RNA editing, an essential post-transcriptional reaction occurring in double-stranded RNA (dsRNA), generates informational diversity in the transcriptome and proteome. In mammals, the main type of RNA editing is the conversion of adenosine to inosine (A-to-I), processed by adenosine deaminases acting on the RNAs (ADARs) family, and interpreted as guanosine during nucleotide base-pairing. It has been reported that millions of nucleotide sites in human transcriptome undergo A-to-I editing events, catalyzed by the primarily responsible enzyme, ADAR1. In hematological malignancies including myeloid/lymphocytic leukemia and multiple myeloma, dysregulation of ADAR1 directly impacts the A-to-I editing states occurring in coding regions, non-coding regions, and immature miRNA precursors. Subsequently, aberrant A-to-I editing states result in altered molecular events, such as protein-coding sequence changes, intron retention, alternative splicing, and miRNA biogenesis inhibition. As a vital factor of the generation and stemness maintenance in leukemia stem cells (LSCs), disordered RNA editing drives the chaos of molecular regulatory network and ultimately promotes the cell proliferation, apoptosis inhibition and drug resistance. At present, novel drugs designed to target RNA editing(e.g., rebecsinib) are under development and have achieved outstanding results in animal experiments. Compared with traditional antitumor drugs, epigenetic antitumor drugs are expected to overcome the shackle of drug resistance and recurrence in hematological malignancies, and provide new treatment options for patients. This review summarized the recent advances in the regulation mechanism of ADAR1-mediated RNA editing events in hematologic malignancies, and further discussed the medical potential and clinical application of ADAR1.

Objective: To analyze and compare therapy responses, outcomes, and incidence of severe hematologic adverse events of flumatinib and imatinib in patients newly diagnosed with chronic phase chronic myeloid leukemia (CML) . Methods: Data of patients with chronic phase CML diagnosed between January 2006 and November 2022 from 76 centers, aged ≥18 years, and received initial flumatinib or imatinib therapy within 6 months after diagnosis in China were retrospectively interrogated. Propensity score matching (PSM) analysis was performed to reduce the bias of the initial TKI selection, and the therapy responses and outcomes of patients receiving initial flumatinib or imatinib therapy were compared. Results: A total of 4 833 adult patients with CML receiving initial imatinib (n=4 380) or flumatinib (n=453) therapy were included in the study. In the imatinib cohort, the median follow-up time was 54 [interquartile range (IQR), 31-85] months, and the 7-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.2%, 88.4%, 78.3%, and 63.0%, respectively. The 7-year FFS, PFS, and OS rates were 71.8%, 93.0%, and 96.9%, respectively. With the median follow-up of 18 (IQR, 13-25) months in the flumatinib cohort, the 2-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.4%, 86.5%, 58.4%, and 46.6%, respectively. The 2-year FFS, PFS, and OS rates were 80.1%, 95.0%, and 99.5%, respectively. The PSM analysis indicated that patients receiving initial flumatinib therapy had significantly higher cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) and higher probabilities of FFS than those receiving the initial imatinib therapy (all P<0.001), whereas the PFS (P=0.230) and OS (P=0.268) were comparable between the two cohorts. The incidence of severe hematologic adverse events (grade≥Ⅲ) was comparable in the two cohorts. Conclusion: Patients receiving initial flumatinib therapy had higher cumulative incidences of therapy responses and higher probability of FFS than those receiving initial imatinib therapy, whereas the incidence of severe hematologic adverse events was comparable between the two cohorts.
Adult ; Humans ; Adolescent ; Imatinib Mesylate/adverse effects* ; Incidence ; Antineoplastic Agents/adverse effects* ; Retrospective Studies ; Pyrimidines/adverse effects* ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy* ; Treatment Outcome ; Benzamides/adverse effects* ; Leukemia, Myeloid, Chronic-Phase/drug therapy* ; Aminopyridines/therapeutic use* ; Protein Kinase Inhibitors/therapeutic use*

