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The emergence and spread of carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) is causing worldwide concern. Sequence type (ST) 86 K. pneumoniae, a major hvKP clone, is rarely resistant to carbapenem. In this study, we report the genomic features and virulence characteristics of a community-acquired bloodstream infection (CA-BSI)-causing CR-hvKP ST86 strain (KPN55602). This strain is resistant to carbapenem but sensitive to amikacin, gentamicin, tigecycline, and colistin. According to in vitro and in vivo virulence assessments, it was classified as hypervirulent. Whole-genome sequencing revealed that KPN55602 has a single 5.13 Mb chromosome and two plasmids. The chromosome of KPN55602 is phylogenetically similar to those of other sequenced ST86 strains. The incompatibility (Inc) group HI1B plasmid pK55602_1, harboring a set of virulence genes, was classified as a virulence plasmid. The IncX6 plasmid pK55602_2, carrying blaKPC-2, was transferable through conjugation and is highly homologous to all five sequenced blaKPC-bearing IncX6 plasmids. In conclusion, to our knowledge, this is the first report of a CA-BSI-causing CR-hvKP ST86 strain harboring an exogenous blaKPC-2-bearing IncX6 plasmid, supplementing existing knowledge on the CR-hvKP evolutionary scenario. The IncX6 plasmid may be an important vehicle for blaKPC, and its horizontal transfer may have led to CR-hvKP evolution in the community setting.

The cosignal molecule B7-H3 is gaining attention due to its abnormal expression and abundant signal transduction in many types of malignancies. B7-H3-induced signaling includes at least three cascades: PI3K/AKT, JAK2/STAT3, and Raf/MEK/ERK1/2, which are also involved in epidermal growth factor receptor- (EGFR-) triggered signaling in lung adenocarcinoma cells. However, the correlation between B7-H3-induced signaling and EGFR signaling, and between B7-H3-targeted immunotherapy and EGFR-targeted therapy in lung adenocarcinoma, remains to be elucidated. Herein we find that knockout of B7-H3 gene decreased cell survival and increased EGFR-tyrosine kinase inhibitor gefitinib susceptibility of both H3255 and HCC827 cells, two lung adenocarcinoma cell lines harboring EGFR L858R (exon 21) and Del E746-A750 (exon 19) mutations, respectively. B7-H3 deletion resulted in dramatic reduction of phosphorylation level of AKT and STAT3 in H3255 cells while having mild-to-moderate suppression on AKT, STAT3, and ERK1/2 in HCC827 cells. Gefitinib had similar effects with B7-H3 deletion both in H3255 and HCC827 cells. Furthermore, B7-H3 ablation had significant synergistic effects with gefitinib in HCC827 cells. Collectively, our study reveals B7-H3-induced signaling in lung adenocarcinoma cell lines with divergent EGFR mutations, and a translational potential of combined targeted therapy of B7-H3 and EGFR in lung adenocarcinoma with EGFR Del E746-A750 mutation.

The soluble amyloid protein procurer α (sAPPα) and β (sAPPβ) have been postulated as promising new cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) and multiple other neurodegenerative diseases, but have failed to meet expectations with their often discordant and even contradictory findings to date. The aim of the study was to systematically explore this issue. Cochrane Library, PubMed, and CNKI were systematically searched without language or date restrictions. This network meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and also adhered to the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. Twenty studies, comprising ten groups, were eligible and included. Overall, 19 eligible studies with 1634 patients contributed to the analysis of CSF sAPPα levels and 16 eligible studies with 1684 patients contributed to the analysis of CSF sAPPβ levels. CSF sAPPβ levels are significantly higher in AD than in corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP); higher in Control than in Depression, CBS and PSP; higher in Parkinson's disease dementia (PDD) than in CBS and PSP; higher in mild cognitive impairment progressed to AD dementia during the follow-up period (pMCI) than in Depression and PSP; higher in stable mild cognitive impairment (sMCI) than in Depression. With regard to CSF sAPPα levels, there were no significant difference among groups. However, surprisingly, the resultant rankings graphically showed that pMCI populations have the highest levels of CSF sAPPα and sAPPβ. Furthermore, it seemed there was a positive correlation between CSF sAPPα and sAPPβ levels. The measurement of CSF sAPPα and sAPPβ levels may provide an alternative method for the diagnosis of early-stage AD, pMCI, which is conducive to preventive therapy.

