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Background Leukemia is a group of hematopoietic malignancies characterized by the accumulation and infiltration of abnormal hematopoietic stem cells or early progenitor cells. T cell acute lymphoblastic leukemia (T-ALL) is a hematologic malignancy occurring in 15 % of pediatric and 25 % of adult ALL cases. Infiltration and metastasis of leukemic cells to specific organs are consequences of disease relapse and dismal prognosis. Long non-coding RNAs (lncRNAs) have been identified to function in the migration, invasion and infiltration of tumors by regulating gene expression. Our previous studies showed that CC chemokine receptor 9 (CCR9), which specifically bind to CC chemokine ligand 25 (CCL25), promotes T-ALL infiltration. Methods Bioinformatic methods were used to screen LINC00853 in gene expression omnibus (GEO) datasets. RT-qPCR, western bolt and flow cytometry were applied to detect the expression of LINC00853 and CCR9. Transwell and martrigel-transwell were employed to assess the cells migration and invasion abilities. Fluorescence microscope was applied to observed the green fluorescence protein positive (GFP+) cells. Lentivirus and adenovirus were packed to construct nc-blank, sh-LINC00853-blank and sh-LINC00853-rescue jurkat cell lines. Results In this study, we found out the negative correlation of LINC00853 and CCR9 expression. LINC00853 was downregulated while CCR9 was upregulated in GEO datasets, T-ALL cell lines and clinical samples. Moreover, LINC00853 suppressed jurkat cells migration and invasion in vitro and restrained infiltration in liver, spleen, kidney, lung, brain, ovary of nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Conclusions These findings indicate that LINC00853 restrains T-ALL cell invasion and infiltration by regulating CCR9/CCL25.

Background The increasing use of colistin causes a serious breach in our last line of defence against MDR Gram-negative pathogens. Our previous study showed that CpxR overexpression increases the susceptibility of acrB and cpxR double-deleted Salmonella enterica serovar Typhimurium to colistin. Objectives To identify the mechanism of CpxAR and efflux pumps that synergistically enhance the susceptibility of S. Typhimurium to colistin. Methods A series of cpxR- and tolC-deleted mutants and a cpxR-complemented strain from a multidrug-susceptible standard strain of S. Typhimurium (JS) were generated in our previous study. Herein, we investigated the susceptibility of these strains to colistin through the broth microdilution method, time–kill curves and survival assays. Growth curves were measured by OD600 in LB broth, tryptone-soy broth (TSB) and M9-glucose (0.2%) minimal media. Finally, molecular mechanisms underlying the mode of action were elucidated by transcriptomic analysis. Results We found that in contrast to JS (0.8 mg/L), the MIC of colistin for JSΔtolC::kan showed a 16-fold decrease (0.05 mg/L). Notably, JSΔcpxRΔtolC and JSΔcpxRΔtolC/pcpxR were associated with a 256-fold decrease (0.0031 mg/L) compared with JS. Growth curves identified that JSΔcpxRΔtolC and JSΔcpxRΔtolC/pcpxR displayed a markedly lower growth rate and poorer adaptability. In addition, time–kill curves and survival assays showed that JSΔcpxRΔtolC and JSΔcpxRΔtolC/pcpxR were more susceptible to colistin. Lastly, double deletion of cpxR and tolC enhanced oxidative damage through promoting oxidative phosphorylation, the tricarboxylic acid (TCA) cycle and trimethylamine N-oxide (TMAO) respiration. Conclusions Our findings revealed that double deletion of cpxR and tolC significantly increases the susceptibility of S. Typhimurium to colistin.

Exercise preconditioning (EP) provides protective effects for acute cardiovascular stress; however, its mechanisms need to be further investigated. Autophagy is a degradation pathway essential for myocardium health. Therefore, we investigated whether intermittent myocardial ischemia-hypoxia affected Beclin1 and whether the changes in autophagy levels contribute to EP-induced early myocardial protective effects. Rats were trained on a treadmill using an EP model (four cycles of 10 minutes of running/10 minutes of rest). Exhaustive exercise (EE) was performed to induce myocardial injury. Cardiac troponin I (cTnI) and ischemia-hypoxia staining were used to evaluate myocardial injury and protection. Double-labeled immunofluorescence staining and western blot analysis were employed to examine related markers. EP attenuated the myocardial ischemic-hypoxic injury induced by EE. Compared with the control (C) group, the dissociations of Beclin1/Bcl-2 ratio and Beclin1 expression were both higher in all other groups. Compared with the C group, PI3KC3 and the LC3-II/LC3-I ratio were higher in all other groups, whereas LC3-II was higher in the EE and EEP + EE groups. p62 was higher in the EE group than in the C group but lower in the EEP + EE group than in the EE group. We concluded that EP increases Beclin1 via intermittent myocardial ischemia-hypoxia and induces autophagy, which exerts early myocardial protective effects and reduces the myocardial ischemic-hypoxic injury induced by exhaustive exercise.

To investigate the genetic features and biological costs of the plasmid pTW4 harboring tet(M) in an isolate of Escherichia coli ST162 from a duck. The complete nucleotide sequence of plasmid pTW4 was determined. The characteristics of plasmid pTW4 in E. coli were investigated by stability and direct competition assays. pTW4 is an IncHI2-type plasmid that contained the resistant genes tet(M), floR, strAB, sul2, rmtB, and blaCMY-2. Tet(M) is located in the composite transposon Tn6539 within the multidrug resistant (MDR) region on this plasmid. Furthermore, the resistance gene rmtB and blaCMY-2 were found outside the MDR region. The plasmid pTW4 remained stable in the host strain E. coli J53 after passage under an antibiotic-free environment for 7 days. However, the strain E. coli J53/pTW4 showed a fitness disadvantage of 6% per ten generations in the process of growth competition with E. coli J53. In conclusion, the plasmid pTW4, a mobile MDR vehicle, may promote the dissemination of tet(M), floR, rmtB, strAB, sul2, and blaCMY-2 among bacteria and then, but it appears to confer growth disadvantage to the host.

Background Gastric cancer (GC) is among the most common forms of cancer affecting the digestive system. This study sought to identify hub genes regulating early GC (EGC) in order to explore their potential for early diagnosis and prognosis of patients. Methods We utilized a publically available dataset from the Gene Expression Omnibus database (GSE55696). Differences between EGC and LGIN with respect to gene expression were compared using the limma software. Identified differentially expressed genes (DEGs) were subjected to gene ontology (GO) and pathway enrichment analyses with the DAVID application, and the STRING website and Cytoscape software were used to construct a protein-protein interaction (PPI) network incorporating these DEGs. This network was in turn used to identify hub genes among selected DEGs, which were analyzed with the Kaplan-Meier Plotter database. In addition, Western blotting, qRT-PCR, immunohistochemistry, and UALCAN were all employed to validate the relationship between the expression of these genes and GC patient prognosis. Results A total of 482 DEGs were identified, with GO analyses indicating an increase in the expression of genes linked with the development of cancer. Pathway analyses also indicated that these genes play a role in certain cancer-related pathways. The PPI network highlighted four potential hub genes, of which only ICAM1 was linked to a poor GC patient prognosis. This link between ICAM1 and GC patient outcomes was confirmed via UALCAN, Western blotting, immunohistochemistry, and qRT-PCR. Conclusion ICAM1 may therefore modulate tumor progression in GC, thus potentially representing a valuable prognostic and diagnostic biomarker of EGC.

Myeloid-derived suppressor cells (MDSCs), a heterogeneous population of myeloid cells, are characterized by their immunosuppressive abilities through the secretion of various cytokines such as inducible nitric oxide synthase, nitric oxide, reactive oxygen species, transforming growth factor-β, and arginase-1. Accumulating evidence highlights its potential role in maintaining immune tolerance in solid organ and hematopoietic stem cell transplantation. Mechanistically, MDSCs-induced transplant tolerance is mainly dependent on direct suppression of allogeneic reaction or strengthened cross-talk between MDSCs and Treg or NKT cells. Adopted transfer of in vitro- or in vivo-induced MDSCs by special drugs therefore becomes a potential strategy for maintaining transplantation tolerance. In this review, we will summarize the previously published data about the role of MDSCs in the biology of transplantation tolerance and gain insights into the possible molecular mechanism governing this process.

