A comprehensive RNA editome reveals that edited Azin1 partners with DDX1 to enable hematopoietic stem cell differentiation.

Adenosine-to-inosine RNA editing and the catalyzing enzyme adenosine deaminase are both essential for hematopoietic development and differentiation. However, the RNA editome during hematopoiesis and the underlying mechanisms are poorly defined. Here, we sorted 12 murine adult hematopoietic cell populations at different stages and identified 30 796 editing sites through RNA sequencing. The dynamic landscape of the RNA editome comprises stage- and group-specific and stable editing patterns, but undergoes significant changes during lineage commitment. Notably, we found that antizyme inhibitor 1 (Azin1) was highly edited in hematopoietic stem and progenitor cells (HSPCs). Azin1 editing results in an amino acid change to induce Azin1 protein (AZI) translocation to the nucleus, enhanced AZI binding affinity for DEAD box polypeptide 1 to alter the chromatin distribution of the latter, and altered expression of multiple hematopoietic regulators that ultimately promote HSPC differentiation. Our findings have delineated an essential role for Azin1 RNA editing in hematopoietic cells, and our data set is a valuable resource for studying RNA editing on a more general basis.

Prolonged usage of fosaprepitant for prevention of delayed chemotherapy-induced nausea and vomiting(CINV) in patients receiving highly emetogenic chemotherapy.

BACKGROUND: Even though chemotherapy-induced nausea and vomiting (CINV) can be well controlled in the acute phase, the incidence of delayed CINV remains high. In this study, we intend to investigate whether prolonged use of NK-1 receptor antagonist (RA) in addition to 5-HT3 RA and dexamethasone (DEX) was more effective in preventing delayed CINV. METHODS: This randomised, open-label, controlled study was designed to compare the efficacy and safety of fosaprepitant 150 mg given on days 1,3 (prolonged group) versus on day 1 (regular group) in patients receiving highly emetogenic chemotherapy (HEC). All patients also treated with palonosetron on day 1 and DEX on days 1-3. The primary endpoint was the incidence of delayed nausea and vomiting. The second endpoint was AEs. All the above endpoints were defined according to CTCAE 5.0. RESULTS: Seventy-seven patients were randomly assigned to prolonged group and seventy-nine to regular group. Prolonged group demonstrated superiority in controlling delayed CINV to regular group, with statistically significant lower incidence of nausea (6.17% vs 12.66%, P = 0.0056), and slightly lower incidence of grade 1 vomiting (1.62% vs 3.80%, P = 0.0953) in the delayed phase. In addition, prolonged use of fosaprepitant was safe. No significant difference was found between the two groups regarding constipation, diarrhea, hiccough, fatigue, palpitation and headache in delayed phase. CONCLUSIONS: Prolonged use of fosaprepitant can effectively and safely prevent delayed CINV in patients receiving HEC.

Histone H4 induces heparan sulfate degradation by activating heparanase in chlorine gas-induced acute respiratory distress syndrome.

