Adaptive evolution of carbapenem-resistant hypervirulent Klebsiella pneumoniae in the urinary tract of a single patient.

The emergence of carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKp) is a growing concern due to its high mortality and limited treatment options. Although hypermucoviscosity is crucial for CR-hvKp infection, the role of changes in bacterial mucoviscosity in the host colonization and persistence of CR-hvKp is not clearly defined. Herein, we observed a phenotypic switch of CR-hvKp from a hypermucoviscous to a hypomucoviscous state in a patient with scrotal abscess and urinary tract infection (UTI). This switch was attributed to decreased expression of rmpADC, the regulator of mucoid phenotype, caused by deletion of the upstream insertion sequence ISKpn26. Postswitching, the hypomucoid variant showed a 9.0-fold decrease in mice sepsis mortality, a >170.0-fold reduction in the ability to evade macrophage phagocytosis in vitro, and an 11.2- to 40.9-fold drop in growth rate in normal mouse serum. Conversely, it exhibited an increased residence time in the mouse urinary tract (21 vs. 6 d), as well as a 216.4-fold boost in adhesion to bladder epithelial cells and a 48.7% enhancement in biofilm production. Notably, the CR-hvKp mucoid switch was reproduced in an antibiotic-free mouse UTI model. The in vivo generation of hypomucoid variants was primarily associated with defective or low expression of rmpADC or capsule synthesis gene wcaJ, mediated by ISKpn26 insertion/deletion or base-pair insertion. The spontaneous hypomucoid variants also outcompeted hypermucoid bacteria in the mouse urinary tract. Collectively, the ISKpn26-associated mucoid switch in CR-hvKp signifies the antibiotic-independent host adaptive evolution, providing insights into the role of mucoid switch in the persistence of CR-hvKp.

Highly Electrically Conductive Polyiodide Ionic Liquid Cathode for High-Capacity Dual-Plating Zinc-Iodine Batteries.

Zinc-iodine batteries are one of the most intriguing types of batteries that offer high energy density and low toxicity. However, the low intrinsic conductivity of iodine, together with high polyiodide solubility in aqueous electrolytes limits the development of high-areal-capacity zinc-iodine batteries with high stability, especially at low current densities. Herein, we proposed a hydrophobic polyiodide ionic liquid as a zinc-ion battery cathode, which successfully activates the iodine redox process by offering 4 orders of magnitude higher intrinsic electrical conductivity and remarkably lower solubility that suppressed the polyiodide shuttle in a dual-plating zinc-iodine cell. By the molecular engineering of the chemical structure of the polyiodide ionic liquid, the electronic conductivity can reach 3.4 × 10-3 S cm-1 with a high Coulombic efficiency of 98.2%. The areal capacity of the zinc-iodine battery can achieve 5.04 mAh cm-2 and stably operate at 3.12 mAh cm-2 for over 990 h. Besides, a laser-scribing designed flexible dual-plating-type microbattery based on a polyiodide ionic liquid cathode also exhibits stable cycling in both a single cell and 4 × 4 integrated cell, which can operate with the polarity-switching model with high stability.

Performance of disk diffusion method for aztreonam in combination with avibactam against Enterobacteriales.

OBJECTIVES: To evaluate the performance of an in-house developed disk diffusion method for aztreonam in combination with avibactam against Enterobacteriales. METHODS: The in vitro antibacterial activity of aztreonam with avibactam against 204 carbapenemase-producing Enterobacteriales was determined by a disk diffusion method, with a broth microdilution method as a reference. RESULTS: The optimal S/R breakpoints for disk diffusion tests of 30/20 and 10/4 µg disks, calculated by the dBETs software using the model-based approaches, were ≥22/≤21 and ≥12/≤11 mm, respectively. On the basis of the estimated breakpoints, the CAs for disk diffusion tests of 30/20 and 10/4 µg aztreonam/avibactam disks were both 98.0%, with 0.5% major error and 37.5% very major error. CONCLUSIONS: The home-made disk diffusion method is an economical and practical method for clinical microbiology laboratories to determine the antibacterial susceptibility of aztreonam with avibactam against Enterobacteriales.

Evaluation of the in vitro activity of ampicillin-sulbactam and cefoperazone-sulbactam against A. Baumannii by the broth disk elution test.