The aim of this paper was to observe the effect of Realgar and arsenic trioxide on gut microbiota. The mice were divided into low-dose Realgar group(RL), medium-dose Realgar group(RM), high-dose Realgar group(RH), and arsenic trioxide group(ATO), in which ATO and RL groups had the same trivalent arsenic content. Realgar and arsenic trioxide toxicity models were established after intragastric administration for 1 week, and mice feces were collected 1 h after intragastric administration on day 8. The effects of Realgar on gut microbiota of mice were observed through bacterial 16 S rRNA gene sequences. The results showed that Lactobacillus was decreased in all groups, while Ruminococcus and Adlercreutzia were increased. The RL group and ATO group were consistent in the genera of Prevotella, Ruminococcus, and Adlercreutzia but different in the genera of Lactobacillus and Bacteroides. Therefore, the effects of Realgar and arsenic trioxide with the same amount of trivalent arsenic on gut microbiota were similar, but differences were still present. Protective bacteria such as Lactobacillus were reduced after Realgar administration, causing inflammation. At low doses, the number of anti-inflammatory bacteria, such as Ruminococcus, Adlercreutzia and Parabacteroides increased, which can offset the slight inflammation caused by the imbalance of bacterial flora. At high doses, the flora was disturbed and the number of Proteobacteria was increased, with aggravated intestinal inflammation, causing edema and other inflammatory reactions. Based on this, authors believe that the gastrointestinal reactions after clinical use of Realgar may be related to flora disorder. Realgar should be used at a small dose in combination with other drugs to reduce intestinal inflammation.
Animals ; Arsenic Trioxide/pharmacology* ; Arsenicals/pharmacology* ; Bacteria/drug effects* ; Gastrointestinal Microbiome/drug effects* ; Mice ; Sulfides/pharmacology*

Objective: High PM concentration is the main feature of increasing haze in developing states, but information on its microbial composition remains very limited. This study aimed to determine the composition of microbiota in PM in Guangzhou, a city located in the tropics in China. Methods: In Guangzhou, from March 5 to 10 , 2016, PM was collected in middle volume air samplers for 23 h daily. The 16S rDNA V4 region of the PM sample extracted DNA was investigated using high-throughput sequence. Results: Among the Guangzhou samples, , , , , and were the dominant microbiota accounting for more than 90% of the total microbiota, and was the dominant gram-negative bacteria, accounting for 21.30%-23.57%. We examined the difference in bacterial distribution of PM between Beijing and Guangzhou at the genus level; was found in both studies, but was only detected in Guangzhou. Conclusion In conclusion, the diversity and specificity of microbial components in Guangzhou PM were studied, which may provide a basis for future pathogenicity research in the tropics.
Air Microbiology ; Air Pollutants ; analysis ; Bacteria ; classification ; isolation & purification ; China ; Cities ; Environmental Monitoring ; Microbiota ; Particle Size ; Particulate Matter ; analysis ; RNA, Bacterial ; analysis ; RNA, Ribosomal, 16S ; analysis

The dynamic accumulation rule of active substances in medicinal plants is of great value not only for medicinal material production and application,but also for the genetic mechanism study on the formation of medicinal ingredients,especially vital to guide medicinal material collection as well as experiment material selection and candidate gene screening in the analysis of biosynthesis pathway. This study investigated the accumulation of curcumins and terpenoids,and the biosynthesis of these metabolites,which are the active metabolites in Curcuma longa,a commonly used traditional Chinese medicine. Rhizoma of C. longa from leaf growing period,rhizome swelling period and dry matter accumulating period were used as experimental materials,to analyze the changes of metabolites and biosynthesis in the three periods by comparative transcriptome and metabolomes analysis.The results indicated that terpenoids accumulation and biosynthesis mainly occurred in leaf growing period,while curcumin accumulation and biosynthesis mainly occurred in dry matter accumulating period. Therefore,we suggested that turmeric rhizomes in leaf growth period were suitable for terpenoids biosynthetic pathway characterization,and rhizome in accumulation of dry matter period was suitable for curcuminoid biosynthesis pathway characterization. This study provides references for medicinal materialproduction and application,as well as biopathway analysis of active compounds for C. longa.
Curcuma ; chemistry ; Curcumin ; analysis ; Phytochemicals ; analysis ; Plants, Medicinal ; chemistry ; Rhizome ; chemistry ; Terpenes ; analysis