Objectives To characterize a novel tigecycline resistance gene, tet(X6), and a novel SXT-related integrative and conjugative element (ICE), ICEPgs6Chn1, found in a tigecycline-resistant Proteus genomospecies 6 strain, T60. Methods Strain T60 was identified by the VITEK 2 system, biochemical reactions and an SNP-based approach. The genetic profile of strain T60 was determined by WGS analysis. ICEPgs6Chn1 was analysed by PCR, conjugation experiments and bioinformatics tools. tet(X6) was characterized by cloning and protein structure prediction. Results Strain T60 was resistant to ampicillin, tetracycline, tigecycline, florfenicol, colistin and kanamycin, but susceptible to cefotaxime; it also exhibited high MICs of eravacycline (32 mg/L) and omadacycline (>64 mg/L). Only one chromosome was identified and tet(X6) was located in chromosomal ICEPgs6Chn1, a member of the SXT/R391 ICE family, of 114 368 bp and encoding the antimicrobial resistance genes floR, strB, strA, aph(3′)-Ia, aac(3)-IV, aph(4)-Ia, tet(X6) and sul2. The circular intermediate of ICEPgs6Chn1 was detected by PCR and sequencing, but conjugation experiments showed that it was not self-transmissible. Cloning of the novel gene tet(X6) and protein structure prediction revealed that Tet(X6) confers tigecycline resistance. Conclusions To our knowledge, this is the first report of a novel SXT/R391 ICE in a Proteus genomospecies 6 strain. Importantly, a novel high-level tigecycline resistance gene, tet(X6), emerged for the first time in the SXT/R391 element of Proteus genomospecies 6, revealing that ICEs may serve as an important platform for the accumulation of antibiotic resistance genes.

This study aims to investigate the prevalence of islet autoantibodies and other organ-specific autoantibodies in type 1 diabetes mellitus (T1DM) patients and characterize their clinical features. Glutamic acid decarboxylase antibody (GADA), insulinoma antigen 2 antibody (IA-2A), zinc transporter 8 antibody (ZnT8A) and tetraspanin7 antibody (TSPAN7A) were assayed by radioligand or luciferase immunoprecipitation system assays in 205 newly diagnosed acute-onset T1DM patients and 170 healthy controls. Other organ-specific autoantibodies, including thyroid peroxidase antibody (TPOA), thyroglobulin antibody (TGA), tissue transglutaminase antibody (tTGA) and 21-hydroxylase antibody (21-OHA), were also measured. The prevalence of GADA, IA-2A, ZnT8A, TSPAN7A, TPOA, TGA and 21-OHA was higher in T1DM patients than in healthy controls. The combinational assay of various islet autoantibodies could increase the frequency of autoantibody positivity in T1DM to 85.4%. GADA+ IA-2A+ T1DM patients preferentially had TPOA and TGA, while IA-2A+ patients often had tTGA. Patients positive for two or more islet autoantibodies often had TPOA and TGA. BMI of multiple islet autoantibody-positive patients was lower than that of patients with single or no islet autoantibodies, and there were no significant differences in C-peptide and glycated hemoglobin between patients positive for islet autoantibodies combined with other organ-specific antibodies and noncombined patients. Younger female patients who were islet autoantibody positive were more likely to have TPOA and TGA. The frequency of Graves' disease was much higher in T1DM patients than in healthy controls. T1DM usually occurs together with other organ-specific autoantibodies. Measuring of other organ-specific autoantibodies will be beneficial for T1DM patients.

Objective To investigate the patient safety culture regarding intravenous therapy in parts of tertiary hospitals in Guangzhou, China. Methods A cross-sectional survey was conducted. A total of 333 medical staffs members from eight hospitals in Guangzhou were included in our study using convenience sampling. An evaluation about the patient safety culture regarding intravenous therapy was conducted. Results The summarized results show that the total and level one items’ scores are greater than 4.3 points (the full mark is 5 points). The lowest scoring of the five level one items is for the hospital’s security resources (4.53±0.526), and the highest is for the hospital’s safety management commitment (4.65±0.445). Among the 25 secondary entries, the four lowest-scoring entries are “doctors who can master the knowledge of drug efficacy and adverse reactions” (4.44±0.622), “doctors who can master the knowledge of the choice of medicine” (4.45±0.621), “a guarantee of sufficient human resources” (4.46±0.647), and “doctors who can master the knowledge related to the observation and complications with the treatment of intravenous therapy operation” (4.435±0.634). Conclusions The patient safety culture regarding intravenous treatment in parts of tertiary hospitals in Guangzhou is promising, but there are still shortcomings, including the need to increase relevant resources, such as equipment facilities, training resources, and especially human input.

The NAD-dependent deacetylase Sirtuin 1 (SIRT1) plays a vital role in leukemogenesis. Nicotinamide (NAM) is the principal NAD+ precursor and a noncompetitive inhibitor of SIRT1. In our study, we showed that NAM enhanced the sensitivity of chronic myeloid leukemia (CML) to doxorubicin (DOX) via SIRT1. We found that SIRT1 high expression in CML patients was associated with disease progression and drug resistance. Exogenous NAM efficiently repressed the deacetylation activity of SIRT1 and induced the apoptosis of DOX-resistant K562 cells (K562R) in a dose-dependent manner. Notably, the combination of NAM and DOX significantly inhibited tumor cell proliferation and induced cell apoptosis. The knockdown of SIRT1 in K562R cells enhanced NAM+DOX-induced apoptosis. SIRT1 rescue in K562R reduced the NAM+DOX-induced apoptosis. Mechanistically, the combinatory treatment significantly increased the cleavage of caspase-3 and PARP in K562R in vitro and in vivo. These results suggest the potential role of NAM in increasing the sensitivity of CML to DOX via the inhibition of SIRT1.

Lung cancer has the highest morbidity and mortality among all cancers. Discovery of early diagnostic and prognostic biomarkers of lung cancer can greatly facilitate the survival rate and reduce its mortality. In our study, by analyzing Gene Expression Omnibus and Oncomine databases, we found a novel potential oncogene uridine‐cytidine kinase 2 (UCK2), which was overexpressed in lung tumor tissues compared to adjacent nontumor tissues or normal lung. Then we confirmed this finding in clinical samples. Specifically, UCK2 was identified as highly expressed in stage IA lung cancer with a high diagnostic accuracy (area under the receiver operating characteristic curve > 0.9). We also found that high UCK2 expression was related to poorer clinicopathological features, such as higher T stage and N stage and higher probability of early recurrence. Furthermore, we found that patients with high UCK2 expression had poorer first progression survival and overall survival than patients with low UCK2 expression. Univariate and multivariate Cox regression analyses showed that UCK2 was an independent risk factor related with worse DFS and OS. By gene set enrichment analysis, tumor‐associated biological processes and signaling pathways were enriched in the UCK2 overexpression group, which indicated that UCK2 might play a vital role in lung cancer. Furthermore, in cytology experiments, we found that knockdown of UCK2 could suppress the proliferation and migration of lung cancer cells. In conclusion, our study indicated that UCK2 might be a potential early diagnostic and prognostic biomarker for lung cancer.

Objectives To characterize the complete sequences of four plasmids in MCR-1-producing clinical Escherichia coli strain D72, and to depict the formation mechanism and characteristics of the cointegrate plasmid derived from the pD72-mcr1 and pD72-F33 plasmids. Methods The genetic profiles of plasmids in strain D72 and its transconjugant were determined by conjugation, S1-PFGE, Southern hybridization, WGS analysis and PCR. Plasmid sequences were analysed with bioinformatic tools. The traits of the fusion plasmid were characterized by cointegration, stability and conjugation assays. Results Strain D72, belonging to ST1114, contained four plasmids, including mcr-1-carrying pD72-mcr1, blaCTX-M-55-carrying pD72-F33, blaTEM-238-bearing pD72-IncP and pD72-IncX1 carrying aph(3′)-Ia, qnrS2 and floR. A single plasmid, pD72C, in the transconjugant was found to be larger than any plasmid in the original strain D72. Sequence analysis showed that pD72C was the fusion product of pD72-mcr1 and pD72-F33, and the recombinant event involved an intermolecular replicative mechanism. Plasmid fusion occurred at a frequency of 1.75 × 10−4 cointegrates per transconjugant. The fusion plasmid presented a high stability and conjugation frequency of 8.00 × 10−3. Conclusions To our knowledge, this is the first report of the IS26-mediated fusion of an IncN1-F33:A−:B− plasmid and an mcr-1-carrying phage-like plasmid, providing evidence for the important role of IS26 in the recombination of plasmids. The biological advantages of the fusion plasmid indicated that the fusion event presumably plays a potential role in the dissemination of mcr-1.

