk patients, or ATRA-ATO-anthracycline versus ATRA-anthracycline-cytarabine for high-risk patients. The primary end point was to assess disease-free survival (DFS) at 3 y by a noninferiority margin of -5%; 855 patients were enrolled with a median follow-up of 54.9 mo, and 658 of 755 patients could be evaluated at 3 y. In the ATO group, 96.1% (319/332) achieved 3-y DFS, compared to 92.6% (302/326) in the non-ATO group. The difference was 3.45% (95% CI -0.07 to 6.97), confirming noninferiority (P < 0.001). Using the Kaplan-Meier method, the estimated 7-y DFS was 95.7% (95% CI 93.6 to 97.9) in ATO and 92.6% (95% CI 89.8 to 95.4) in non-ATO groups (P = 0.066). Concerning secondary end points, the 7-y cumulative incidence of relapse (CIR) was significantly lower in ATO (2.2% [95% CI 1.1 to 4.2]) than in non-ATO group (6.1% [95% CI 3.9 to 9.5], P = 0.011). In addition, grade 3 to 4 hematological toxicities were significantly reduced in the ATO group during consolidation. Hence, ATRA-ATO in both chemotherapy-replacing and -reducing settings in consolidation is not inferior to ATRA-chemotherapy (https://www.clinicaltrials.gov/, NCT01987297).

The deubiquitinase USP36 promotes snoRNP group SUMOylation and is essential for ribosome biogenesis.

SUMOylation plays a crucial role in regulating diverse cellular processes including ribosome biogenesis. Proteomic analyses and experimental evidence showed that a number of nucleolar proteins involved in ribosome biogenesis are modified by SUMO. However, how these proteins are SUMOylated in cells is less understood. Here, we report that USP36, a nucleolar deubiquitinating enzyme (DUB), promotes nucleolar SUMOylation. Overexpression of USP36 enhances nucleolar SUMOylation, whereas its knockdown or genetic deletion reduces the levels of SUMOylation. USP36 interacts with SUMO2 and Ubc9 and directly mediates SUMOylation in cells and in vitro. We show that USP36 promotes the SUMOylation of the small nucleolar ribonucleoprotein (snoRNP) components Nop58 and Nhp2 in cells and in vitro and their binding to snoRNAs. It also promotes the SUMOylation of snoRNP components Nop56 and DKC1. Functionally, we show that knockdown of USP36 markedly impairs rRNA processing and translation. Thus, USP36 promotes snoRNP group SUMOylation and is critical for ribosome biogenesis and protein translation.

KIF18A knockdown reduces proliferation, migration, invasion and enhances radiosensitivity of esophageal cancer.

Kinesin family member 18A (KIF18A) is significantly overexpressed and is related to the poor prognosis of human cancers. However, the function of KIF18A in esophageal cancer (EC) is still unclear. Human EC cell lines were used in this study. KIF18A expression in human tissues was assessed using Gene Expression Profiling Interactive Analysis 2.0 (GEPIA2). The expressions of KIF18A or IGF2BP3 in EC cells were detected using qRT-PCR or WB. Cells were transfected using si-KIF18A, si-IGF2BP3, and plasmid IGF2BP3. The abilities of proliferation, migration, and invasion were detected by EdU, wound-healing, and transwell assay. The interaction between KIF18A and IGF2BP3 was predicted by starBase v3.0 and studied by RIP and RNA stability assay. Colony formation assay was used to reflect the changes of radiosensitivity in EC cells. KIF18A was upregulated in EC, and KIF18A knockdown inhibited EC cell proliferation, migration, invasion, and radioresistance. The prediction in starBase and RIP assay results showed that KIF18A mRNA could bind to IGF2BP3 protein in EC cells. RNA stability assay was performed to confirm that IGF2BP3 affects mRNA stability of KIF18A. Further studies also showed that IGF2BP3 could positively regulate KIF18A on proliferation, migration, invasion, and radioresistance. Our findings first revealed an oncogenic effect of KIF18A in human EC progression. KIF18A expression was associated with radioresistance of EC cells. The binding relationship between KIF18A and IGF2BP3 might influence the mRNA stability of KIF18A in EC cell lines.