BACKGROUND: Heparan sulfate (HS) degradation mediates pulmonary endothelial hyper-permeability and acute pulmonary edema during acute respiratory distress syndrome (ARDS). The aim of this study was to examine whether histone H4 induced HS degradation by activating heparanase (HPSE) in chlorine gas (Cl2)-induced ARDS. METHODS: Acute lung injury was induced by Cl2 exposure or histone H4 injection in C57BL/6 mice. Histone H4 in bronchoalveolar lavage fluid (BALF) and plasma was measured by ELISA. HS degradation was measured by immunostaining, ELISA, and flow cytometry. HPSE mRNA and protein were measured by real-time qPCR and western blot analysis, respectively, at preset timepoints. The HPSE inhibitor OGT2115 and specific siRNAs were used to study the role of HPSE during HS degradation caused by Cl2 exposure or histone H4 challenge. Blocking antibodies against TLR1, TLR2, TLR4, or TLR6 were used in vitro to investigate which signaling pathway was involved. The transcriptional regulation of HPSE was studied vis-à-vis NF-κB, which was assessed by nuclear translocation of NF-κB p65 and phosphorylation of I-κBα protein. RESULTS: Histone H4 in BALF and plasma increased evidently after Cl2 inhalation. Cl2 exposure or histone H4 challenge caused obvious acute lung injury in mice, and the pulmonary glycocalyx was degraded evidently as observed from endothelial HS staining and measurement of plasma HS fragments. Pretreatment with OGT2115, an HPSE inhibitor, relieved the acute lung injury and HS degradation caused by Cl2 exposure or histone H4 challenge. Targeted knockdown of HPSE by RNA interference (RNAi) significantly inhibited histone H4 induced HS degradation in HPMECs, as measured by immunofluorescence and flow cytometry. By inducing phosphorylation of I-κB α and nuclear translocation of NF-κB p65, histone H4 directly promoted mRNA transcription and protein expression of HPSE in a dose-dependent manner. Additionally, a blocking antibody against TLR4 markedly inhibited both activation of NF-κB and expression of HPSE induced by histone H4. CONCLUSIONS: Histone H4 is a major pro-inflammatory mediator in Cl2-induced ARDS in mice, and induces HS degradation by activating HPSE via TLRs- and NF-κB-signaling pathways.

Glycine/glycine N-methyltransferase/sarcosine axis mediates benzene-induced hematotoxicity.

Benzene, an important and widely used industrial chemical, is the cause of different types of blood disorders. However, the mechanisms of benzene-induced hematotoxicity are still unclear. This study aimed to explore the effects of benzene on metabolism, especially in amino acid metabolism, in human peripheral blood B lymphocyte cells (AHH-1 cells) treated with 1,4-benzoquinone (1,4-BQ) and in benzene-exposed population based on the un-targeted and targeted metabolomics platforms. The results showed that 1,4-BQ disturbed the metabolic activity, such as arginine biosynthesis, citrate cycle, glycine, serine, and threonine metabolism pathways, and significantly upregulated the ratio of sarcosine/glycine in vitro. Meanwhile, the targeted metabolomics further showed that the ratio of sarcosine/glycine was also increased in the benzene exposure population. Notably, the expression of glycine N-methyltransferase (GNMT), an enzyme catalyzing the transformation of glycine to sarcosine, was upregulated both in 1,4-BQ treated AHH-1 cells and benzene-exposed workers. These results imply that the glycine/GNMT/sarcosine axis was involved in benzene-induced hematotoxicity. Such evidence will help to develop a better understanding of the underlying mechanism of benzene-induced hematotoxicity at the level of amino acid metabolism.

Association between benzene exposure, serum levels of cytokines and hematological measures in Chinese workers: A cross-sectional study.

BACKGROUND: Low benzene exposure leads to hematotoxicity, but we still lack sensitive early monitoring and early warning markers. Benzene is associated with inflammation, which is mainly mediated by cytokines network. However, until now few studies have conducted high-throughput detection of multi-cytokines to get a global view of cytokine changes and screen for markers of benzene-induced toxicity. We hypothesized that cytokine profiles mediate benzene-induced hematotoxicity. METHODS: 228 subjects consisting of 114 low benzene exposed workers and 114 healthy controls were recruited at Research Center of Occupational Medicine, Peking University Third Hospital, Beijing. The serum concentrations of 27 cytokines were detected by cytokinomics array, urinary benzene series metabolites were measured by UPLC-MS/MS, and peripheral blood cell counts were observed by basic blood test. RESULTS: Among 27 cytokines, IL-9 and MIP1-α were significantly lower, but IL-4, IL-10, IL-15, MCP-1, TNF-α and VEGF were significantly higher in benzene exposure group than controls. Urinary benzene metabolite S-phenylmercapturic acid (S-PMA) was significantly higher in benzene exposure group and had a negative linear relationship with WBC count. S-PMA was only significantly associated with IL-9, meanwhile IL-9, IL-15 and VEGF had a positive linear relationship with WBC count. The bootstrapping mediation models showed that the effect of S-PMA on WBC count was partially explained by IL-9 for 10.11%. CONCLUSION: This study suggests that exposure to benzene was associated with alternation of blood cell count and cytokine profiles in workers exposed to low levels of benzene, especially decreases of WBC count and IL-9. We also found IL-9 partially mediated the effect of low benzene exposure on WBC count, which may be a potential and promising early monitoring and early warning marker of benzene hematotoxicity.