Aims Rituximab is a chimeric IgG-1 monoclonal antibody that depletes B cells, aiding in the treatment of several conditions including autoimmune diseases. It is not licensed for use in children. This study aimed to quantify the B cell-related pharmacodynamics of rituximab in children with autoimmune disease. Methods Routine electronic health record data were collected at a large paediatric tertiary hospital in London, UK. Dosing protocols were either 2 × 750 mg/m2 intravenous infusions of rituximab on days 1 and 15, or 4 × 375 mg/m2 infusions on days 1, 8, 15 and 22. Rituximab pharmacokinetics (PK) were not measured but CD19+ lymphocyte counts were taken before and after rituximab treatment. A dose-response model was constructed describing the life cycle of CD19+ lymphocytes, with rituximab assumed to increase the death rate. Rituximab effect was assumed to decay by first-order kinetics. Results In total, 258 measurements of CD19+ lymphocyte counts were collected from 39 children with 8 autoimmune diseases. The elimination rate constant (% relative standard error) of rituximab effect decay was 0.036 (22.7%) days-1 and CD19+ turnover was 0.02 (41%) days-1 corresponding to half-lives of 19 and 35 days respectively. Rituximab increased CD19+ death rate 35-fold, with methotrexate and cyclophosphamide associated with further increases. Simulations suggested that a single infusion of 750 mg/m2 provides similar 6-month suppression of CD19+ lymphocytes to current dosing. Conclusions Rituximab pharmacodynamics (PD) in paediatric autoimmune diseases has been described. Compared with rituximab alone, the additional effect of methotrexate or cyclophosphamide was statistically significant but small.

Objectives Secondary spinal cord injury (SCI), a reversible pathological change, involves neural inflammation and apoptosis. This study explored how microRNA (miR)-488, an inflammatory regulator as reported affected secondary SCI. Methods In vivo, Wistar rats were clipped on the spinal cord for SCI induction. In vitro, PC-12 cells were treated with lipopolysaccharide (LPS) to induce cell injuries to mimic the environment during the secondary SCI. Cell viability and apoptosis were measured by CCK-8 assay and flow cytometry. The levels of inflammation-related factors (interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF)-α) in the serum and PC-12 cells were determined by ELISA. The expressions of miR-488, high mobility group box 1 (HMGB1), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), cleaved caspase-3, toll-like receptor 4 (TLR4), phosphorylated (p)-p65 and total-p65 in rat spinal cord or PC-12 cells were analyzed by quantitative reverse transcription PCR or western blot. Results After SCI induction, rats exhibited low Basso-Beattie-Bresnahan scores, promoted the release of inflammation-related factors and downregulated miR-488. LPS treatment decreased cell viability, enhanced apoptosis and downregulated miR-488. Upregulating miR-488 neutralized LPS-induced releases of inflammation-related factors and expressions of Bax and cleaved caspase-3 and counteracted LPS-induced inhibition on Bcl-2 expression. MiR-488 directly targeted HMGB1 and miR-488 mimic decreased LPS-induced HMGB1 expression. Overexpressing HMGB1 counteracted miR-488 mimic-induced decreases in the expressions of TLR4 and p-p65 and the ratio of p-p65 to Total-p65 in LPS-treated PC-12 cells. Conclusion MiR-488 inhibited neural inflammation and apoptosis in SCI via its binding with HMGB1-mediated restraint on the TLR4/NF-κB signaling pathway.

The cardioprotection of exercise preconditioning (EP) has been well documented. EP can be divided into two phases that are the induction of exercise preconditioning (IEP) and the protection of exercise preconditioning (PEP). PEP is characterized by biphasic protection, including early exercise preconditioning (EEP) and late exercise preconditioning (LEP). LC3 lipidation-mediated autophagy plays a pivotal role in cardioprotection. This study aimed to investigate the alterations of LC3 lipidation-associated proteins during EP-induced cardioprotection against myocardial injury induced by exhaustive exercise (EE) was used in a rat model of EP. These rats were subjected to an intermittent exercise consisting of four periods, with each period including 10 min of running at 30 m/min and 0% grade (approximately 75% VO2max) followed by 10 min of intermittent rest. A model of EE-induced myocardial injury was developed by subjecting rats to a consecutive running (30 m/min, 0% grade) till exhaustion. Following EEP, the colocalization of LC3 with Atg7 was significantly increased, and LC3-I, LC3-II, LC3-II/LC3-I, Atg7, Atg4B, and Atg3 levels were significantly increased. Atg7, Atg4B, and Atg3 mRNAs were all significantly upregulated, and LC3 mRNAs tended to be higher. Following LEP, Atg4B, and Atg3 levels were significantly increased. Atg7, Atg4B, and Atg3 mRNAs were all significantly upregulated, and LC3 mRNAs tended to be higher. A group of rats were subjected to EEP followed by EE, and the co-localization of LC3 with Atg7 was significantly increased, while LC3-I, LC3-II, LC3-II/LC3-I, Atg7, Atg4B, and Atg3 levels were also significantly increased. Moreover, there was a significant increase in the co-localization of LC3 with Atg7, LC3-I, LC3-II, Atg7, and Atg4B levels during LEP followed by EE. The formation of autophagosome during LEP followed by EE may have been weaker than that during EEP followed by EE due to the lower lipidation of LC3. EP may promote autophagy to maintain cell homeostasis and survival, which cooperates for cardioprotection of alleviating exhaustive exercise-induced myocardial injury by increasing LC3 lipidation-associated proteins. There is a difference between EEP and LEP in terms of the mechanisms of cardioprotection afforded by these respective conditions. The positive regulation of transcription and translation level of LC3 lipidation-associated proteins may all be involved in the mechanism of EEP and LEP, while compared with LEP, the regulation of translation level of EEP is more positively to promote autophagy.

Background Since the winter of 2018 to the end of 2019, there has been an epidemic of Adenovirus infection in southern China, including Zhejiang province, and the number of children suffering from adenovirus pneumonia has increased significantly. Adenovirus pneumonia is often accompanied by other infections in children[3,4], but the effect of other Pathogenic coinfection on the AP has been reported few. Mycoplasma pneumoniae is also an important pathogen of community-acquired pneumonia, accounting for 20-40% of children's CAP[5]. As we know the Impact of Mycoplasma pneumoniae coinfection in children with adenovirus pneumonia, which has drawn the attention of the society and the Paediatrician now has not been reported before. This study aimed to investigate the impacts of MP coinfection on hospitalized AP patients, to identify the risk factors for those patients. Methods Nasopharyngeal swabs (NPSs) or sputum specimens for Culturing were collected from patients once they were admitted to our hospital. ADV-Ag, MP-IgM and MP nucleic acid was tested at the same time, then we classify under two groups(single AP groups and AP groups coinfected with MP) . The clinical manifestations, laboratory and imaging findings and clinical medication of the two groups were compared and analyzed.Results A total of 171 patients diagnosed with single AP and 125 patients diagnosed with AP coinfected with MP. Coinfection group lead to a significantly longer duration of fever than single AP group(p=0.03). Shortness of breath was more commonly found in the coinfection group(P = 0.023).there was no statistical difference in pulmonary signs and blood tests between the two groups (P > 0.05). pulmonary imaging, such as pulmonary consolidation, atelectasis, pleural effusion and multi lobe lesions were more common in the coinfection group (P < 0.05). The patients with coinfection had a more severe symptom, leading to a significantly longer hospitalization time, and increasing the proportion of patients using glucocorticoids and / or gamma globulin, needing oxygen inhalation(P < 0.05). Conclusions The occurrence of adenovirus pneumonia coinfected MP is high. prediction factors of prolonged fever duration and pulmonary imaging can be used to predict MP coinfection in children with adenovirus pneumonia. AP patients coinfected MP may easily turn into severe illness, and a reasonable change in treatment is necessary.