Factors predicting the severity of acute pancreatitis in elderly patients.

BACKGROUND: Moderately severe acute pancreatitis (MSAP) and severe acute pancreatitis (SAP) are associated with organ failure (OF), which can be lethal. AIMS: This study determined the factors that predict the severity of AP at admission in elderly patients. METHODS: In this retrospective study, the data from elderly patients (> 60 years of age) admitted within 72 h of onset of symptoms without OF were collected. These data at admission were analyzed and correlated with the severity of AP. To identify the factors associated with more serious AP (i.e. MSAP and SAP), patients were divided into mild acute pancreatitis (MAP) and MSAP + SAP groups. RESULTS: A total of 198 patients [MAP group (n = 135) and MSAP + SAP group (n = 63)] were included. Biliary disease was the most common etiology. Respiratory failure was the most common OF. Logistic regression analyses indicated that idiopathic etiology (odds ratio [OR]: 3.029, 95% confidence interval [CI]: 1.017-9.022, p = 0.047), pre-existing pulmonary disease (OR: 7.104, CI 1.750-28.84, p = 0.006), increased hematocrit level (OR: 3.717, 95%CI 1.372-10.070, p = 0.010), serum calcium (OR: 0.023, 95%CI 0.001-0.371, p = 0.008), serum glucose (OR: 1.157, 95%CI 1.031-1.299, p = 0.013), arterial partial pressure of oxygen (PaO2) (OR: 0.914, 95%CI 0.874-0.956, p < 0.001), and pleural effusion (OR: 4.979, 95%CI 1.863-13.303, p = 0.001) were independent predictors of more serious AP. CONCLUSION: This study found that idiopathic etiology, pre-existing pulmonary diseases, increased hematocrit level or pleural effusion, higher serum glucose, and lower serum calcium or PaO2 at the time of admission independently correlated with more serious AP in the elderly patients.

miR-184 Inhibits Tumor Invasion, Migration and Metastasis in Nasopharyngeal Carcinoma by Targeting Notch2.

BACKGROUND/AIMS: A recent study found that dysregulated microRNA-184 (miR-184) is involved in the proliferation and survival of nasopharyngeal carcinoma (NPC). This study aimed to evaluate the detailed mechanisms of invasion, migration and metastasis of NPC cells. METHODS: Quantitative reverse-transcription PCR (qRT-PCR) and Western blot were used to confirm the expression levels of miR-184 and Notch2. NPC cell invasion and migration were subsequently examined using in vitro cell invasion and wound-healing assays, respectively. MicroRNA (miRNA) target gene prediction databases and dual-luciferase reporter assay were adopted to validate the target genes of miR-184. RESULTS: MiR-184 was downregulated in the NPC cell lines. The miR-184 inhibitor increased the number of invading NPC cells, whereas miR-184 mimics inhibited the invasive ability of such cells. The protein level of E-cadherin decreased, whereas those of N-cadherin and vimentin increased in the anti-miR-184 group. This result showed that miR-184 inhibited NPC cell invasion and metastasis by regulating EMT progression. MiRNA target gene prediction databases indicated the potential of Notch2 as a direct target gene of miR-184. Such a notion was then validated by results of dual-luciferase reporter assay. Notably, shRNANotch2 restrained the EMT and partially abrogated the inhibitory effects of miR-184 on EMT progression in NPC cells. CONCLUSION: MiR-184 functions as a tumour-suppressive miRNA targeting Notch2 and inhibits the invasion, migration and metastasis of NPC.

Arsenic trioxide at conventional dosage does not aggravate hemorrhage in the first-line treatment of adult acute promyelocytic leukemia.