To evaluate the in vitro activity of ampicillin-sulbactam and cefoperazone-sulbactam against A. baumannii using the broth disk elution testing, a total of 150 A. baumannii isolates were collected from across China between January 2019 and January 2021, including 51 carbapenem-susceptible and 99 carbapenem-resistant isolates. Broth disk elution (BDE) and the broth microdilution (BMD) method were performed for all strains. The concentration range of the BDE was 10/10 µg/mL, 20/20 µg/mL, and 30/30 µg/mL for ampicillin-sulbactam, and 37.5/15 µg/mL, 75/30 µg/mL, 112.5/45 µg/mL, and 150/60 µg/mL for cefoperazone-sulbactam, respectively. Compared with BMD, the BDE results of ampicillin-sulbactam and cefoperazone-sulbactam showed a categorical agreement of 83.3% (125/150) and 95.3% (143/150), with minor errors of 16.7% (25/150) and 4.7% (7/150), respectively. No major error or very major errors were detected. The sensitivity differences by BDE of carbapenem-resistant A. baumannii (CRAb) to different concentrations of ampicillin-sulbactam showed statistically significant (p < 0.017), while those to cefoperazone-sulbactam at 37.5/15 µg/mL, 75/30 µg/mL, and 112.5/45 µg/mL were significant (p < 0.008). However, no significant difference in sensitivity was observed between 112.5/45 µg/mL and 150/60 µg/mL (p > 0.008). In conclusion, the BDE is a reliable and convenient method to detect the in vitro activity of cefoperazone-sulbactam against A. baumannii, and the results could serve as a clinical reference value when deciding whether or not to use high-dose sulbactam for the treatment of A. baumannii infections.

Modification of carbapenemase inhibition test and comparison of its performance with NG-Test CARBA 5 for detection of carbapenemase-producing Enterobacterales.

AIMS: Adequately and accurately identifying carbapenemase-producing Enterobacterales (CPE) is vital for selecting appropriate antimicrobial therapy and implementing effective infection control measures. This study aims to optimize the phenotypic detection method of carbapenemase for routine diagnostics in clinical microbiology laboratories. METHODS AND RESULTS: Carbapenemase genes in 2665 non-duplicate CRE clinical strains collected from various regions of China were confirmed through whole-genome sequencing (WGS). The carbapenemase inhibition test (CIT) was conducted and interpreted using different methods and breakpoints, then compared with the NG-Test CARBA 5 for carbapenemase detection. The diagnostic performance of the CIT method was optimal when the carbapenemase types were determined by comparing the inhibition zone diameters of the imipenem disc with 3-aminophenylboronic acid (APB) plus ethylenediaminetetraacetic acid (EDTA) to those of the imipenem disc with either APB or EDTA alone, with a breakpoint of 4 mm. The overall sensitivities of the current CIT, the modified CIT, and NG-Test CARBA 5 were 91.4%, 94.9%, and 99.9%, respectively. For detecting isolates co-producing Klebsiella pneumoniae carbapenemase (KPC) and metallo-ß-lactamases (MBLs), the modified CIT method had higher sensitivity than the current method (70.0% vs. 53.3%), though this difference was not statistically significant (P = 0.063). The NG-Test CARBA 5 showed excellent performance for multi-carbapenemases diagnosis, with sensitivity and specificity of 97.1% and 100%, respectively. CONCLUSIONS: Optimizing and standardizing the CIT method for clinical use is necessary. It has certain advantages in diagnosing multi-carbapenemase and rare carbapenemase production. However, for identifying common carbapenemase types, the NG-Test CARBA 5 demonstrated superior performance.

Suppressed Dissolution of Fluorine-Rich SEI Enables Highly Reversible Zinc Metal Anode for Stable Aqueous Zinc-Ion Batteries.

The instability of the solid electrolyte interface (SEI) is a critical challenge for the zinc metal anodes, leading to an erratic electrode/electrolyte interface and hydrogen evolution reaction (HER), ultimately resulting in anode failure. This study uncovers that the fluorine species dissolution is the root cause of SEI instability. To effectively suppress the F- dissolution, an introduction of a low-polarity molecule, 1,4-thioxane (TX), is proposed, which reinforces the stability of the fluorine-rich SEI. Moreover, the TX molecule has a strong affinity for coordinating with Zn2+ and adsorbing at the electrode/electrolyte interface, thereby diminishing the activity of local water and consequently impeding SEI dissolution. The robust fluorine-rich SEI layer promotes the high durability of the zinc anode in repeated plating/stripping cycles, while concurrently suppressing HER and enhancing Coulombic efficiency. Notably, the symmetric cell with TX demonstrates exceptional electrochemical performance, sustaining over 500 hours at 20 mA cm-2 with 10 mAh cm-2. Furthermore, the Zn||KVOH full cell exhibits excellent capacity retention, averaging 6.8 mAh cm-2 with 98 % retention after 400 cycles, even at high loading with a lean electrolyte. This work offers a novel perspective on SEI dissolution as a key factor in anode failure, providing valuable insights for the electrolyte design in energy storage devices.