Characterization of gut microbiota, metabolism and cytokines in benzene-induced hematopoietic damage.

Benzene exposure leads to hematopoietic dysfunction and is characterized clinically by a decrease in blood cells, but the underlying mechanisms remain elusive. Disturbed gut microbiota may induce host metabolic, immune disorders and the onset of disease. However, the characterization of gut microbiota, metabolism, cytokines and their association with benzene-induced hematopoietic toxicity lacks systematic evidence. Here, the microbiomics, metabolomics and cytokine network were applied to find out the critical characteristics of gut microbiota, metabolism and cytokines in mice involved in the benzene-induced hematopoietic toxicity. We found that the decline in hematopoietic stem cells was earlier than the hematological changes in the 5 mg/kg and 25 mg/kg benzene exposure groups. While 125 mg/kg benzene exposure resulted in a significant decline in whole blood cells. High-throughput sequencing results showed that benzene exposure disrupted homeostasis of gut microbiota, metabolism and cytokine in mice. 6 bacteria, 12 plasma metabolites and 6 cytokines were associated with benzene-induced hematopoietic damage. Notably, IL-5 was significantly increased in benzene exposure group in a dose-dependent manner, and a significant negative correlation was found between IL-5 and hematopoietic damage. We further found that increased Family_XIII_AD3011_group at the genus level and decreased Anaerotruncus_sp at the species level in benzene-exposed group were strongly associated with hematopoietic toxicity and IL-5. Furthermore, the abundance of Family_XIII_AD3011_group and Anaerotruncus_sp were negatively correlated with Adipic acid and 4-Hydroxyproline, respectively. Our findings indicated that altered flora structure of gut microbiota affects the metabolic phenotype which acts as messengers for the gut microbes, affecting host inflammation. This preliminary study provides new insight into the potential mechanisms of benzene-induced hematopoietic toxicity, further exploration by functional studies is required in the future.

[Value of body fat mass measured by bioelectrical impedance analysis in predicting abnormal blood pressure and abnormal glucose metabolism in children].

OBJECTIVE: To study the value of body fat mass measured by bioelectrical impedance analysis (BIA) in predicting abnormal blood pressure and abnormal glucose metabolism in children. METHODS: Stratified cluster sampling was used to select the students aged 6-16 years, and a questionnaire survey and physical examination were performed. The BIA apparatus was used to measure body fat mass. Body mass index (BMI), body fat mass index (FMI), and fat mass percentage (FMP) were calculated. Fasting blood glucose level were measured. RESULTS: A total of 14 293 children were enrolled, among whom boys accounted for 49.89%. In boys and girls, the percentile values (P60, P65, P70, P75, P80, P85, P90, P95) of FMI and FMP fitted by the LMS method were taken as the cut-off values. Based on the receiver operating characteristic curve analysis, the P70 values with a better value in predicting abnormal blood pressure and blood glucose metabolism were selected as the cut-off values for excessive body fat. When FMI or FMP was controlled below P70, the incidence of abnormal blood pressure or abnormal glucose metabolism may be decreased in 8.25%-43.24% of the children. CONCLUSIONS: The evaluation of obesity based on FMI and FMP has a certain value in screening for hypertension and hyperglycemia in children, which can be further verified in the future prevention and treatment of obesity and related chronic diseases in children.

Polycyclic aromatic hydrocarbons exposure and hematotoxicity in occupational population: A two-year follow-up study.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental and occupational pollutants. To date, the effect and mechanism by which PAHs exposure impaired hematopoietic system remains unclear. METHODS: We examined the capability of PAHs to disrupt hematopoiesis in a study of 639 male participants in China by measuring complete blood counts (CBC) in 2013 and 2014. Gas chromatography-mass spectrometry (GC/MS) method was used to measure airborne levels of PAHs and benzene. We measured 1-hydroxypyrene (1-OHP), S-phenylmercapturic acid (SPMA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in urinary by ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS/MS) method. RESULTS: We found decreased dose-response of white blood cells, eosinophils, monocytes and lymphocytes with increased PAHs exposure in two consecutive years. We did not find association between benzene with CBC in our study. After stratification analysis by smoking status, the findings were highly consistent. White blood cells, monocytes and red blood cell counts were decreased in high urinary 8-OHdG group. CONCLUSIONS: Our study showed that PAHs could impair the hematopoietic system independently, and oxidative stress might play an important role in potential hematotoxicity.