OBJECTIVES: The arsenic trioxide (ATO) plus all-trans retinoic acid (ATRA) therapy has demonstrated a tremendous success in the first-line treatment of acute promyelocytic leukemia (APL). Actually, early death (ED) is currently thought as a major challenge in APL. ATO has been reported to inhibit platelet function in vitro, and whether it increases the ED rate by exacerbating the hemorrhagic symptoms remains to be investigated. METHODS: Effects of ATO on platelet aggregation and adhesion were evaluated in vitro and in thirty-two complete remission (CR) and four newly diagnosed APL patients. Furthermore, concentrations of plasma total arsenic were monitored in APL patients via ICP-MS. RESULTS: The inhibition of platelet function, either aggregation or adhesion, did occur in vitro when the concentration of ATO reached 2 µmol/L. However, in CR APL patients receiving ATO with normal platelet count, the platelets responded normally when being activated and so did those in the newly diagnosed patients with thrombocytopenia. Our data further showed that the conventional dosage of ATO reached a plasma concentration substantially below the required concentration to inhibit platelets. CONCLUSIONS: In the first-line treatment of APL, the use of ATO is safe and effective and does not compromise the hemostatic potential that may eventually increase ED rate.

Determination of Pb, Cr, Cd, and As in Aluminum-Plastic Packaging Materials via Inductively Coupled Plasma-Mass Spectrometry with Microwave Digestion.

Microwave digestion was performed to study the pretreatment methods of aluminum-plastic packaging materials (APPMs). Five different digestion reagent combinations and proportions were thoroughly considered. Digestion results indicated that the most suitable reagent combination was sulfuric and nitric acids with the optimal proportion of 1∶7 after the orthogonal experiment. Moreover, the possible reasons of the experimental phenomenon were analyzed. The contents of Pb, Cr, Cd, and As in APPMs were subsequently determined via inductively coupled plasma-mass spectrometry (ICP-MS). The satisfactory linearity of calibration curves was obtained with the linear correlation coefficients above 0.999 5, and the instrument detection limits of Pb, Cr, Cd, and As for the current method were 0.215, 0.067, 0.006 and 0.020 ng·mL-1, respectively. Furthermore, the recoveries of standard addition ranged from 83.8% to 111.6%, and the relative standard deviations ranged from 0.5% to 7.4%. Two independent parallel determination results of Pb, Cr, Cd, and As in APPMs were approaching, and the student's t-test (confidence level, α=0.05) showed that the determination results had no significant differences. In conclusion, the present method exhibited fine linearity, low detection limit, high recovery, and good precision, which can accurately be utilized to analyze Pb, Cr, Cd, and As elements in APPMs or other similar materials.

Probing Neutrino Hierarchy and Chirality via Wakes.

The relic neutrinos are expected to acquire a bulk relative velocity with respect to the dark matter at low redshifts, and neutrino wakes are expected to develop downstream of the dark matter halos. We propose a method of measuring the neutrino mass based on this mechanism. This neutrino wake will cause a dipole distortion of the galaxy-galaxy lensing pattern. This effect could be detected by combining upcoming lensing surveys with a low redshift galaxy survey or a 21 cm intensity mapping survey, which can map the neutrino flow field. The data obtained with LSST and Euclid should enable us to make a positive detection if the three neutrino masses are quasidegenerate with each neutrino mass of ∼0.1 eV, and a future high precision 21 cm lensing survey would allow the normal hierarchy and inverted hierarchy cases to be distinguished, and even the right-handed Dirac neutrinos may be detectable.

Measurement of neutrino masses from relative velocities.

We present a new technique to measure neutrino masses using their flow field relative to dark matter. Present day streaming motions of neutrinos relative to dark matter and baryons are several hundred km/s, comparable with their thermal velocity dispersion. This results in a unique dipole anisotropic distortion of the matter-neutrino cross power spectrum, which is observable through the dipole distortion in the cross correlation of different galaxy populations. Such a dipole vanishes if not for this relative velocity and so it is a clean signature for neutrino mass. We estimate the size of this effect and find that current and future galaxy surveys may be sensitive to these signature distortions.

Wave function for harmonically confined electrons in time-dependent electric and magnetostatic fields.