Efficacy and safety of PD-1 inhibitor alone or combined with chemotherapy in patients with relapsed or refractory extranodal natural Killer/T cell lymphoma: A retrospective study.

Extranodal natural killer/T cell lymphoma (ENKTL) patients typically face a grim prognosis after relapse or progression following asparaginase-based chemotherapy. Currently, programmed cell death protein-1 (PD-1) immune checkpoint blockade has shown promising efficacy as an optimal regimen for relapsed or refractory ENKTL (rrENKTL) patients. This study retrospectively investigated the efficacy, safety, and factors influencing the survival of 26 rrENKTL patients who underwent monoclonal antibody treatment using PD-1 (Sintilimab or Camrelizumab) alone or combined with chemotherapy from January 2018 to February 2022. The disease control rate was 73.1%, and the objective response rate was 50.0%. 15.4% of the patients achieved complete remission, and 34.6% achieved partial remission (PR). After a median follow-up of 12 (range 3-47) months, the median progression-free survival (PFS) and overall survival (OS) were 6.5 and 13.3 months. The 1-year PFS and OS rate were 23.1% and 53.8%. 96.2% of patients experienced at least one adverse event and 26.9% experienced grade 1-2 immune-related adverse events. PD-1 inhibitor improved rrENKTL patient survival, and the AEs were controlled. We also observed that the prognostic index for NK cell lymphoma including Epstein-Barr virus (EBV) (PINK-E) and the nomogram-revised risk indexz for ENKTL patients could help identify a potentially unfavorable prognosis in this era of immunotherapy. More attention should be paid to the presence of EBV after anti-PD-1 immunotherapy, as it more accurately indicates a poor prognosis.

Enzymatic basis for stepwise C-glycosylation in the formation of flavonoid di-C-glycosides in sacred lotus (Nelumbo nucifera Gaertn.).

Lotus plumule, the embryo of the seed of the sacred lotus (Nelumbo nucifera), contains a high accumulation of secondary metabolites including flavonoids and possesses important pharmaceutical value. Flavonoid C-glycosides, which accumulate exclusively in lotus plumule, have attracted considerable attention in recent decades due to their unique chemical structure and special bioactivities. As well as mono-C-glycosides, lotus plumule also accumulates various kinds of di-C-glycosides by mechanisms which are as yet unclear. In this study we identified two C-glycosyltransferase (CGT) genes by mining sacred lotus genome data and provide in vitro and in planta evidence that these two enzymes (NnCGT1 and NnCGT2, also designated as UGT708N1 and UGT708N2, respectively) exhibit CGT activity. Recombinant UGT708N1 and UGT708N2 can C-glycosylate 2-hydroxyflavanones and 2-hydroxynaringenin C-glucoside, forming flavone mono-C-glycosides and di-C-glycosides, respectively, after dehydration. In addition, the above reactions were successfully catalysed by cell-free extracts from tobacco leaves transiently expressing NnCGT1 or NnCGT2. Finally, enzyme assays using cell-free extracts of lotus plumule suggested that flavone di-C-glycosides (vicenin-1, vicenin-3, schaftoside and isoschaftoside) are biosynthesized through sequentially C-glucosylating and C-arabinosylating/C-xylosylating 2-hydroxynaringenin. Taken together, our results provide novel insights into the biosynthesis of flavonoid di-C-glycosides by proposing a new biosynthetic pathway for flavone C-glycosides in N. nucifera and identifying a novel uridine diphosphate-glycosyltransferase (UGT708N2) that specifically catalyses the second glycsosylation, C-arabinosylating and C-xylosylating 2-hydroxynaringenin C-glucoside.

Association of recurrent APOBEC3B alterations with the prognosis of gastric-type cervical adenocarcinoma.