Bone marrow endothelial cell-derived interleukin-4 contributes to thrombocytopenia in acute myeloid leukemia.

Normal hematopoiesis can be disrupted by the leukemic bone marrow microenvironment, which leads to cytopenia-associated symptoms including anemia, hemorrhage and infection. Thrombocytopenia is a major and sometimes fatal complication in patients with acute leukemia. However, the mechanisms underlying defective thrombopoiesis in leukemia have not been fully elucidated. In the steady state, platelets are continuously produced by megakaryocytes. Using an MLL-AF9-induced acute myeloid leukemia mouse model, we demonstrated a preserved number and proportion of megakaryocyte-primed hematopoietic stem cell subsets, but weakened megakaryocytic differentiation via both canonical and non-canonical routes. This primarily accounted for the dramatic reduction of megakaryocytic progenitors observed in acute myeloid leukemia bone marrow and a severe disruption of the maturation of megakaryocytes. Additionally, we discovered overproduction of interleukin-4 from bone marrow endothelial cells in acute myeloid leukemia and observed inhibitory effects of interleukin-4 throughout the process of megakaryopoiesis in vivo Furthermore, we observed that inhibition of interleukin-4 in combination with induction chemotherapy not only promoted recovery of platelet counts, but also prolonged the duration of remission in our acute myeloid leukemia mouse model. Our study elucidates a new link between interleukin-4 signaling and defective megakaryopoiesis in acute myeloid leukemia bone marrow, thereby offering a potential therapeutic target in acute myeloid leukemia.

lncRNAVNN3 mediated benzene-induced hematotoxicity through promoting autophagy and apoptosis.

The potential toxicity of low-dose benzene exposure to human health has received attention, but the mechanisms of low-dose benzene-induced hematotoxicity remain largely unknown. The purpose of our study was to investigate the relationships between lncRNAVNN3 expression with benzene-induced autophagy and apoptosis in control and benzene-exposed workers. Seventy benzene-exposed workers and seventy non-benzene-exposed healthy workers were recruited. The expression of lncRNAVNN3, serum autophagy-associated and apoptosis-associated proteins were evaluated, and the relationship among them were also analysed. Furthermore, the mechanism of lncRNAVNN3 on autophagy and apoptosis induced by benzene metabolite (1, 4-benzoquinone, 1, 4-BQ) was investigated in vitro. The results showed that the expression of lncRNAVNN3 increased in benzene-exposed workers (p < 0.05). A positive correlation was found between lncRNAVNN3, serum autophagy-associated and apoptosis-associated proteins. In addition, we found that the knockdown of lncRNAVNN3 reduced phosphorylation of beclin1 and Bcl-2, which mediated 1, 4-benzoquinone-induced autophagy and apoptosis. Overall, lncRNAVNN3 mediated 1, 4-benzoquinone-induced autophagy and apoptosis though regulating phosphorylation of beclin1 and Bcl-2, suggesting that lncRNAVNN3 might be a novel early sensitive biomarker of benzene-induced hematotoxicity.

SIRT1 exhibits antioxidative effects in HT22 cells induced by tert-butyl alcohol.