We derive via the interaction "representation" the many-body wave function for harmonically confined electrons in the presence of a magnetostatic field and perturbed by a spatially homogeneous time-dependent electric field-the Generalized Kohn Theorem (GKT) wave function. In the absence of the harmonic confinement - the uniform electron gas - the GKT wave function reduces to the Kohn Theorem wave function. Without the magnetostatic field, the GKT wave function is the Harmonic Potential Theorem wave function. We further prove the validity of the connection between the GKT wave function derived and the system in an accelerated frame of reference. Finally, we provide examples of the application of the GKT wave function.

The Ubiquitin-specific Protease USP36 Associates with the Microprocessor Complex and Regulates miRNA Biogenesis by SUMOylating DGCR8.

miRNA biogenesis is a cellular process that produces mature miRNAs from their primary transcripts, pri-miRNAs, via two RNAse III enzyme complexes: the Drosha-DGCR8 microprocessor complex in the nucleus and the Dicer-TRBP complex in the cytoplasm. Emerging evidence suggests that miRNA biogenesis is tightly regulated by posttranscriptional and posttranslational modifications and aberrant miRNA biogenesis is associated with various human diseases including cancer. DGCR8 has been shown to be modified by SUMOylation. Yet, the SUMO ligase mediating DGCR8 SUMOylation is currently unknown. Here, we report that USP36, a nucleolar ubiquitin-specific protease essential for ribosome biogenesis, is a novel regulator of DGCR8. USP36 interacts with the microprocessor complex and promotes DGCR8 SUMOylation, specifically modified by SUMO2. USP36-mediated SUMOylation does not affect the levels of DGCR8 and the formation of the Drosha-DGCR8 complex, but promotes the binding of DGCR8 to pri-miRNAs. Consistently, abolishing DGCR8 SUMOylation significantly attenuates its binding to pri-miRNAs and knockdown of USP36 attenuates pri-miRNA processing, resulting in marked reduction of tested mature miRNAs. Induced expression of a SUMOylation-defective mutant of DGCR8 inhibits cell proliferation. Together, these results suggest that USP36 plays an important role in regulating miRNA biogenesis by SUMOylating DGCR8. Significance: This study identifies that USP36 mediates DGCR8 SUMOylation by SUMO2 and is critical for miRNA biogenesis. As USP36 is frequently overexpressed in various human cancers, our study suggests that deregulated USP36-miRNA biogenesis pathway may contribute to tumorigenesis.

Hypoxia inhibits the spontaneous calcification of bone marrow-derived mesenchymal stem cells.

Bone marrow-derived mesenchymal stem cells (BM-MSCs) are the popular seed cells for regenerative medicine, and there has been a rapid increase in the number of BM-MSC-based clinical trials. However, the safety of these cells should also be closely studied. In this study, spontaneous calcification of BM-MSCs from rats was evaluated in normoxia (20% O(2)) without osteogenic medium after continuous culture for 21 days; obvious mineralized nodules were observed, which were positive for Alizarin Red, collagen-I (Col-I), osteocalcin (OC) and alkaline phosphatase (ALP), and mainly consisted of C, O and Ca elements. Interestingly, hypoxia (2% O(2)) significantly inhibited this spontaneous calcification. In addition, the ALP and calcium content of rBM-MSCs were sharply reduced. Based on RT-PCR results, the expression of osteogenic genes (Cbfa1/Runx2, Col-I, ALP, and OC) was reduced compared to that in normoxia. These results demonstrate a natural and unique characterization of rat BM-MSCs in normoxia after continuous culture and highlight the inhibiting effects of hypoxia. Finally, this study contributes to the information regarding the application of BM-MSCs in the regeneration of various tissues.

Sonic hedgehog enhances the proliferation and osteogenic differentiation of bone marrow-derived mesenchymal stem cells.