Background: To understand the prevalence of HIV-1 drug resistance and the mutation patterns in ART-failure individuals in Liaoning Province, China, we conducted a cross-sectional survey.Patients and methods: Plasma samples were collected from HIV-1-positive individuals who experienced ART failure in Liaoning Province between April 2018 and September 2019.Genotype resistance test was performed using an in-house assay on these collected samples. Factors associated with drug resistance were identified by logistic regression analysis.Results: A total of 256 HIV-1-positive individuals experiencing ART failure were tested for drug resistance from April 2018 to September 2019. Of these, the most predominant genotype was CRF01_AE, accounting for 77.73%. The resistance rate to any of the three classes of antiretroviral drugs (NNRTIs, NRTIs, and PIs) was 64.84%. Among 256 ART-failure patients, 62.89% showed drug resistance to NNRTIs, 50.39% to NRTIs, and 3.13% to PIs. G190S (31.25%) and Y181C (25.78%) mutations were the most common NNRTIs resistance mutations, and K65R (29.69%), M184V (28.52%) were the most common NRTIs resistance mutations. Factors associated with drug resistance included current ART regimen, viral load.Conclusion: The high drug resistance rate among ART-failure individuals in Liaoning Province needs more attention. Corresponding strategies for the risk factors associated with HIV drug resistance can better control and prevent the prevalence of resistance.

Exercise preconditioning (EP) can alleviate myocardial ischemic/hypoxic injury by inducing endogenous cardioprotection. Hematoxylin–eosin (HE), hematoxylin-basic fuchsin-picric acid (HBFP), and chromotrope-2R brilliant green (C-2R BG) staining have been used to visualize myocardial ischemic/hypoxic changes in previous EP studies, but comprehensive evaluation and comparisons of these methods are lacking. This study evaluated ischemic/hypoxic changes in adjacent myocardial sections by HE, HBFP, and C-2R BG and compared the characteristics of sections stained by these three methods to show changes associated with exercise-induced myocardial ischemic/hypoxic injury. Rats were randomly divided into four groups: control (C), exercise preconditioning (EP), exhaustive exercise (EE), and exercise preconditioning + exhaustive exercise (EP + EE). Adjacent myocardial sections were stained as described above and compared to evaluate the effects of exercise-induced myocardial ischemic/hypoxic injury. The three staining methods revealed consistent localization patterns of myocardial ischemic/hypoxic injury in all groups. Results suggest that EP can alleviate exhaustive exercise-induced myocardial ischemic/hypoxic injury, and the three staining methods are suitable for the histological study of exercise-induced myocardial ischemic/hypoxic injury and protection. HE staining is a simple procedure but is not specific for myocardial ischemic/hypoxic injury. HBFP and C-2R BG staining can be used to specifically visualize myocardial ischemic/hypoxic injury.

Background and Purpose: Compared with singleton births, twin pregnancies are at increased risk of significant child morbidity, particularly cerebral palsy, after high-order fetal reduction. This is termed the vanishing-twin syndrome, and is an important etiology of cerebral palsy. Antenatal corticosteroid therapy (CCT) is widely used during preterm labor to enhance lung maturity. The use of dexamethasone, however, increases the risk for detrimental long-term neurodevelopmental effects. Thus, in this study we assess the effect of CCT on neurological disability and congenital abnormality in twins over 2 years of age after fetal reduction. Methods: The CCT (38 sets of twins) and control (56 sets) groups were compared for the incidences of cerebral palsy and congenital abnormalities, as well as mean birth weight, maternal age, and mean gestational age at delivery and at fetal reduction using records from Shin-Kong Memorial Hospital for the period 1992~2000. Results: There were 94 quadruplet-reduced sets of twins in our study. All of these twins were alive and aged over 2 years at the time of this writing. The gestational age at the time of delivery was 32.4±2.7 weeks for the CCT group vs. 36±2.9 weeks for the controls, with mean birth weights of 2099±555 vs. 2405±519g, respectively (p＜0.01). All 94 sets of twins were delivered by cesarean section, with only 1 case of cerebral palsy in the CCT group, while the others had developed normally by the age of 2 years. Only mean birth weight and gestational age at delivery showed significant differences in comparisons of the 2 groups of twins. Conclusion: Limiting the number of embryo transfers is essential for preventing adverse effects of the vanishing-twin syndrome. When reduction has been performed, a prolonged gestational age at delivery is mandatory for twin babies.

Background In recent years, with the development of molecular epidemiology, molecular transmission networks based on evolutionary theory and sequence analysis have been widely used in the study of HIV-1 transmission kinetics and precision intervention in high-risk populations ,especially HIV − 1 Long-term monitoring of drug resistance and real-time prevention interventions. To analyze the characteristics of HIV-1 molecular transmission network in Liaoning, China .Methods A study on HIV infected persons with STIs in Liaoning Province from 2003 to 2019. HIV-1 RNA was extracted, amplified and sequenced, and a phylogenetic tree was constructed to determine the subtype using the well matched pol gene region sequence. The gene distance between sequences was calculated, the threshold was determined, and the propagation network was constructed.Results 109 samples of pol gene region were obtained, The main subtype of HIV-1 was CRF01, followed by B, CRF07, BC, etc.12.8% of them were resistant to HIV.At the threshold of 0.55% gene distance, 60.6% of them entered the HIV-1 molecular transmission network. Workers, sample source VCT, other testing, subtype B and drug resistance are the factors influencing the access to HIV-1 molecular transmission network.The subtype of CRF01 _ AE propagated in the molecular network to form six clusters. In the network, the difference of connection degree between different subtypes was statistically significant .Conclusion Liaoning Province should build a molecular transmission network and carry out long-term monitoring, so as to take targeted measures to block the spread of HIV and achieve accurate prevention and control.

Nonalcoholic steatohepatitis (NASH) is becoming one of the leading causes of hepatocellular carcinoma (HCC). Sorafenib is the only first-line therapy for advanced HCC despite its serious adverse effects. Here, we report that at an equivalent of approximately one-tenth the clinical dose for HCC, sorafenib treatment effectively prevents the progression of NASH in both mice and monkeys without any observed significant adverse events. Mechanistically, sorafenib's benefit in NASH is independent of its canonical kinase targets in HCC, but involves the induction of mild mitochondrial uncoupling and subsequent activation of AMP-activated protein kinase (AMPK). Collectively, our findings demonstrate a previously unappreciated therapeutic effect and signaling mechanism of low-dose sorafenib treatment in NASH. We envision that this new therapeutic strategy for NASH has the potential to translate into a beneficial anti-NASH therapy with fewer adverse events than is observed in the drug's current use in HCC.

This study aims to investigate the efficacy and safety of agomelatine, sertraline, and escitalopram for patients with senile post-stroke depression (SPSD, aged over 65 years).A total of 165 patients (aged over 65 years) with post-stroke depression (PSD) were recruited. These patients were randomly assigned to one of four groups and given an anti-depressant or a placebo as follows: group A (agomelatine in combination with conventional cerebrovascular disease medication) 48 patients; group B (sertraline in combination with conventional cerebrovascular disease medication) 47 patients; group C (escitalopram in combination with conventional cerebrovascular disease medication) 50 patients; and, a control group (conventional treatment alone) 20 patients. The efficacy of the different treatments was evaluated using the Hamilton Depression Scale (HAMD), the National Institute of Health Stroke Scale (NIHSS), and the Activities of Daily Living (ADL) Barthel index (BI) at one, two, four, and six weeks after treatment began.According to the HAMD, NIHSS score, and BI index, the patients who received one of the three antidepressant treatments showed significant improvement compared with the control group (p 0.05), but there was no significant difference between the three groups receiving anti-depressant medication (p 0.05). Laboratory tests showed that the general adverse effects of the treatments were mild in all three groups, and patients generally tolerated the treatments.A decrease of HAMD and NIHSS scores and an increase in the BI index could be observed in the patients receiving agomelatine, sertraline, or escitalopram treatment. Thus, it would appear that the condition of SPSD in older patients can be improved with the use of either agomelatine, sertraline, or escitalopram.