Tertiary butyl alcohol (TBA) is a principal metabolite of methyl tertiary-butyl ether (MTBE), a common pollutant worldwide in the ground or underground water, which is found to produce nervous system damage. Nevertheless, few data regarding the effects of TBA has been reported. Studies indicated that oxidative stress plays a pivotal role in MTBE neurotoxic mechanism. Sirtuin 1 (SIRT1) has been reported to exert a neuroprotective effect on various neurologic diseases via resistance to oxidative stress by deacetylating its substrates. In this study, we examined levels of oxidative stress after exposure to TBA for 6 h in HT22 cells and HT22 cells with SIRT1 silencing (transfected with SIRT1 siRNA) or high expression (preconditioned with agonists SRT1720). We found that TBA activated oxidative stress by increasing generation of intracellular reactive oxygen species (ROS), malondialdehyde (MDA) and Oxidized glutathione (GSSG), and decreasing contents of superoxide dismutase (SOD) and glutathione reductase (GSH). In additional, levels of TBA-induced oxidative stress were aggravated when SIRT1 silenced but alleviated when SIRT1 enhanced. Our study indicated that SIRT1 mitigated oxidative stress induced by TBA.

Nonadiabatic ab initio molecular dynamics study of photoisomerization in N-salicilydenemethylfurylamine (SMFA).

The photoisomerization mechanisms of N-salicilydenemethylfurylamine upon excitation to the first singlet state are investigated by means of surface-hopping dynamics simulations based on the Zhu-Nakamura theory. Due to different orientations of the methyl-furyl part with respect to the salicylaldimine part and different orientations of hydroxy group with respect to the benzene ring, various stable structures are obtained in the optimization. The enol isomer, S0-ENOL-5a, is the most stable conformer. An ultrafast excited-state intramolecular proton transfer is observed after photoexcitation of the most stable enol conformer and then the molecule reaches the excited-state minimum. After the internal conversion around a conical intersection, the system relaxes to either the cis-keto or trans-keto region in the ground state. The potential energy profiles of the ground and the first excited singlet state are also calculated. According to full-dimensional nonadiabaticdynamics simulations and potential energy profiles, the trans-keto and cis-keto photoproducts can be responsible for the photochromic effect of N-salicilydenemethylfurylamine.

CRISPR-Cas9 for medical genetic screens: applications and future perspectives.

CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats-CRISPR associated nuclease 9) systems have emerged as versatile and convenient (epi)genome editing tools and have become an important player in medical genetic research. CRISPR-Cas9 and its variants such as catalytically inactivated Cas9 (dead Cas9, dCas9) and scaffold-incorporating single guide sgRNA (scRNA) have been applied in various genomic screen studies. CRISPR screens enable high-throughput interrogation of gene functions in health and diseases. Compared with conventional RNAi screens, CRISPR screens incur less off-target effects and are more versatile in that they can be used in multiple formats such as knockout, knockdown and activation screens, and can target coding and non-coding regions throughout the genome. This powerful screen platform holds the potential of revolutionising functional genomic studies in the near future. Herein, we introduce the mechanisms of (epi)genome editing mediated by CRISPR-Cas9 and its variants, introduce the procedures and applications of CRISPR screen in functional genomics, compare it with conventional screen tools and at last discuss current challenges and opportunities and propose future directions.

All-Trans Retinoic Acid Attenuates Hypoxia-Induced Injury in NRK52E Cells via Inhibiting NF-x03BA;B/VEGF and TGF-ß2/VEGF Pathway.

BACKGROUND/AIMS: Hypoxia has recently been proposed as one of the most important factors in progressive renal injury. Hypoxia-induced vascular endothelial growth factor (VEGF) expression may play a critical role in maintaining peritubular capillary endothelium in renal disease. This study was designed to investigate the effect and underlying mechanism of all-trans retinoic acid (ATRA) on hypoxia-induced injury in NRK52E cells. METHODS: For mimicking hypoxia, cells were treated with 100 µM of cobalt chloride (CoCl2). The cell viability, expression of VEGF, p65, transforming growth factor-ß2 (TGF-ß2) and serine carboxypeptidase 1 (Scpep1), and nuclear factor of kappaB (NF-x03BA;B) activities after ATRA treatment were determined by MTT, western blot and electrophoretic mobility shift assay. Co-immunoprecipitation analysis was performed to demonstrate whether Scpep1 interacted with TGF-ß2. RESULTS: It was found that CoCl2 triggered hypoxia injury and significantly reduced cell viability. ATRA pretreatment increased the cell survival rate. Under hypoxic conditions, the expression of VEGF, p65 and TGF-ß2 increased. Addition of ATRA significantly attenuated the expression of VEGF, p65 and TGF-ß2. There was a corresponding variation of NF-x03BA;B/DNA binding activities. In addition, ATRA stimulated Scpep1 expression under normoxic and hypoxia condition. Furthermore, TGF-ß2 interacted with Scpep1. CONCLUSIONS: This study indicated that ATRA may attenuate hypoxia-induced injury in NRK52E cells via inhibiting NF-x03BA;B/VEGF and TGF-ß2/VEGF pathway.