MSCs (mesenchymal stem cells) may be promising seed cells for tissue regeneration because of their self-renewal and multi-differentiation potential. Shh (sonic hedgehog) is involved in the skeletal formation during embryo development and skeletal regeneration. However, how Shh regulates the biological characteristics of BM-MSCs (bone marrow-derived MSCs) is poorly understood. We have investigated the effect of rShh-N (recombinant N-terminal Shh) on the proliferation and osteogenic differentiation of rBM-MSCs (rat BM-MSCs) in vitro. rBM-MSCs were treated with rShh-N at concentrations up to 200 ng/ml. Proliferation and colony-forming ability of rBM-MSCs were increased in a dose-dependent manner. rShh-N increased the ratio of cells in S and G2/M phase, as well as the number of Ki-67+ cells. In addition, ALP (alkaline phosphatase) activity and matrix mineralization were enhanced by 200 ng/ml rShh-N. Real-time PCR showed that rShh-N (200 ng/ml) up-regulated the expression of genes encoding Cbfa-1 (core-binding factor α1), osteocalcin, ALP and collagen type I in rBM-MSCs. This information reveals some potential of rShh-N in the therapeutics of bone-related diseases.

Evaluation of cardiomyocyte hypoxia injury models for the pharmacological study in vitro.

CONTEXT: Traditional Herbal Medicine (THM) has many advantages that make it a promising choice for the treatment of ischemic heart disease (IHD). To study the mechanism of IHDs or pharmacological actions of THM, many hypoxia-induced cardiomyocyte injury models have been established. Radix Salvia miltorrhiza (Danshen) was used as a representative of THM. Danshen is a famous medicinal herb widely applied in Asia to relieve ischemic cardiovascular diseases. OBJECTIVE: To investigate the effects of various hypoxic conditions and discuss a suitable hypoxia model, cell viability, apoptosis, release of myocardial injury markers, and mRNA levels of target genes were tested for the first time. MATERIALS AND METHODS: Radix Salvia miltorrhiza (Danshen) was purchased from a GMP-compliant producer and both its preparation method and quality control were standardized. Cellular status, such as cell viability, apoptosis, releases of myocardial injury markers, and the mRNA level of target gene were tested by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) method, biochemical analyzer, flow cytometry, Hoechst 33258 staining, and real-time PCR, respectively. RESULTS: Based on our data, we found a treppe response of cardiomyocyte in the hypoxic condition and suggested that 8 h in 2% O2 might be a suitable condition for in vitro pharmacological study of cardiomyocytes. DISCUSSION AND CONCLUSIONS: Our findings outlined more extended and in-depth capability of cardiomyocyte suffering from hypoxia, and might be of particular interest due to the high prevalence of THM pharmacological study.

Creating Extraordinary From Ordinary: High Resource Efficiency of Underdog Entrepreneurs and Its Mechanism.

Existing theory has not documented the potential benefits of facing the challenges of underdog entrepreneurs, who may succeed unexpectedly. This research explains why, and under what circumstances, the underdog status of entrepreneurs can promote entrepreneurial success rather than just hinder it. We predict that the underdog effect has the potential to boost entrepreneurial resource efficiency when entrepreneurs hold an incremental (vs. entity) theory, enter a low-barrier (vs. high-barrier) industry, and are in a favorable (vs. unfavorable) business environment. Study 1 provides support for the positive relationship between underdog status and resource efficiency through an ordinary least squares (OLS) regression analysis, which is accompanied by a moderating effect of the implicit theory, industry context, and business environment. The data was obtained from two nationwide surveys. By extending a qualitative comparative analysis (QCA) of multiple case studies, Study 2 reveals support for a synergistic effect of the above factors. Our research results examine the assumption that perceiving underdog status is detrimental and offer meaningful insights into why and when underdog entrepreneurs have good performance in entrepreneurial resource efficiency. We provide a psychological and behavioral explanation for the underdog effect, extending the underdog effect theory to the field of entrepreneurship for the first time from the perspective of the actors. Finally, theoretical contributions and practical implications are discussed by indicating the limitations of the research.

An analysis of the trickle-down effect of supervisor knowledge hiding on subordinate knowledge hiding based on displaced aggression theory.