Background The two-component signalling systems PmrAB and PhoPQ of Salmonella have been extensively studied with regard to colistin resistance. We previously showed that overexpressed CpxR could significantly increase the colistin susceptibility (16-fold compared with the WT strain) of Salmonella enterica serovar Typhimurium (Salmonella Typhimurium) through PmrAB and PhoPQ. Objectives To identify the potential target genes of CpxR in PmrAB- and PhoPQ-related signalling pathways. Methods His6-CpxR was prokaryotically expressed and purified by Ni-NTA resin affinity chromatography. β-Galactosidase activity assays were conducted to investigate whether CpxR could regulate the promoters of colistin resistance-related genes (CRRGs). Electrophoretic mobility shift assays (EMSAs) were used to further detect His6-CpxR complexes with promoters of CRRGs. Results We demonstrated for the first time (to the best of our knowledge) that CpxR and the AcrAB–TolC efflux pump have reciprocal effects on CRRG transcription. Additionally, CpxR could regulate the colistin susceptibility of Salmonella Typhimurium by binding directly to the promoters of phoPQ, pmrC, pmrH and pmrD at the CpxR box-like sequences or indirectly through other regulators including pmrAB and mgrB. Conclusions CpxR could regulate the colistin susceptibility of Salmonella Typhimurium by a multitarget mechanism.

Patients with hepatocellular carcinoma (HCC) have different prognoses depending on whether or not they also have fibrosis. Since long non‑coding RNAs (lncRNAs) affect tumor formation and progression, the present study aimed to investigate whether their expression might help predict the survival of patients with HCC. Expression profiles downloaded from The Cancer Genome Atlas database were examined to identify lncRNAs differentially expressed (DElncRNAs) between HCC patients with or without fibrosis. These DElncRNAs were then used to develop a risk scoring system to predict overall survival (OS) or recurrence‑free survival (RFS). A total of 142 significant DElncRNAs were identified using data from 135 patients with fibrosis and 72 without fibrosis. For HCC patients with fibrosis, a risk scoring system to predict OS was constructed based on five lncRNAs (AL359853.1, Z93930.3, HOXA‑AS3, AL772337.1 and AC012640.3), while the risk scoring system to predict RFS was based on 12 lncRNAs (PLCE1‑AS1, Z93930.3, LINC02273, TRBV11‑2, HHIP‑AS1, AC004687.1, LINC01857, AC004585.1, AP000808.1, CU638689.4, AC090152.1 and AL357060.1). For HCC patients without fibrosis, the risk scoring system to predict OS was established based on seven lncRNAs (LINC00239, AC104971.4, AP006285.2, HOXA‑AS3, AC079834.2, NRIR and LINC01929), and the system to predict RFS was based on five lncRNAs (AC021744.1, NRIR, LINC00487, AC005858.1 and AC107398.3). Areas under the receiver operating characteristic curves for all risk scoring systems exceeded 0.7. Uni‑ and multivariate Cox analyses showed that the risk scoring systems were significant independent predictors of OS for HCC patients with fibrosis, or of OS and RFS for HCC patients without fibrosis, after adjusting for clinical factors. Functional enrichment analysis suggested that, depending on the risk scoring system, highly associated genes were involved in pathways mainly associated with the cell cycle, chemokines, Th17 cell differentiation or thermogenesis. The findings of the present study indicate that risk scoring systems based on lncRNA expression can effectively predict the OS of HCC patients with fibrosis as well as the OS or RFS of HCC patients without fibrosis.

Exercise has been reported to induce autophagy. We hypothesized that exercise preconditioning (EP)-related autophagy in cardiomyocytes could be attributed to intermittent ischemia–hypoxia, allowing the heart to be protected for subsequent high-intensity exercise (HE). We applied approaches, chromotrope-2R brilliant green (C-2R BG) staining and plasma cTnI levels measuring, to characterize two periods of cardioprotection after EP: early EP (EEP) and late EP (LEP). Further addressing the relationship between ischemia–hypoxia and autophagy, key proteins, Beclin1, LC3, Cathepsin D, and p62, were determined by immunohistochemical staining, western blotting, and by their adjacent slices with C-2R BG. Results indicated that exercise-induced ischemia–hypoxia is a key factor in Beclin1-dependent autophagy. High-intensity exercise was associated with the impairment of autophagy due to high levels of LC3II and unchanged levels of p62, intermittent ischemia–hypoxia by EP itself plays a key role in autophagy, which resulted in more favorable cellular effects during EEP-cardioprotection compared to LEP.

Background Colistin has been used as the last therapeutic resort for treatment of MDR Gram-negative bacteria infections in humans. The two-component system CpxAR has been reported to contribute to the MDR of bacteria. There may be a more complex network mediated by CpxAR contributing to colistin susceptibility than previously understood. Methods A series of AcrB or CpxR deletion mutants of a multidrug-susceptible standard strain of Salmonella enterica serovar Typhimurium (Salmonella Typhimurium) was constructed in our previous study. MICs of colistin were determined by the 2-fold serial broth microdilution method. Time-kill and survival assays were carried out with various concentrations of colistin. Growth curves and starvation survival were measured by OD600 or cfu count in LB and M9-glucose (0.2%) minimum media. Quantitative RT-PCR was used to determine the mRNA expression levels of target genes. Results The results showed that the MIC of colistin for the CpxR-overexpressed strain JSΔacrBΔcpxR::kan/pcpxR was dramatically decreased (0.05 mg/L) by 16-fold compared with JS (0.8 mg/L) and JSΔacrBΔcpxR::kan (0.8 mg/L). Colistin time-kill and survival assays showed that JSΔacrBΔcpxR::kan/pcpxR was more susceptible to colistin (0.05 mg/L), but had a considerably higher survivability regarding prolonged starvation stress compared with JSΔacrBΔcpxR::kan. Furthermore, the expression levels of colistin resistance-related genes (phoP, phoQ, pmrB, pmrC, pmrH and pmrD) were found to be remarkably down-regulated and the negative regulatory protein mgrB was significantly up-regulated. Conclusions This study demonstrated that CpxR may regulate the colistin susceptibility of Salmonella Typhimurium through the PmrAB and PhoPQ regulatory systems.

Eight rmtB-carrying avian Escherichia coli strains from a farm in China were characterised in our previous study, but little is known about the backbones and entire multiresistance regions (MRRs) of these plasmids. Here, three rmtB-carrying IncI1 ST136 plasmids were analysed by whole-plasmid sequencing and were compared. These plasmids were composed of an 83 470-bp IncI1 backbone carrying genes responsible for plasmid replication, transfer, maintenance and stability functions, as well as a 17 330-bp MRR for pEC006 and pEC007, and a 34 626-bp MRR for pEC008. Plasmid pEC006 was not transferable, thus truncation of the traI gene may explain the inability to conjugate. pEC008 harboured the blaTEM-1, rmtB, aacC2, tetA, floR and strAB genes as well as a class 1 integron cassette array (|dfrA12|orfF|aadA2|), which were interspersed with different mobile elements, including Tn2, Tn1721, Tn1722, Tn5393, ISCfr1, IS5057, ISCR1 and ISCR2, and three copies of IS26. The MRR of pEC008 may have resulted from transposition of Tn1722 into the plasmid backbone. Acquisition and rearrangement of MRRs demonstrated the accumulation of different resistance determinants.