OBJECTIVE: To explore the role of Ca-NFAT signaling pathway in Ph-ALL drug resistance mediated by bone marrow stromal cells. METHODS: The transcription level of NFAT mRNA in Sup-B15 cells and Ph ALL primary cells was detected by polymerase chain reaction. The expression of P-glycoprotein in Sup-B15 cells was detected by flow cytometry. The change of NFAT protein in Sup-B15 cells was detected by Western blot. AnnexinV/7-AAD was used to label cells. Flow cytometry was used to detect cell apoptosis; Fluo 3-AM dye was used to label cells, and flow cytometry used to detect changes of Ca concentration in leukemia cells. RESULTS NFAT expression could be detected in both Sup-B15 and Ph ALL primary cells; P-glycoprotein could not be detected by flow cytometry; CAS could significantly inhibit NFAT protein expression in clinically applied drug concentrations (2.5, 5 μmol/L); Clinically applied concentration of CAS (2.5, 5 μmol / L) has no significant effect on the apoptosis of Sup-B15 cells, while higher concentration of CAS (10 μmol / L) could induce apoptosis of Sup-B15 cells. Bone marrow stromal cells OP9 could, decrease the sensitivity of Sup-B15 cells and Ph ALL primary cells to imatinib (IM); After co-culture with bone were marrow stromal cells, the Ca concentration in Sup-B15 cells was enhanced, the levels of NFAT protein and nullear protein in sup-B15 cells also were enhanced. The addition of CAS in co-culture system could inlibit the Ca-NFAT signaling pathway, reduce the protective effect of OP9 on Sup-B15 cells.Conclution:The Ca-NFAT sigualing pathway, contributes to the survival of Ph ALL cells. Bone marrow stromal cells can mediate the resistance of Ph ALL cells to IM by activating Ca-NFAT signaling pathway.
Bone Marrow Cells ; Cell Line, Tumor ; Humans ; Imatinib Mesylate ; Mesenchymal Stem Cells ; NFATC Transcription Factors ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; Signal Transduction

OBJECTIVE: To investigate the effect of stably down-regulating the FMI expression of K562 cells on the sensitivity of K562 cells to Imatinib (IM) and its possible mechanism. METHODS: Western-blot was used to detect the expression of FMI protein in K562 cells and peripheral blood mononuclear cells from the patients with chronic myelogenous leukemia, chronic myeloid blast crisis and healthy volunteers. The specific interference sequences targeting at the human FMI gene were designed and ligated into the lentiviral vector LV3; the three plasmid system-packaged lentivirus particles were used to transfect K562 cells to screen K562 cells that stably down-regulated FMI. CCK-8 assay and flow cytometry were used to determine effect of IM on cell proliferation and apoptosis. The transcription level of FMI and Fz8 in leukemia cells was detected by fluorescent quantitative PCR. The protein expression levels of FMI, Fz8, NFAT1, BCR-ABL and β-catenin in leukemia cells were detected by Western-blot. RESULTS: The expression of FMI protein could be detected in peripheral blood mononuclear cells of the patients with CML-BC and K562 cells, the FMI expression could not be detected in all the patients with CML-CP and healthy volunteers. The recombinant lentiviral vector LV3/FMI had been successfully constructed the lentivirus was packaged, and the K562 cells stably down-regulating the FMI protein were screened. After stable down-regulation of FMI expression in K562 cells, the proliferation rate of leukemia cells decreased and the apoptosis rate was increased under the same drug concentration. Both the transcription and protein expression levels of Fz8 decreased. The NFAT1 total protein level increased, as well as the nuclear translocation of protein was enhanced. There was no significant change in the expression level of BCR-ABL fusion protein. The expression level of β-catenin protein decreased. CONCLUSION After the stable down-regulation of FMI expression, the sensitivity of K562 cells to IM and apoptosis of cells increase, which are performed possibly by inhibiting the FMI-Fz8 signaling pathway and activating the Ca-NFAT and Wnt/β-catenin signaling pathway.
Apoptosis ; Drug Resistance, Neoplasm ; Fusion Proteins, bcr-abl ; Humans ; Imatinib Mesylate ; K562 Cells ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; Leukocytes, Mononuclear

OBJECTIVETo evaluate the value of blood lactic acid (BLA) as a predictor for the severity and prognosis of neonatal shock.

METHODSA total of 326 neonates with shock were enrolled and divided into three groups based on the severity, namely mild group (n=147), moderate group (n=105), and severe group (n=74). BLA level was measured during and early after (about 6 hours later) fluid resuscitation, and lactate clearance rate (LCR) was calculated. The receiver operating characteristic (ROC) curve was applied to evaluate the predictive value of BLA in neonatal shock.