OBJECTIVE: Gastric-type cervical adenocarcinoma (GCA) is a rare and aggressive type of endocervical adenocarcinoma (ECA) with distinct histopathologic features and unfavorable treatment outcomes, but no genomic prognostic factor has been revealed. We aimed to systematically investigate the somatic alterations of GCA at genome-wide level and evaluate their prognostic value. METHODS: We performed whole-exome sequencing (WES) on 25 pairs of tumor and matched normal samples to characterize the genomic features of Chinese patients with GCA and investigated their relations to histopathological characterizations and prognosis. The prognostic value of the genomic alterations was evaluated in a total of 58 GCA patients. RESULTS: Mutations were commonly observed in reported GCA-related driver genes, including TP53 (32%), CDKN2A (20%), SKT11 (20%), BRCA2 (12%), SMAD4 (12%), and ERBB2 (12%). Recurrent novel trunk mutations were also observed in PBRM1 (12%), FRMPD4 (12%), and NOP2 (8%) with high variant allele frequency. Moreover, enrichment of the APOBEC signature was attributed to frequent gain of somatic copy number alteration (SCNA) of APOBEC3B (20%), which perfectly matched the nuclear-positive staining of APOBEC3B through immunohistochemistry. In contrast, APOBEC3B alteration was absent in patients with conventional type of ECA (N = 52). Notably, positive APOBEC3B was consistently enriched in patients with favorable prognosis in both the discovery cohort and an additional 33 GCA patients, thus indicating a significant association with lower relapse risk of GCA independent of cancer stage (P = 0.02). CONCLUSION: Our results can aid understanding of the molecular basis of GCA in the Chinese population by providing genomic profiles and highlighting the potential prognostic value of APOBEC3B for GCA through routine clinical IHC.

Analysis of the expression and prognosis for leukocyte immunoglobulin-like receptor subfamily B in human liver cancer.

BACKGROUND: Leukocyte immunoglobulin-like receptor subfamily B (LILRB), including 5 subtypes, is a group of inhibitory receptors in the immune system. The LILRB family is known to be involved in the tumor progression of various cancer types, especially liver cancer. However, the expression patterns and prognostic values of LILRB family members in liver cancer tissues remain unclear. METHODS: We used the Oncomine database, GEPIA database, Kaplan-Meier Plotter, Timer, and TISIDB to assess the expression and prognostic value of the LILRB family in liver cancer patients. We also verified the expression of the LILRB family in tumor tissues and tumor-free liver tissues at the protein level by using immunohistochemistry. The STRING website was used to explore the interaction between the LILRB family and their related genes. The DAVID database was used to perform the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Flow cytometry was used to assess the infiltrated NK cells in liver cancer tissues. RESULTS: Our study revealed that the mRNA expression of LILRB1, LILRB2, LILRB3, and LILRB5 was downregulated, while compared with normal tissues, the mRNA expression of LILRB4 was upregulated in liver cancer tissues. Survival analysis revealed that LILRB2 and LILRB5 mRNA expression levels were significantly positively associated with overall survival (OS) and disease-free survival (DSS) and that the mRNA expression of all LILRB family members was significantly positively correlated with recurrence-free survival (RFS) and progression-free survival (PFS). Next, we further found that the mRNA expression of all LILRB family members was significantly associated with the infiltration of B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells in liver cancer. Finally, GO and KEGG analyses found that the LILRB family and its related genes were involved in antigen processing and presentation and natural killer cell-mediated cytotoxicity pathways. CONCLUSIONS: Our study suggested that LILRB family expression was associated with the prognosis of liver cancer patients and infiltrated immune cells. The LILRB family might be involved in antigen processing and presentation and natural killer cell-mediated cytotoxicity pathways.

Partial Hydrolysis of Cyanide Coordination Polymers Induced by a Pillar Ligand with Optimized Electrochemical Kinetics for Rechargeable Alkaline Batteries.

Coordination polymers are promising cathode materials for rechargeable alkaline batteries. Therefore, the precise modulation of these cathodes by chemical structure and in-depth structure transform study is necessary. Here, two model coordination polymer battery cathodes were designed to demonstrate the dynamic structure-performance relationship. We studied the electrochemical performance of two kinds of nickel-based coordination polymer, comprising a planar 2D cyanide-bridged network and a 3D cyanide-bridged network pillared by pyrazine molecules. The 2D coordination polymer showed serious voltage degradation with poor rate capability, whereas the 3D coordination polymer exhibited stable voltage output coupled with high rate at various current densities. The investigation revealed the underlining relationship of plateau voltage degradation and hydrolysis process of electrodes. It was revealed that the pyrazine pillar molecules in the 3D coordination polymer could suppress the hydrolysis and lead to the in situ formation of partially hydrolyzed structure with excellent electrochemical kinetics; this exhibited obvious smaller peak separation (27 mV compared with 149 mV) and hence an almost twofold increase in capacity retention (31.9 to 50.0 %) and energy density retention (18.2 to 35.9 %) at 10 A g-1 .