In this study, two new coordination polymers (CPs) containing Co(II) ions as nodes were successfully prepared via hydrothermal synthesis employing 3′-nitro-biphenyl-2,4,4′-tricarboxylic acid (H3nbtc) and different N-donor co-ligand as the building blocks, and their chemical formulae are {[Co3(μ4-nbtc)2(μ-4,4′-bipy)2.5(μ-H2O)(H2O)3]•4H2O}n (1) and {[Co2(μ5-nbtc)(μ3 OH)(μ-4,4′-bipy)]•4,4′-bipy•H2O}n (2). Their application values in bone healing were evaluated, and their corresponding mechanism was explored. Real-time reverse transcription-polymerase chain reaction was implemented to measure the inflammatory response levels in mesenchymal stem cells after treatment with the compound. Afterward, enzyme-linked immunosorbent assay was conducted, and the TNF-α and IL-1β contents released by the mesenchymal stem cells were measured. Next, the levels of osteogenic differentiation were assessed via Western blot analysis by measuring alkaline phosphatase expression. Finally, the percentage of the Runx2 positive mesenchymal stem cells after compound treatment was determined by flow cytometry.

Introduction: In recent years, with the development of molecular epidemiology, molecular transmission networks based on evolutionary theory and sequence analysis have been widely used in research on human immunodeficiency virus (HIV)-1 transmission dynamics and precise intervention for high-risk populations. The HIV-1 molecular transmission network is a new method to study the population's access to the network, the characteristics of clustering, and the characteristics of interconnection in the network. Here, we analyzed the characteristics of the HIV-1 molecular transmission network of sexually transmitted people in Liaoning Province. Methods: A study of HIV-infected persons who were sexually transmitted in Liaoning Province from 2003 to 2019. HIV-1 RNA was extracted, amplified and sequenced, and a phylogenetic tree was constructed to determine the subtype using the well matched pol gene region sequence. The gene distance between sequences was calculated, the threshold was determined, and the molecular transmission network was constructed. Results: 109 samples of pol gene region were obtained. The main subtype of HIV-1 was CRF01_AE, followed by B, CRF07_BC, etc. 12.8% of them were resistant to HIV. At the threshold of 0.55 gene distance, 60.6% of them entered the HIV-1 molecular transmission network. Workers, sample source voluntary counseling and testing, other testing, subtype B and drug resistance are the factors influencing the access to HIV-1 molecular transmission network. The subtype of CRF01_AE formed 6 clusters in the molecular transmission network. In the network, the difference of connection degree between different subtypes was statistically significant. Discussion: The three subtypes CRF01_AE, CRF07_BC and B that enter the molecular transmission network do not have interconnections, and they form clusters with each other. It shows that the risk of transmission among the three subtypes is less than the risk of transmission within each subtype. The factors affecting HIV-1 entry into the molecular transmission network were occupation, sample source, genotype and drug resistance. The L33F mutation at the HIV-1 resistance mutation site constitutes the interconnection in the largest transmission cluster in the network. The epidemiological characteristics of HIV-infected persons in each molecular transmission cluster show that 97% of the study subjects come from the same area and have a certain spatial aggregation. Conclusion: Constructing a molecular transmission network and conducting long-term monitoring, while taking targeted measures to block the spread of HIV can achieve precise prevention and control.

// Xinzhou Deng 1, 2, * , Zhenbo Tu 1, * , Meng Xiong 1, * , Kingsley Tembo 1 , Lu Zhou 3 , Pan Liu 1 , Shan Pan 1 , Jie Xiong 1 , Xiangyong Yang 4 , Jun Leng 1 , Qian Zhang 5 , Ruijing Xiao 1 and Qiuping Zhang 1, 6 1 Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China 2 Department of Clinical Oncology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China 3 Department of Hematology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China 4 Department of Biochemical Engineering, Hubei University of Technology Engineering and Technology College, Wuhan, Hubei, China 5 Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China 6 Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, Hubei, China * These authors have contributed equally to this work Correspondence to: Qiuping Zhang, email: qpzhang@whu.edu.cn Ruijing Xiao, email: xrj7619@aliyun.com Keywords: Wnt5a, CCL25/CCR9, T-cell acute lymphoblastic leukemia, PI3K, RhoA Received: July 20, 2016 Accepted: February 27, 2017 Published: March 25, 2017 ABSTRACT Adult T-cell acute lymphoblastic leukemia (T-ALL) is a refractory leukemia. We previously showed that CCL25/CCR9 promotes T-ALL metastasis. In the present study, we assessed the effects of CCL25 on Wnt expression and the effects of Wnt5a and CCL25 on PI3K/Akt and RhoA activation. Transwell assays and mouse xenograft experiments were utilized to assess the effects of Wnt5a and CCL25 on MOLT4 cell invasion, migration and metastasis. The effects of Wnt5a on MOLT4 cell actin polarization and pseudopodium formation were examined using laser scanning confocal microscopy and scanning electron microscopy. CCL25 induced Wnt5a expression in MOLT4 cells by promoting protein kinase C (PKC) expression and activation. Wnt5a promoted MOLT4 cell migration, invasion, actin polarization, and lamellipodium and filopodia formation via PI3K/Akt-RhoA pathway activation. These effects were rescued by PI3K/Akt or RhoA knockdown or inhibition. Additionally, Wnt5a in cooperation with CCL25 promoted MOLT4 cell mouse liver metastasis and stimulated RhoA activation. These results show that CCL25/CCR9 upregulates Wnt5a by promoting PKC expression and activation in MOLT4 cells. This in turn promotes cell migration and invasion via PI3K/Akt-RhoA signaling, enhancing cell polarization and pseudopodium formation. These findings indicate that the PI3K/Akt-RhoA pathway is likely responsible for Wnt5a-induced adult T-ALL cell migration and invasion.

Cancer has been a major public health problem that has threatened human life worldwide throughout history. The main causes that contribute to the poor prognosis of cancer are metastasis and recurrence. Cancer stem cells are a group of tumor cells that possess self-renewal and differentiation ability, which is a vital cause of cancer metastasis and recurrence. Long non-coding RNAs refer to a class of RNAs that are longer than 200 nt and have no potential to code proteins, some of which can be specifically expressed in different tissues and different tumors. Long non-coding RNAs have great biological significance in the occurrence and progression of cancers. However, how long non-coding RNAs interact with cancer stem cells and then affect cancer metastasis and recurrence is not yet clear. Therefore, this review aims to summarize recent studies that focus on how long non-coding RNAs impact tumor occurrence and progression by affecting cancer stem cell self-renewal and differentiation in liver cancer, prostate cancer, breast cancer, and glioma. Electronic supplementary material The online version of this article (doi:10.1186/s13045-017-0428-9) contains supplementary material, which is available to authorized users.

Introduction Even after reconstructive surgery, it is still difficult for patients with severe burns to achieve independent eating activity. In this project, we customized the forearm pronation’s assistant tableware to assist in improvement with eating activities. Methods From January 2017 to December 2018, 28 patients with severe burns including the hands were recruited. For the patient's independent eating activities, we customized forearm pronation’s tableware (forks and spoons). We compared modified Barthel index (MBI) and Visual analogue scale (VAS) of satisfaction under three conditions: no auxiliary tableware, ADL universal cuff, or forearm pronation tableware; to compare the duration and the weight of food spilled during lunch when the patients wore the ADL universal cuff or the forearm pronation’s tableware. Differences in MBI (rank data) were tested by the Friedman test, differences in VAS (normal distribution) were tested with One-way ANOVA (Bonferroni), differences in the duration and the weight (normal distribution data) were tested by paired sample t test. Results After wearing the forearm pronation’s assistant tableware, MBI VAS both increased more than when the patients did not wear the auxiliary tableware (all p＜0.05). When the subjects wore forearm pronation tableware, the duration of lunch significantly decreased and the quality of eating activity significantly improved compared to the ADL universal cuff in eating activity (all p＜0.05). Conclusion After wearing the forearm pronation‘s assistant tableware, the patients with severe burns completely or almost completely accomplished independent eating, the duration was decreased, and during eating activity the quality and the satisfaction were improved. Clinical trial registration Chinese Clinical trial registry, ChiCTR1800019963.