This study was conducted to clarify the associations of tumor necrosis factor-α induced protein 3 (TNFAIP3) and TNFAIP3-interacting protein 1 (TNIP1) genetic polymorphisms with ankylosing spondylitis (AS) susceptibility. Five single nucleotide polymorphisms (SNPs) in TNFAIP3 gene and four in TNIP1 gene were genotyped in 667 AS patients and 667 matched healthy controls. Genotypes and haplotype analysis were conducted by using SPSS 23.0 and Haploview 4.2 software. The T allele and CT genotype in TNFAIP3 rs10499194 were significantly associated with a reduced AS risk (T allele vs. C allele, OR = 0.619, 95% CI = 0.430–0.889, P = 0.009; CT vs. CC, OR = 0.603, 95% CI = 0.416–0.875, P = 0.007). However, no association remained significant after Bonferroni correction. The rs13207033A- rs10499194T haplotype of TNFAIP3 conferred a protective effect on AS susceptibility. Stratification analyses suggested that rs10499194 polymorphism decreased the risk of AS in the male subgroup, subgroup aged ≥ 29, HLA-B27 positive subgroup as well as the subgroups of BASFI P

The emergence and spread of carbapenem-resistant hypervirulent

The aim of this study is to explore and identify ventilator-associated pneumonia (VAP)-related prognostic immune factors and further detect the drug-resistant pathogens to establish the theoretical guidance for clinical prevention and treatment strategies of VAP. A total of 478 patients using ventilator who were hospitalized in July 2014 to November 2016 in our hospital were enrolled in this study. About 103 patients with VAP (21.5%, 103/478) among 478 cases of patients using ventilator. Among the 103 patients with VAP, the distribution of pathogenic bacteria and drug resistance in patients with VAP were detected and analyzed. In the VAP group, 35 patients died and 43 patients had simultaneous sepsis. Compared with those of non-VAP group, the proportion of CD3+ (P = .012), CD3+CD4+ (P = .024) and CD8+CD28+ ( P = .017) T cells in VAP group increased significantly, which indicated more severe immune response. Multivariate regression model analysis revealed that tracheotomy of mechanical ventilation (P = .013), mechanical ventilation time ≥7 days (P = .02) and aspiration and reflux (P = .011) were independent risk factors associated with VAP. According to the results of bacterial culture and drug sensitivity test, rational selection of antibiotics and monitoring of patients within intensive care unit can effectively control the incidence of VAP and improve the prognosis of patients.

Introduction: To date, the relationship between the causative pathogens and the changes of hematological parameters was rarely referred and deserves further investigation. Methodology: A total of 825 adult patients, including 134 negative blood cultures patients and 691 bloodstream infection (BSI) patients, were screened for eligibility in this study. Receiver operating characteristic curves and binary logistic regression models were used to assess the power of hematological parameters to distinguish patients with BSI caused by different pathogens. Results: Except for platelet-to-lymphocyte ratio (PLR) and platelet larger cell count (P-LCC), the other hematological parameters investigated in the study were significantly different in patients with BSI caused by different pathogens, including Candida. The specific combinations of lymphocyte count (LYM), platelet count (PLT), neutrophil-to-lymphocyte ratio (NLR), mean platelet volume (MPV), MPV-to-PLT ratio (MPV/PLT), platelet larger cell ratio (P-LCR), and C-reactive protein (CRP) can improve the ability to distinguish various BSI from negative blood cultures. The highest area under the curve of was 0.753 (95% CI 0.709-0.797) for positive blood cultures, 0.715 (95% CI 0.658-0.771) for Gram-positive pathogens BSI, 0.777 (95% CI 0.730-0.824) for Gram-negative pathogens BSI, 0.797 (95% CI 0.747-0.846) for Escherichia coli BSI, 0.943 (95% CI 0.899-0.987) for Enterobacter aerogenes BSI, 0.830 (95% CI 0.740-0.921) for Pseudomonas aeruginosa BSI, and 0.767 (95% CI 0.695-0.839) for Staphylococcus aureus BSI. Conclusions: The specific combinations of hematological parameters can improve the power to distinguish patients with BSI caused by different pathogens. Attention to these parameters can be easily integrated into daily medical activities, without extra costs.