Comparative activities of sitafloxacin against recent clinical isolates in hospitals across China.

Sitafloxacin is one of the newer generation fluoroquinolones. Considering the ever-changing antimicrobial resistance, it is necessary to monitor the activities of sitafloxacin against recent pathogenic isolates. Therefore, we determined the minimum inhibitory concentrations (MICs) of sitafloxacin and comparators by broth microdilution or agar dilution method against 1101 clinical isolates collected from 2017 to 2019 in 31 hospitals across China. Sitafloxacin was highly active against gram-positive isolates evidenced by the MICs required to inhibit the growth of 50%/90% isolates (MIC50/90): ≤ 0.03/0.25, ≤ 0.03/0.125, ≤ 0.03/2, 0.125/0.25, 0.25/2, and 0.125/0.125 mg/L for methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-susceptible coagulase-negative Staphylococcus (MSCNS), methicillin-resistant S. aureus (MRSA), methicillin-resistant CNS, Enterococcus faecalis, and Streptococcus pneumoniae, respectively. Sitafloxacin inhibited 82.8% of the MRSA strains and 97.5% of MRCNS strains. Sitafloxacin was also potent against ciprofloxacin-susceptible Escherichia coli (MIC50/90: ≤ 0.03/0.06 mg/L) and Klebsiella pneumoniae (MIC50/90: ≤ 0.03/0.125 mg/L), non-ESBL-producing E. coli (MIC50/90: ≤ 0.03/1 mg/L) and K. pneumoniae (MIC50/90: ≤ 0.03/0.5 mg/L), Haemophilus influenzae (MIC50/90: ≤0.015/0.06 mg/L), Haemophilus parainfluenzae (MIC50/90: 0.125/0.5 mg/L), Moraxella catarrhalis (MIC50/90: ≤ 0.015/≤ 0.015 mg/L), Bacteroides fragilis (MIC50/90: 0.06/2 mg/L), Peptostreptococcus (MIC50/90: 0.125/4 mg/L), and Mycoplasma pneumoniae (≤ 0.03/≤ 0.03 mg/L). However, sitafloxacin was less active for Enterococcus faecium, ciprofloxacin-resistant and/or ESBL-producing E. coli, and K. pneumoniae strains. Sitafloxacin was superior or comparable to most of the comparators in activities against the abovementioned isolates, so sitafloxacin is still highly active against most of the clinical isolates in hospitals across China, proving its utility in treatment of the abovementioned susceptible strains.

Performance of VITEK 2, E-test, Kirby-Bauer disk diffusion, and modified Kirby-Bauer disk diffusion compared to reference broth microdilution for testing tigecycline susceptibility of carbapenem-resistant K. pneumoniae and A. baumannii in a multicenter study in China.

Tigecycline is an alternative antibiotic for managing carbapenem-resistant Gram-negative bacterial infections. However, disk diffusion and automated testing often show false-intermediate or false-resistant results in tigecycline susceptibility, misleading clinical antimicrobial therapy. Broth microdilution (BMD) is the reference method for testing tigecycline susceptibility, but it is labor intensive and time consuming to perform in clinical laboratories. Therefore, a simple and accurate method is urgently needed. We evaluated the performance of VITEK 2, E-test, Kirby-Bauer disk diffusion (KB), and modified KB disk diffusion (mKB) versus BMD in testing tigecycline susceptibility of 372 strains of carbapenem-resistant Klebsiella pneumoniae (CRKP) and 346 strains of carbapenem-resistant Acinetobacter baumannii (CRAB). BMD confirmed that 96.8% of CRKP and 91% of CRAB strains were susceptible to tigecycline. E-test, VITEK 2, KB, and mKB yielded categorical agreement of 96.7/59.3%, 69.9/54.3%, 78.5/87.3%, and 96.5%/91% for CRKP/CRAB, respectively. No very major error was found for either CRKP or CRAB by any method. No major error was found for CRKP or CRAB by the mKB method. The mKB method enhanced by R-buffer is simple, accurate, and inexpensive for clinical laboratories to test the susceptibility of CRKP and CRAB isolates to tigecycline.