Accumulating evidence shows that the AMPK-mTOR pathway modulates autophagy via coordinated phosphorylation of ULK1. The aim of the present study was to investigate the relationship between AMPK, mTOR, and ULK1 during late exercise preconditioning (LEP), and to explore whether LEP-induced myocardial protection is related to the autophagy. The exercise preconditioning (EP) protocol was as follows: rats were instructed to for run four repeated in duration of 10 minutes (including 10 minutes rest between each period) on a treadmill. Exhaustive exercise (EE) after LEP pretreatment and administration of wortmannin (an autophagy inhibitor that suppresses Class III PI3K-kinase (PI3KC3) activity) were added to test the protective effect. Cardiac troponin I (cTnI), and transmission electron microscopy (TEM), along with hematoxylin-basic fuchsin-picric acid (HBFP) staining, were used to evaluate the myocardial ischemic-hypoxic injury and protection. Western blot was used to analyze the relationship of autophagy-associated proteins. Exhaustive exercise caused severe myocardial ischemic-hypoxic injury, which led to an increase in cTnI levels, changes of ischemia–hypoxia, and cells ultrastructure. Compared with the EE group, LEP significantly suppressed exhaustive exercise-induced myocardial injury. However, wortmannin attenuated LEP-induced myocardial protection by inhibiting autophagy. Compared with the C group, AMPK was increased in the LEP, EE, and LEP+EE groups, but phosphorylation of AMPK at Thr172 was not significantly changed. Exercise did not have any effect on mTOR expression. Compared with the C group, ULK1 was increased and the ULK1ser757/ULK1 ratio was decreased in the LEP and LEP+EE groups. ULK1 was not significantly affected in the EE group, however, phosphorylation of ULK1 at Ser757 was remarkably decreased. To sum up, our results suggested that LEP promoted autophagy through the activation of AMPK-mTOR-ULK1 pathway, and that activated autophagy was partially involved in myocardial protection against EE-induced myocardial ischemic-hypoxic injury.

Importance: High-cost biologic therapies have transformed the management of immune-mediated inflammatory diseases. To optimize outcomes and reduce costs, dose adjustment informed by measurement of circulating drug levels has been shown to be effective in various settings. However, limited evidence exists for this approach with the interleukin 12 and interleukin 23 inhibitor ustekinumab.\ud \ud Objective: To evaluate clinical utility of therapeutic drug monitoring for ustekinumab in patients with psoriasis.\ud \ud Design, Setting, and Participants: A prospective observational cohort of 491 adults with psoriasis was recruited to the multicenter Biomarkers of Systemic Treatment Outcomes in Psoriasis study within the British Association of Dermatologists Biologic and Immunomodulators Register from June 2009 to December 2017; samples from some patients were taken between 2009 and 2011 as part of a pilot study with the same inclusion criteria.\ud \ud Exposure: Serum ustekinumab level measured at any point during the dosing cycle using an enzyme-linked immunosorbent assay.\ud \ud Main Outcomes and Measures: Disease activity measured using the Psoriasis Area and Severity Index (PASI) score. Treatment response outcomes were PASI75 (75% reduction in PASI score from baseline [primary outcome]), PASI90 (90% reduction of PASI score from baseline), and absolute PASI score of 1.5 or less.\ud \ud Results: A total of 491 patients (171 women and 320 men; mean [SD] age, 45.7 [12.8] years) had 1 or more serum samples (total, 853 samples obtained 0-56 weeks from start of treatment) and 1 or more PASI scores within the first year of treatment. Antidrug antibodies were detected in only 17 of 490 patients (3.5%). Early measured drug levels (1-12 weeks after starting treatment) were associated with PASI75 response 6 months after starting treatment (odds ratio, 1.38; 95% CI, 1.11-1.71) when adjusted for baseline PASI score, age, and ustekinumab dose. However, this finding was not consistent across the other PASI outcomes (PASI90 and PASI score of ≤1.5).\ud \ud Conclusions and Relevance: This real-world study provides evidence that measurement of early serum ustekinumab levels could be useful to direct the treatment strategy for psoriasis. Adequate drug exposure early in the treatment cycle may be particularly important in determining clinical outcome.

Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is the only curative treatment for multiple hematologic malignancies and non-malignant hematological diseases. However, graft-vs.-host disease (GVHD), one of the main complications after allo-HSCT, remains the major reason for morbidity and non-relapse mortality. Emerging evidence has demonstrated that innate lymphoid cells (ILCs) play a non-redundant role in the pathophysiology of GVHD. In this review, we will summarize previously published data regarding the role of ILCs in the pathogenesis of GVHD.

Acute myeloid leukemia (AML) is a myeloid malignancy characterized by the proliferation of abnormal and immature myeloid blasts in the bone marrow. Circular RNA (circRNA) is a novel class of long non-coding RNA with a stable circular conformation that regulates various biological processes. The aberrant expression of circRNA and its impact on AML progression has been reported by a number of studies. Despite recent advances in circRNA research, our understanding of the leukemogenic mechanism of circRNA remains very limited, and translating the current circRNA-related research into clinical practice is challenging. This review provides an update on the functional roles of and research progress on circRNAs in AML with an emphasis on mechanistic insights. The challenges and opportunities associated with circRNA-based diagonostic and therapeutic development in AML are also outlined.

The role of autophagy in the cardioprotection conferred by ischemic preconditioning (IPC) has been well described. This study aimed to investigate the changes in autophagy levels during the cardioprotective effects initiated by exercise preconditioning (EP).Rats were randomly divided into 4 groups: group C (control), group EP, group EE (exhaustive exercise), and group EP + EE (EP pretreatment at 0.5 hours before EE). The EP protocol included 4 periods of 10 minutes of treadmill running each at 30 m/minute with intervening 10 minute periods of rest. Hematoxylin-basic fuchsin-picric acid (HBFP) staining and plasma levels of cardiac troponin I (cTnI) were used to evaluate the ischemia-hypoxia injury in rat myocardium. Alteration levels in several autophagy proteins in the left ventricular myocardium were analyzed by Western blot. The phasic alterations of autophagy levels during EP-initiated cardioprotective phase were also examined.Compared with group C, the ischemia-hypoxia positive areas and IOD value in HBFP-staining and cTnI plasma levels increased significantly in group EE. Compared with group EE, the ischemia-hypoxia injury was markedly attenuated in group EP + EE. Compared with group C, the LC3-II/LC3-I ratio, a marker of autophagosome formation, was reduced in group EE, but the LC3-II/LC3-I ratio remained unaltered in group EP + EE. Furthermore, the LC3-II/LC3-I ratio increased significantly at 2 hours during the cardioprotective phase after EP.These results suggest that the activated autophagy level during the EP-initiated cardioprotective phase may be partly involved in the cardioprotective effects by maintaining a normal autophagy basal level during the subsequent exhaustive exercise in rat myocardium.

Tet(M)-type proteins confer resistance to tetracycline and related antibiotics by interacting with the ribosome. Genes encoding Tet(M) have been found in a range of bacteria, including Escherichia coli. In the current study, conjugation experiments were performed between seven different tetracycline-resistant, azide-susceptible E. coli strains isolated from ducks and tetracycline-sensitive, azide-resistant E.coli J53. Transconjugants were obtained from two of the strains at a frequency of 1.2 × 10−8. PCR, southern blotting and sequencing demonstrated that tet(M) in the transconjugants was located on a ~50 kb IncHI2-type plasmid and was part of a composite transposon, designated Tn6539. This transposon is flanked by two IS26 elements in opposite orientation and contains the Tn3ΔtnpA+Δorf13-lp-tet(M)+gamma delta+tnpX+ΔtnpR sequences. The Δorf13-lp-tet(M) sequence was a highly conserved genetic fragment in E. coli harboring tet(M) and mainly located in the composite transposons flanked by IS6-family elements. In summary, Tn6539 is a new composite transposon capable of horizontal transfer of tet(M) among E. coli isolates.