BACKGROUND: Carbapenem-resistant hypervirulent (hypermucoviscous) Klebsiella pneumoniae (CR-HMKP) poses a significant public health challenge. We investigated its epidemiology and molecular characteristics in a tertiary care hospital in eastern China. METHODS: CR-HMKP were identified among 106 non-duplicated carbapenem-resistant K. pneumoniae isolates (from June 2013 to September 2017) using the string test. The pulsotype (PT) and sequence type (ST) of CR-HMKP isolates were determined using pulsed-field gel electrophoresis and multilocus sequence typing. Resistance determinants, capsular serotypes, and virulence genes were detected by PCR and sequencing. Representative isolates from each PT were selected, and their virulence phenotypes were established using the serum killing and Galleria mellonella lethality assays. RESULTS: Of the 106 isolates, 13 (12.3%) were CR-HMKP. Seven were positive for blaNDM-1 and shared the same genotype (PT5/ST1764); the others were positive for blaKPC-2, belonged to ST11, and were divided into four different PTs. The serotype of all blaNDM-1-positive isolates was K64, while that of blaKPC-2-positive isolates were K47 (N=4) and K64 (N=2). The NDM-1-producing HMKP isolates were positive for aerobactin, exhibited high serum resistance, and elicited significantly increased larval mortality compared with the other isolates. All patients had received invasive treatment prior to infection by NDM-1-producing HMKP. The infections occurred between July and August 2016 and were hospital-acquired. CONCLUSIONS: NDM-1-producing HMKP ST1764 isolates were identified; this is the first report worldwide on an outbreak of nosocomial infection caused by these isolates. Effective surveillance and strict infection control strategies should be implemented to prevent CR-HMKP dissemination. ispartof: ANNALS OF LABORATORY MEDICINE vol:39 issue:2 pages:167-+ ispartof: location:Korea (South) status: published

Objective: The aim of this meta-analysis was to investigate the association of neutrophil lymphocyte ratio (NLR) with AS (ankylosing spondylitis) patients.Methods: PubMed, Web of Science, Cochrane ...

Various studies have investigated the serum sclerostin and bone morphogenetic protein-2 (BMP-2) levels in patients with ankylosing spondylitis (AS), but the results were inconsistent. The aim of this meta-analysis was to synthetically assess the associations of serum levels of sclerostin and BMP-2 with AS. Multiple electronic databases were searched to locate relevant articles published before November 2018. Pooled standard mean difference (SMD) with 95% confidence interval (CI) was calculated by the random-effect model. Totally, 21 studies were included. Meta-analysis results showed no significant difference between AS group and control group in serum sclerostin levels (SMD = 0.098, 95% CI − 0.395 to 0.591, p = 0.697). Nevertheless, serum BMP-2 levels in AS patients were higher than that in controls (SMD = 1.184, 95% CI 0.209 to 2.159, p = 0.017). Subgroup analysis demonstrated that European and South American AS patients had lower serum levels of sclerostin than controls. AS patients with age ≥ 40 years, erythrocyte sedimentation rate (ESR) ≤ 20 mm/h and Bath Ankylosing Spondylitis Functional Index (BASFI)