[Influence of Nitrogen Flow Rate on the Structure and Luminescence Properties of Silicon-Rich Silicon Nitride Film Materials in a High Hydrogen Atmosphere].

High hydrogenated silicon-rich silicon nitride(SiNx∶H)thin films are deposited on the glass and monocrystalline silicon(110) substrates by plasma enhanced chemical vapor deposition using SiH4 and H2 as the main reaction gas with doping the N2. The ultraviolet-visible absorption spectrum, Fourier transform infrared absorption spectroscopy, Raman spectroscopy and photoluminescence spectrum are applied to characterize the changes of the band gap, the microstructure and related photoluminescence properties of the nitrogen-doped silicon film. It shows that hydrogen atoms can suppress the defects in the film and make film present silicon-rich under the low SiH4/H2 flow ratio, but they are not beneficial to the formation of silicon clusters in a hydrogen atmosphere. With the incorporation of nitrogen atoms, all the content of Si-N bonds, band gap and the degree of disorder in the microstructure of the films increase, films produce light emission related to the defect states. While the content of doped nitrogen atoms are further increased, it appears the band tail emission. Then the relationships between several light emissions and microstructure to be discussed. These results are useful for the optimization of light emission and microstructure for the silicon-rich silicon nitride film material prepared by PECVD.

Effect of bone morphogenic protein-7 on the expression of epithelial-mesenchymal transition markers in silicosis model.

This study presented the effect of bone morphogenic protein-7 (BMP-7) inhibiting epithelial-mesenchymal transition (EMT) in silicosis model. In vivo, Wistar rats were exposed to silica by intratracheal instillation. Seven days later rats were treated with BMP-7. Rats were sacrificed at 15 and 30days after exposure of silica. The results demonstrated vimentin expression was down-regulated; and E-cadherin was up-regulated after intervention with BMP-7. The TGF-ß expression and phosphorylation-p38 were lower in BMP-7 treated group than in silica group. In vitro, p38 MAPK/Snail signaling pathway was involved in the occurrence of EMT in A549 cells treated by silica. EMT was inhibited by BMP-7. The data showed BMP-7 inhibited EMT induced by silica associated with inhibition of p38 MAPK/Snail pathway.

[Study on the relations among the screen-based sedentary behaviors, family factors and body mass index of children].

OBJECTIVE: To explore the relations among screen-based sedentary behaviors (SSB), family factors and body mass index (BMI) of children, and to study how family factors have effect on BMI through influencing SSB. METHODS: A total of 1,846 students aged 7-11 years from 12 primary schools in one district of Beijing were included. Their body weight and height were measured to calculate the BMI. The time of SSB and family factors were investigated by using questionnaires. The time of SSB was the total time of watching TV and videos, playing computer games and iPad each day during the past 7 days recalled by children. The family factors included the parents' education, occupation, the parents'time of SSB, whether the parents told their child the harm of SSB, the parents'time limit for the children's SSB. The parents'education and occupation were used for calculating the family socioeconomic score. RESULTS: The median time of SSB for children was 1 hour/day, and the interquartile range was 1 hour/day. The BMI of the children with the parents' time limit for the children's SSB less than 120 min/day were smaller than the children with the parents'time limit not less than 120 min/day, in both the boys (1.63 kg/m2, P<0.001) and the girls (0.85 kg/m2, P=0.004). The family socioeconomic score, the parents'SSB time, whether the parents told their children the harm of SSB were not related to the children's BMI . The mediation effects of SSB time for children on the association between the parents'time limit for the children's SSB and BMI were -0.222 kg/m2 (95%CI:-0.432, -0.095) for boys and -0.187 kg/m2 (95%CI: -0.507, -0.049) for girls, which accounted for 13.67% of the total effects for boys and 22.11% for girls. CONCLUSION: The parents' time limit for the children's SSB has effect on their BMI through influencing their SSB time. Parents' supervision on the behaviors of children produces larger benefit for BMI than health education conveyed by parents. Therefore, parents' participation in supervising the behaviors of children are indispensable for preventing and controlling childhood obesity.