To analyze characteristics and underlying evolutionary processes of IncC and IncI1 plasmids in a multidrug-resistant avian E. coli strain, antibiotic susceptibility testing, PCR, conjugation assays, and next-generation sequencing were performed. The type 1 IncC plasmid pEC009.1 harbored three antimicrobial resistance regions including ISEcp1-blaCMY-2-blc-sugE, ARI-B resistance island, and ARI-A island that was a mosaic multidrug resistance region (MRR) comprised of a class 1 integron with cassette array |aac(6')-II(aacA7)|qacE∆1|sul1|, IS26-mphR(A)-mrx-mph(A)-IS26, IS26-fosA3-IS26, and mercury resistance cluster merRTPABDE. It is the first report of three different size circular forms derived from IS26-mphR(A)-mrx-mph(A)-IS26-fosA3-IS26 in ARI-A of type 1 IncC plasmid. In IncI1/ST136 pEC009.2, the truncated transposon Tn1722 carrying blaTEM-1b, rmtB, aac(3)-IId(aacC2d), and a class 1 integron with cassette array |dfrA12|orfF|aadA2|, inserted into the plasmid backbone generating 5-bp direct repeats (DRs, TATAA) at the boundaries of the region, which was highly similar to that of other IncI1 plasmids, and differed by the arrangements of resistance determinants. Comparison among two epidemic plasmid lineages showed complex MRRs respectively located in the specific position in type 1 IncC and IncI1/ST136 plasmids with conserved backbones, and these have evolved via multiple events involved in mobile elements-mediated loss and gain of resistance genes and accessory genes. Strains harboring these plasmids may serve as a reservoir for antibiotic resistance genes, thereby contributing to the rapid spread of resistance genes and posing a public health threat.

With tetracycline and anphotericin as control, using discdiffusion technique to determine the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of extracts from 110 medicinal herbs, investigating their antimicrobial activities. Found that 3 medicinal herbs, Fructus mume, Rhizoma coptidis and Flos caryophyllata have great inhibitory effect on Bacillus subtilis but no obviously inhibitory effect on Aspergillus oryzae. It is evident that the extracts of Fructus mume, Rhizoma coptidis and Flos caryophyllata have antibacterial activities and are potential preservatives in soy sauce fermentation.

Paternally expressed imprinted gene 10 (PEG10), derived from the Ty3/Gypsy family of retrotransposons, has been implicated as a genetic imprinted gene. Accumulating evidence suggests that PEG10 plays an important role in tumor growth in various cancers, including hepatocellular carcinoma, lung cancer and prostate cancer. However, the correlation between PEG10 and breast cancer remains unclear. In the present study, we evaluated and characterized the role of PEG10 in human breast cancer proliferation, cell cycle, clone formation, migration and invasion. The expression level of PEG10 was significantly elevated in breast cancer tissues and associated with distant metastasis and poor clinical outcome. Gene set enrichment analysis indicated that high expression of PEG10 could enrich cell cycle-related processes in breast cancer tissues. Ectopic overexpression of PEG10 in breast cancer cells enhanced cell proliferation, cell cycle, clone formation along with migration and invasion. Cell-to-cell junction molecule E-cadherin was downregulated and matrix degradation proteases MMP-1, MMP-2, MMP-9 were up-regulated after PEG10 overexpression. Our results demonstrated that PEG10 is a crucial oncogene and has prognostic value for breast cancer, which could be applied in breast cancer diagnosis and targeting therapy in future.

Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, are involved in a variety of physiological and pathological processes. We analyzed 11 data sets from Gene Expression Omnibus Database and found that MMP7 and MMP15 were highly expressed in multiple carcinomas. GSE13204 showed that MMP7 and MMP15 were overexpressed in acute myeloid leukemia (AML) patients. The Cancer Genome Atlas data set exhibited that high expression of MMP7 or MMP15 in bone marrow (BM) of AML patients predicted poor overall survival. The χ 2 test results indicated that high expression level of MMP7 and MMP15 were correlated with high-risk stratification and high BM blast cell percentage in AML patients. To confirm these findings, we performed reverse-transcription quantitative polymerase chain reaction (RT-qPCR) and found that MMP7 and MMP15 were highly expressed in three AML cell lines. Further study showed that MMP7 and MMP15 were highly expressed both in BM and peripheral blood in collected AML samples compared with healthy individuals. Additionally, long noncoding RNA (lncRNA) microarray of BM samples of AML patients revealed that multiple lncRNAs were correlated with MMP7 and MMP15, suggesting that lncRNAs might be involved in the pathogenesis of AML via modulating MMPs. In conclusion, our study uncovers the potential roles of MMP7 and MMP15 in the prognosis of AML.

BACKGROUND IS26-flanked transposons played an increasingly important part in the mobilization and development of resistance determinants. Heterogeneous resistance-encoding plasmid clusters with polymorphic MDR regions (MRRs) conferred by IS26 in an individual Escherichia coli isolate have not yet been detected. OBJECTIVES To characterize the complete sequence of a novel blaCTX-M-65- and fosA3-carrying IncZ-7 plasmid with dynamic MRRs from an E. coli isolate, and to depict the mechanism underlying the spread of resistance determinants and genetic polymorphisms. METHODS The molecular characterization of a strain carrying blaCTX-M-65 and fosA3 was analysed by antimicrobial susceptibility testing and MLST. The transferability of a plasmid bearing blaCTX-M-65 and fosA3 was determined by conjugation assays, and the complete structure of the plasmid was obtained by Illumina, PacBio and conventional PCR mapping, respectively. The circular forms derived from IS26-flanked transposons were detected by reverse PCR and sequencing. RESULTS A novel IncZ-7 plasmid pEC013 (∼118kb) harbouring the blaCTX-M-65 and fosA3 genes was recovered from E. coli isolate EC013 belonging to D-ST117. The plasmid was found to have heterogeneous and dynamic MRRs in an individual strain and the IS26-flanked composite transposon-derived circular intermediates were identified and characterized in pEC013. CONCLUSIONS The heterogeneous MRRs suggested that a single plasmid may actually be a cluster of plasmids with the same backbone but varied MRRs, reflecting the plasmid's heterogeneity and the survival benefits of having a response to antimicrobial-related threatening conditions in an individual strain.

Background Staphylococcus aureus is one of the most prevalent pathogens and a causative agent of a variety of infections in humans and animals. A total of 640 samples were collected from healthy animals and patients from 2013 to 2014 in Henan Province, China, to investigate the prevalence and perform molecular characterization of S. aureus. Antimicrobial resistance and virulence genes were determined and pulsed-field gel electrophoresis (PFGE) and staphylococcal cassette chromosome mec (SCCmec) typing were performed. Results Overall, 22.3% (n = 143) of the samples were positive for S. aureus. The prevalence of methicillin-resistant S. aureus (MRSA) was 5.59%. Capsular polysaccharide locus type 5 (Cap5; 56.64%) was the dominant serotype. S. aureus strains showed high resistance to penicillin (96.50%), ciprofloxacin (52.45%), amikacin (67.83%), erythromycin (96.50%), lincomycin (97.20%), and tetracycline (68.53%) and 109 (76.2%) isolates harbored six or more tested resistance genes. The most predominant resistance genes were aphA (52.45%), ermC (53.15%), and tetM (52.45%). Eighty-seven (60.8%) isolates harbored six or more tested virulence genes. The most predominant enterotoxin genes were sed (20.28%), sej (20.98%), sep (14.69%), and set (37.76%). The prevalence of lukED gene was (57.34%), and a small number of isolates carried pvl (5.59%) and TSST-1 (2.80%). A total of 130 (82.52%) isolates could be typed by PFGE with SmaI digestion. PFGE demonstrated that 45 different patterns (P) that were grouped into 17 pulsotypes and 28 separate pulsotypes using a 90% cut-off value. A total of 118 (82.52%) isolates were successfully typed by spa, and 26 spa types were identified, t15075 (14.00%) and t189 (12.59%) were the most common types. SCCmec types were detected from eight MRSA isolates, with the most prevalent type being SCCmec IVa. MRSA-SCCmec Iva-t437 was observed in human isolates. Conclusion This study revealed a high prevalence of S. aureus in healthy animals and patients from Henan Province, China. Resistant S. aureus exhibited varying degrees of multidrug resistance. The presence of antibiotic resistance and virulence genes may facilitate the spread of S. aureus strains and pose a potential threat to public health, highlighting the need for vigilant monitoring of these isolates at the human–animal interface. Electronic supplementary material The online version of this article (10.1186/s13099-018-0254-9) contains supplementary material, which is available to authorized users.