Background Carbapenem-resistant hypervirulent (hypermucoviscous) Klebsiella pneumoniae (CR-HMKP) poses a significant public health challenge. We investigated its epidemiology and molecular characteristics in a tertiary care hospital in eastern China. Methods CR-HMKP were identified among 106 non-duplicated carbapenem-resistant K. pneumoniae isolates (from June 2013 to September 2017) using the string test. The pulsotype (PT) and sequence type (ST) of CR-HMKP isolates were determined using pulsed-field gel electrophoresis and multilocus sequence typing. Resistance determinants, capsular serotypes, and virulence genes were detected by PCR and sequencing. Representative isolates from each PT were selected, and their virulence phenotypes were established using the serum killing and Galleria mellonella lethality assays. Results Of the 106 isolates, 13 (12.3%) were CR-HMKP. Seven were positive for blaNDM-1 and shared the same genotype (PT5/ST1764); the others were positive for blaKPC-2, belonged to ST11, and were divided into four different PTs. The serotype of all blaNDM-1-positive isolates was K64, while that of blaKPC-2-positive isolates were K47 (N=4) and K64 (N=2). The NDM-1-producing HMKP isolates were positive for aerobactin, exhibited high serum resistance, and elicited significantly increased larval mortality compared with the other isolates. All patients had received invasive treatment prior to infection by NDM-1-producing HMKP. The infections occurred between July and August 2016 and were hospital-acquired. Conclusions NDM-1-producing HMKP ST1764 isolates were identified; this is the first report worldwide on an outbreak of nosocomial infection caused by these isolates. Effective surveillance and strict infection control strategies should be implemented to prevent CR-HMKP dissemination.

The B7 family member B7-H3 (CD276) is involved in tumor immunity including Non-small-cell lung cancer (NSCLC). We have previously demonstrated an elevated circulating level of the soluble form of B7-H3 (sB7-H3) in NSCLC patients. However, the expression of sB7-H3 in NSCLC-derived malignant pleural effusions (MPEs) and its clinical significance remain elusive.We measured and compared sB7-H3 levels in NSCLC-derived MPEs (n=52) and nonneoplastic pleural effusions (NPEs) (n=47), and then evaluated the diagnostic performance for sB7-H3 in NSCLC-derived MPEs. The correlation between MPE-derived sB7-H3 and clinical characteristics including TNM staging system was also analyzed.The median value of sB7-H3 in 52 MPEs and 47 NPEs were 41.60ng/ml (interquartile range: 36.76-51.30ng/ml) and 31.55ng/ml (interquartile range: 26.97-36.63ng/ml) (P0.0001), respectively. At the proposed cut-off value at 38.41ng/ml, sB7-H3 was capable of discriminating NSCLC-derived MPEs from NPEs with a sensitivity of 67.3% and a specificity of 91.5% respectively. Furthermore, MPEs-derived sB7-H3 was correlated with smoking status (P=0.005), primary tumor size (T factor, P=0.03), regional lymph node dissemination (N factor, P=0.019) and distant metastasis (M factor, P=0.009) of NSCLC patients.Upregulated sB7-H3 expression in MPEs is correlated with TNM stage of NSCLC and may serve as a potential biomarker for NSCLC-derived MPEs.