RESULTSBLA level was high in all subjects prior to treatment, and was highest in the severe group and lowest in the mild group (P<0.01). BLA level was significantly higher among patients with septic shock than among those with hypovolemic, cardiogenic, and asphyxiating shock (P<0.05). BLA level was significantly reduced in patients in recovery after treatment (P<0.05). Mortality was significantly lower in patients with BLA level ≤4 mmol/L or LCR ≥10% than in those with BLA level >4 mmol/L or LCR <10% (P<0.01). BLA at 11.15 mmol/L had 100% sensitivity and 96.8% specificity in predicting severe shock. BLA at 10.65 mmol/L had 88.9% sensitivity and 74.1% specificity in predicting the prognosis (survival or dead) of newborns with shock.

CONCLUSIONSIn neonates with shock, arterial BLA level increases as the disease severity increases and is associated with prognosis, so it is a useful predictor of the severity and prognosis of neonatal shock.

OBJECTIVETo evaluate the long-term prognosis of CML patients whose BCR-ABL transcript level was warning and best response at 12 months of treatment with tyrosine kinase inhititor (TKI), and to investigate the factors affecting therapeutic efficacy and prognosis.

METHODSThe clinical data of patients with newly diagnosed CML were analyzed retrospectively. According to BCR-ABL transcript level, the 80 patients were divided into group A and group B, the patients with BCR-ABL >0.1% and ≤ 1% (warning response) were entolled in group A, and the patients with BCR-ABL ≤ 0.1% (best response) were enrolled in group B as control. The ratio of patients with main molecular response (MMR) and deep molecular response (DMR), as well as aquistation rate and cummulative rate of MR (DMR) at specified fine points in 2 groups were compared, the independent risk factors affecting the therapeutic efficacy and prognosis were analyzed.

RESULTSThe MMR and MR of the B group at 15, 18 and 24 months after TKI treatment were significantly higher than those of the A group, and the patients in the B group reached MR faster. In the 3 months, 6 months and 12 months after the demarcation point (TKI 12 months), the A group was much less easy to obtain MR (P<0.05) than the B group. Through survival analysis, there were more patients in the B group than the A group at different time points to reach MR, and the difference was statistically significant (P<0.01). The single factor analysis showed that the splenomegaly (below rib edge)> 10cm (P<0.01) and lactate dehydrogenase > 400 U/L (P<0.05) were the long-term warning factors for patients. Multivariate analysis showed that the size of the spleen was an independent factor (P<0.01) to affect the prognosis of the patients who had been warned for 12 months.

CONCLUSIONPatients at 12 months warning effect are slower and less easier to get DMR, which has a poor long-term prognosis. The size of the spleen in the patient at warning for 12 months of treatment effect can predict the relatively poor long-term prognosis. For a patient with a 12 months response to the warning, an early replacement therapy is available on the basis of combining other factors..

OBJECTIVETo investigate the effect of steadily down-regulating the expression of VE-cadherin on the chemotheraputic sensitivity of K562 cells, and explore its possible mechanism.

METHODSSpecifically targeting interference sequences carrying human VE-cadherin were designed, the recombinant lentiviral vector containing the IRES-GFP and NEO segment was constructed; recombinant lentivirus was generated by three-plasmids packing system, and transfected into K562 cells, then the cells steadily down-regulated were sorted. CCK-8 assay was performed to evaluate the VE-cadherin of chemotherapeutic (Imatinib) sensitivity of K562 cells. The apoptosis was analyzed by flow cytometry with Annexin V/7-AAD double labeling. The expressions of CD133 and ALDH1 mRNA were determined by real time PCR. The protein expressions of VE-cadherin, BCR-ABL and β-catenin were analyzed by Western blot.

RESULTSThe recombinant lentiviral vector pLB-shVEC-NEO-IRES-GFP was successfully constructed, packed into the lentivirus, then the K562 cells steadily down-regulating VE-cadherin expression was obtained. When VE-cadherin was down-rengulated in K562 cells, the proliferation rate was reduced while the the apoptosis rate was increased; the mRNA levels of CD133 and ALDH1 also were reduced; BCR-ABL fusion protein was not obviously changed; the total β-catenin protein, as well as the nuclear β-catenin protein were decreased in the K562/shVEC cells. Conclution: K562 cells are more susceptible to chemotherapy when VE-cadherin is down-regulated, that may be realized via reducing the stability and the nuclear transfer of β-catenin protein.