[The role of long non-coding RNAs in hematologic malignancies].

With the rapid development of molecular biology technology, researchers have got much deeper understanding of the role of long non-coding RNA (lncRNA). It is not only indispensable for biological processes, but also plays an important role in human diseases especially in tumor. Previous studies have shown that a variety of lncRNAs are closely associated with hematologic malignancies. These lncRNAs are involved in diseases through diverse functions including affecting the expression of tumor suppressor gene p15, regulating p53 protein function, and interacting with miRNAs. In this review, we summarize the hematological tumor-associated lncRNAs and focus on p15, p53 and miRNA-related lncRNAs as well as the role of their interaction in hematological malignancies, which may provide a comprehensive understanding of the role of hematological tumor-associated lncRNAs and some insights for research, diagnosis and treatment of hematologic malignancies.

Aberrant hypomethylated STAT3 was identified as a biomarker of chronic benzene poisoning through integrating DNA methylation and mRNA expression data.

Chronic occupational benzene exposure is associated with an increased risk of hematological malignancies such as aplastic anemia and leukemia. The new biomarker and action mechanisms of chronic benzene poisoning are still required to be explored. Aberrant DNA methylation, which may lead to genomic instability and the altered gene expression, is frequently observed in hematological cancers. To gain an insight into the new biomarkers and molecular mechanisms of chronic benzene poisoning, DNA methylation profiles and mRNA expression pattern from the peripheral blood mononuclear cells of four chronic benzene poisoning patients and four health controls that matched age and gender without benzene exposure were performed using the high resolution Infinium 450K methylation array and Gene Chip Human Gene 2.0ST Arrays, respectively. By integrating DNA methylation and mRNA expression data, we identified 3 hypermethylated genes showing concurrent down-regulation (PRKG1, PARD3, EPHA8) and 2 hypomethylated genes showing increased expression (STAT3, IFNGR1). Signal net analysis of differential methylation genes associated with chronic benzene poisoning showed that two key hypomethylated STAT3 and hypermethylated GNAI1 were identified. Further GO analysis and pathway analysis indicated that hypomethylated STAT3 played central roles through regulation of transcription, DNA-dependent, positive regulation of transcription from RNA polymerase II promoter, JAK-STAT cascade and adipocytokine signaling pathway, Acute myeloid leukemia, and JAK-STAT signaling pathway. In conclusion, the aberrant hypomethylated STAT3 might be a potential biomarker of chronic benzene poisoning.

Long non-coding RNA NR_045623 and NR_028291 involved in benzene hematotoxicity in occupationally benzene-exposed workers.

Benzene is an established human hematotoxicant and leukemogen. New insights into the pathogenesis of benzene hematotoxicity are urgently needed. Long non-coding RNA (lncRNA) widely participate in various physiological and pathological processes. It has been shown that lncRNA plays an important role in hematologic malignancy tumorigenesis. However, the expression and biological function of lncRNA during benzene hematotoxicity progress remain largely unknown. An integrated analysis of differentially expressed lncRNA and mRNA was performed to identify genes which were likely to be critical for benzene hematotoxicity through Microarray analysis. Dynamic gene network analysis of the differentially expressed lncRNA and mRNA was constructed and two main lncRNA (NR_045623 and NR_028291) were discovered and two key lncRNA subnets were involved in immune responses, hematopoiesis, B cell receptor signaling pathway and chronic myeloid leukemia. These findings suggested that NR_045623 and NR_028291 might be the key genes associated with benzene hematotoxicity.