Emergence and Recovery of Ceftazidime-avibactam Resistance in blaKPC-33-Harboring Klebsiella pneumoniae Sequence Type 11 Isolates in China.

This is the first report of ceftazidime-avibactam resistance caused by the blaKPC-33 mutation through the D179Y variant during the treatment of blaKPC-2-positive Klebsiella pneumoniae-related infections in China. The blaKPC-33-containing K. pneumoniae was susceptible to meropenem-vaborbactam, cefepime-zidebactam, tigecycline, and polymyxin B. The blaKPC-33 gene was located on a 77 551-bp transformable plasmid harboring qnrS1 and blaLAP-2. Detecting blaKPC-33-positive K. pneumoniae clinical strains is important for infection control.

In Vitro Activity of Cefepime-Zidebactam, Ceftazidime-Avibactam, and Other Comparators against Clinical Isolates of Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii: Results from China Antimicrobial Surveillance Network (CHINET) in 2018.

This study evaluated the in vitro activity of cefepime-zidebactam in comparison with that of ceftazidime-avibactam and other comparators against clinically significant Gram-negative bacillus isolates. A total of 3,400 nonduplicate Gram-negative clinical isolates were collected from 45 medical centers across China in the CHINET Program in 2018, including Enterobacterales (n = 2,228), Pseudomonas aeruginosa (n = 657), and Acinetobacter baumannii (n = 515). The activities of cefepime-zidebactam and 20 comparators were determined by broth microdilution as recommended by the Clinical and Laboratory Standards Institute. Cefepime-zidebactam demonstrated potent activity against almost all Enterobacterales (MIC50/90, 0.125/1 mg/liter) and good activity against P. aeruginosa (MIC50/90, 2/8 mg/liter). Among the 373 carbapenem-resistant Enterobacteriaceae isolates, 57.3% (213/373) and 15.3% (57/373) were positive for blaKPC-2 and blaNDM, respectively. Cefepime-zidebactam showed a MIC of ≤2 mg/liter for 92.0% (196/213) of blaKPC-2 producers and 79.7% (47/59) of blaNDM producers. Ceftazidime-avibactam showed good in vitro activity against Enterobacterales (MIC50/90, 0.25/2 mg/liter; 94.0% susceptible) and P. aeruginosa (MIC50/90, 4/16 mg/liter; 86.9% susceptible). Ceftazidime-avibactam was active against 9.1% of carbapenem-resistant Escherichia coli isolates (63.6% were blaNDM producers) and 84.6% of Klebsiella pneumoniae isolates (74.3% were blaKPC producers). Most (90.1%) blaKPC-2 producers were susceptible to ceftazidime-avibactam. Cefepime-zidebactam demonstrated limited activity (MIC50/90, 16/32 mg/liter) against the 515 A. baumannii isolates (79.2% were carbapenem resistant), and ceftazidime-avibactam was less active (MIC50/90, 64/>64 mg/liter). Cefepime-zidebactam was highly active against clinical isolates of Enterobacterales and P. aeruginosa, including blaKPC-2-positive Enterobacterales and blaNDM-positive Enterobacterales and carbapenem-resistant P. aeruginosa And ceftazidime-avibactam was highly active against blaKPC-2-positive Enterobacterales and carbapenem-resistant P. aeruginosa.

Comparative In Vitro Activities of Ceftaroline and Tedizolid against Clinical Strains of Staphylococcus aureus and Enterococcus: Results from the China Antimicrobial Surveillance Network (CHINET) in 2018.

The in vitro activities of ceftaroline and tedizolid were compared against Staphylococcus aureus, Enterococcus faecalis, and Enterococcus faecium clinical isolates collected from the China Antimicrobial Surveillance Network. Ceftaroline demonstrated potent activity against S. aureus isolates (MIC50/90, ≤0.25/1 mg/liter). Tedizolid was also highly active against S. aureus (MIC50/90, 0.25/0.5 mg/liter) and Enterococcus (MIC50/90, 0.5/0.5 mg/liter) isolates. Our results support the clinical usefulness of ceftaroline and tedizolid in treating Gram-positive infections.

Simultaneous Discrimination of Hypochlorite and Single Oxygen during Sepsis by a Dual-Functional Fluorescent Probe.