The harm of horizontal knowledge hiding behavior (colleague-colleague) to individuals and organizations has been discussed and confirmed by many studies. The negative consequences of top-down (supervisor-subordinate) knowledge hiding have now emerged as a new focus of research. This study aims to enrich the understanding of the consequences of supervisor knowledge hiding by exploring its trickle-down effect and mechanism. Based on the displaced aggression theory in psychology, this paper analyses and examines the cognitive psychological process and mechanism informing employee knowledge hiding from colleagues when faced with their supervisor's malicious knowledge hiding behavior. Using a three-stage time-lag questionnaire survey strategy, we collect 233 valid samples of full-time employees from representative provinces and cities in China, covering multiple industries. The following findings are observed: (1) Supervisor knowledge hiding from subordinates (SKHS) positively affects subordinate knowledge hiding from colleagues (SKHC); (2) Revenge motivation plays a mediating role; (3) Traditionality weakens the influence of supervisor knowledge hiding on a subordinates' revenge motivation. This study confirms the trickle-down effects of supervisor knowledge hiding behavior, extends research on the consequences of top-down knowledge hiding and its mechanism and provides new insights for organizational practice.

Study on the characteristics of intestinal motility of constipation in patients with Parkinson's disease.

BACKGROUND: Constipation is one of the most important nonmotor symptoms in Parkinson's disease (PD) patients, and constipation of different severities is closely related to the pathogenesis of PD. PD with constipation (PDC) is considered a unique type of constipation, but its mechanism of formation and factors affecting its severity have been less reported. Understanding the gastrointestinal motility characteristics and constipation classification of PDC patients is essential to guide the treatment of PDC. In this study, the colonic transit test and high-resolution anorectal manometry were used to identify the intestinal motility of PDC to provide a basis for the treatment of PDC. AIM: To investigate the clinical classification of PDC, to clarify its characteristics of colonic motility and rectal anal canal pressure, and to provide a basis for further research on the pathogenesis of PDC. METHODS: Twenty PDC patients and 20 patients with functional constipation (FC) who were treated at Xuanwu Hospital of Capital Medical University from August 6, 2018 to December 2, 2019 were included. A colonic transit test and high-resolution anorectal manometry were performed to compare the differences in colonic transit time, rectal anal canal pressure, and constipation classification between the two groups. RESULTS: There were no statistically significant differences in sex, age, body mass index, or duration of constipation between the two groups. It was found that more patients in the PDC group exhibited difficulty in defecating than in the FC group, and the difference was statistically significant. The rectal resting pressure, anal sphincter resting pressure, intrarectal pressure, and anal relaxation rate in the PDC group were significantly lower than those in the FC group. The proportion of paradoxical contractions in the PDC group was significantly higher than that in the FC group. There was a statistically significant difference in the type composition ratio of defecatory disorders between the two groups (P < 0.05). The left colonic transit time, rectosigmoid colonic transit time (RSCTT), and total colonic transit time were prolonged in PDC and FC patients compared to normal values. The patients with FC had a significantly longer right colonic transit time and a significantly shorter RSCTT than patients with PDC (P < 0.05). Mixed constipation predominated in PDC patients and FC patients, and no significant difference was observed. CONCLUSION: Patients with PDC and FC have severe functional dysmotility of the colon and rectum, but there are certain differences in segmental colonic transit time and rectal anal canal pressure between the two groups.

Importance of monitoring arsenic methylation metabolism in acute promyelocytic leukemia patients receiving the treatment of arsenic trioxide.