To compare the CC-chemokine ligand 18 (CCL18) expression in the serum and malignant pleural effusion (MPE) of NSCLC patients and explore its regulatory effect on differentiation of monocyte-derived dendritic cells (Mo-DC).CCL18 levels in the serum and MPE from 62 NSCLC patients were quantitated by immunoassay. CCL18 in sera from 26 healthy individuals, 28 exudative pleural effusions from inflammatory pulmonary diseases and 17 transudative pleural effusions from non-inflammatory diseases were used as control. Mo-DC was generated by culturing NSCLC-derived monocytes with GM-CSF and IL-4 in the presence or absence of CCL18. The mean fluorescent intensity (MFI) of CD14, CD80, CD83, CD86 and HLA-DR were analyzed by flow cytometry (FCM). Mo-DC was then co-cultured with purified T cells and the percence of CD25(+)FoxP3(+) cells was assayed by FCM.CCL18 levels in the sera of NSCLC patients and healthy individuals were (132.70 ± 15.52) ng/ml and (18.44 ± 0.99) ng/ml, respectively (P0.001). The levels of CCL18 in MPE, exudative PE and transudative PE were (155.6 ± 13.58) ng/ml, (190.4 ± 22.33) ng/ml and (20.89 ± 3.03) ng/ml, respectively. CCL18 in the MPE was significantly higher than that in transudates (P0.001), however, no significant difference was observed between CCL18 expression in exudative PE and MPE (P = 0.172). Of note, a moderate positive correlation (r = 0.421, P0.01) was observed between CCL18 levels in the paired MPE and serum of NSCLC. In the healthy control group, Mo-DC cultured in the presence of CCL18 showed 31.4 ± 15.8 (MFI) of CD14 expression, which was significantly higher than that in Mo-DC cultured in the absence of CCL18 (18.5 ± 8.9, P0.05). In contrast, the expressions of MFI of CD80, CD83, CD86 and HLA-DR were significantly decreased upon CCL18 induction (P0.05). In the NSCLC group, GM-CSF+IL-4+CCL18 induced a MFI of 45.2 ± 13.8 of CD14 expression in Mo-DC, which was also significantly higher than that of GM-CSF+ IL-4 induction (22.6 ± 10.5, P0.01). Similarly, the expressions of MFI of CD80, CD83, CD86 and HLA-DR were significantly decreased in the presence of CCL18 (P0.05). Furthermore, the MFI of CD14, CD83, CD86 and HLA-DR had significant differences between GM-CSF/IL-4/CCL18-induced Mo-DC derived from NSCLC patients and healthy control (P0.05). Finally, CD4(+) T cells co-cultured with NSCLC-derived, GM-CSF/IL-4/CCL18-treated Mo-DC had significantly higher percent of CD25(+)FoxP3(+) cells compared with that of CD4(+) T cells stimulated with Mo-DC induced by GM-CSF/IL-4(P0.01).CCL18 is present at a high level in MPE and serum of NSCLC patients complicated with pleural effusion and a moderate positive correlation exists between CCL18 levels in the two fluids. CCL18 inhibits maturation of Mo-DC, which consequently stimulates T cells to differentiate into CD25(+)FoxP3(+) regulatory T cells.

CD83 is a widely recognized surface marker for mature dendritic cells, which are essential for priming naive CD4+ T cells into effector cells. However, CD83 is also expressed on activated CD4+ T cells, which remains an enigma in T-cell mediated immunity. Therefore, the identification of the biological features and regulation of the expression of CD83 on activated CD4+ T cells is important in understanding the function of CD83 in the adaptive immune response. The present study revealed a time-dependent manner of the expression of CD83 on anti-CD3/CD28-stimulated human CD4+ T cells, which is characterized by the maximum expression at day 2 and a significant decrease at day 3. The reduced expression is not a result of a reduced rate of cell proliferation. The activation of interleukin-2 and secretion of interferon-γ accumulated progressively from day 1 to 3. Of note, sustained expression of CD83 was observed when CD4+ T cells were induced by transforming growth factor-β to differentiate into CD4+CD25+ forkhead box P3+ regulatory T (iTreg) cells. Confocal immunofluorescence microscopy analysis demonstrated that CD83 was highly co-localized with CD25 on activated CD4+ T cells. In conclusion, the findings of the present study suggested that the continuous expression of CD83 on activated human CD4+ T cells is correlated with their differentiation into iTreg cells.