BACKGROUND: Arsenic trioxide [ATO, inorganic arsenite (iAsIII) in solution] plays an important role in the treatment of acute promyelocytic leukemia (APL). However, the long-term adverse effects (AEs) and the retention of arsenic among APL patients are rarely reported. In this study, we focused on arsenic methylation metabolism and its relationship with chronic hepatic toxicity, as we previously reported, among APL patients who had finished the treatment of ATO. METHODS: A total of 112 de novo APL patients who had completed the ATO-containing treatment were enrolled in the study. Arsenic species [iAsIII, inorganic arsenate (iAsV), and their organic metabolites, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA)] in patients' plasma, urine, hair and nails were detected by high-performance liquid chromatography combined with inductively coupled plasma mass spectrometry (HPLC-ICP-MS). Eighteen single nucleotide polymorphisms (SNPs) of the arsenic (+ 3 oxidative state) methylation transferase (AS3MT) gene, which was known as the main catalyzer for arsenic methylation, were tested with the polymerase chain reaction method. RESULTS: The study showed the metabolic pattern of arsenic in APL patients undergoing and after the treatment of ATO, in terms of total arsenic (TAs) and four species of arsenic. TAs decreased to normal after 6 months since cessation of ATO. But the arsenic speciation demonstrated significantly higher portion of iAsIII in patient's urine (40.08% vs. 1.94%, P < 0.001), hair (29.25% vs. 13.29%, P = 0.002) and nails (30.21% vs. 13.64%, P = 0.003) than the healthy controls', indicating a decreased capacity of arsenic methylation metabolism after the treatment of ATO. Urine primary methylation index (PMI) was significantly lower in patients with both chronic liver dysfunction (0.14 vs. 0.28, P = 0.047) and hepatic steatosis (0.19 vs. 0.3, P = 0.027), suggesting that insufficient methylation of arsenic might be related to chronic liver disorders. Two SNPs (A9749G and A27215G) of the AS3MT gene were associated with impaired urine secondary methylation index (SMI). CONCLUSIONS: The long-term follow-up of arsenic speciation indicated a decreased arsenic methylation metabolism and a probable relationship with chronic hepatic disorders among APL patients after the cessation of ATO. Urine PMI could be a monitoring index for chronic AEs of ATO, and the SNPs of AS3MT gene should be considered when determining the dosage of ATO.

Effect of methylprednisolone in severe and critical COVID-19: Analysis of 102 cases.

BACKGROUND: The coronavirus disease 2019 (COVID-19) outbreak has brought great challenges to public health. Aggravation of COVID-19 is closely related to the secondary systemic inflammatory response. Glucocorticoids are used to control severe diseases caused by the cytokine storm, owing to their anti-inflammatory effects. However, glucocorticoids are a double-edged sword, as the use of large doses has the potential risk of secondary infection and long-term serious complications, and may prolong virus clearance time. Nonetheless, the risks and benefits of glucocorticoid adjuvant therapy for COVID-19 are inconclusive. AIM: To determine the effect of methylprednisolone in severe and critically ill patients with COVID-19. METHODS: This single-center retrospective study included 102 adult COVID-19 patients admitted to a ward of a designated hospital in Wuhan, Hubei Province from January to March 2020. All patients received general symptomatic treatment and organ function support, and were given different respiratory support measures according to their conditions. In case of deterioration, considering the hyperinflammatory state of the patients, methylprednisolone was intravenously administered at 0.75-1.5 mg/kg/d, usually for less than 14 d. Patient vital signs and oxygenation were closely monitored, in combination with imaging and routine blood tests such as C-reactive protein, biochemical indicators (liver and kidney function, myocardial enzymes, electrolytes, etc.), and coagulation function. Patient clinical outcomes were discharge or death. RESULTS: A total of 102 severe and critically ill COVID-19 patients were included in this study. They were divided into treatment (69, 67.6%) and control groups (33, 32.4%) according to methylprednisolone use. Comparison of baseline data between the two groups showed that the treatment group patients had higher aspartic acid aminotransferase, globulin, hydroxybutyrate dehydrogenase, and lactate dehydrogenase. There was no significant difference in other baseline data between the two groups. With regard to prognosis, 29 (78.4%) patients in the treatment group died as opposed to 40 (61.5%) in the control group. The mortality was higher in the treatment group than in the control group; however, according to the log-rank test and the Kaplan-Meier survival curve, the difference in mortality between both groups was insignificant (P = 0.655). The COX regression equation was used to correct the variables with differences, and the results showed that methylprednisolone treatment did not improve prognosis. CONCLUSION: Methylprednisolone treatment does not improve prognosis in severe and critical COVID-19 patients.