Hypochlorite (ClO-) and singlet oxygen (1O2) commonly coexist in living systems and exert important interplaying roles in many diseases. To dissect their complex inter-relationship, it is urgently required to construct a fluorescent probe that can discriminate ClO- and 1O2 in living organisms. Herein, by taking the 3-(aliphaticthio)-propan-1-one group as the unique recognition unit for both ClO- and 1O2, we proposed the first fluorescent probe, Hy-2, to simultaneously discriminate ClO- and 1O2 with high sensitivity and selectivity. Probe Hy-2 itself showed fluorescence in blue channel. After treatment with ClO- and 1O2, respectively, pronounced fluorescence enhancements were observed in the green channel and red channel correspondingly. Moreover, upon development of the probe with aggregation-induced emission (AIE) characteristics, the probe could work well in a solution with high water volume fraction. Probe Hy-2 was also able to accumulate into mitochondria and was utilized as an effective tool to image exogenous and endogenous ClO- and 1O2 in mitochondria. Significantly, as the first trial, probe Hy-2 was employed to simultaneously monitor the variation of ClO- and 1O2 level in cecal tissues of rat in the cecal ligation and puncture (CLP)-induced polymicrobial sepsis model. The results demonstrated that the expressed ClO- and 1O2 levels were tightly correlated with the severity of sepsis, inferring that the overproduction of ClO- and 1O2 is an important factor in the pathogenesis of sepsis. The probe illustrated herein may provide a guide for further exploring the functions of ClO- and 1O2 in various diseases.

Results from the China Antimicrobial Surveillance Network (CHINET) in 2017 of the In Vitro Activities of Ceftazidime-Avibactam and Ceftolozane-Tazobactam against Clinical Isolates of Enterobacteriaceae and Pseudomonas aeruginosa.

The in vitro activities of ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C-T), and comparators were determined for 1,774 isolates of Enterobacteriaceae and 524 isolates of Pseudomonas aeruginosa collected by 30 medical centers from the China Antimicrobial Surveillance Network (CHINET) in 2017. Antimicrobial susceptibility testing was performed by the CLSI broth microdilution method, and blaKPC and blaNDM were detected by PCR for all carbapenem-resistant Enterobacteriaceae (CRE). Ceftazidime-avibactam demonstrated potent activity against almost all Enterobacteriaceae (94.6% susceptibility; MIC50, ≤0.25 mg/liter; MIC90, ≤0.25 to >32 mg/liter) and good activity against P. aeruginosa (86.5% susceptibility; MIC50/90, 2/16 mg/liter). Among the CRE, 50.8% (189/372 isolates) were positive for blaKPC-2, which mainly existed in ceftazidime-avibactam-susceptible Klebsiella pneumoniae isolates (92.1%, 174/189). Among the CRE, 17.7% (66/372 isolates) were positive for blaNDM, which mainly existed in strains resistant to ceftazidime-avibactam (71.7%, 66/92). Ceftolozane-tazobactam showed good in vitro activity against Escherichia coli and Proteus mirabilis (MIC50/90, ≤0.5/2 mg/liter; 90.5 and 93.8% susceptibility, respectively), and the rates of susceptibility of K. pneumoniae (MIC50/90, 2/>64 mg/liter) and P. aeruginosa (MIC50/90, 1/8 mg/liter) were 52.7% and 88.5%, respectively. Among the CRE strains, 28.6% of E. coli isolates and 85% of K. pneumoniae isolates were still susceptible to ceftazidime-avibactam, but only 7.1% and 1.9% of them, respectively, were susceptible to ceftolozane-tazobactam. The rates of susceptibility of the carbapenem-resistant P. aeruginosa isolates to ceftazidime-avibactam (65.7%) and ceftolozane-tazobactam (68%) were similar. Overall, both ceftazidime-avibactam and ceftolozane-tazobactam were highly active against clinical isolates of Enterobacteriaceae and P. aeruginosa recently collected across China, and ceftazidime-avibactam showed activity superior to that of ceftolozane-tazobactam against Enterobacteriaceae, whereas ceftolozane-tazobactam showed a better effect against P. aeruginosa.

Caspase 3 may participate in the anti-tumor immunity of dendritic cells.

BACKGROUND: Caspase 3 is not only involved in apoptosis, but also participates in the nonapoptotic functions. Previously, we found that caspase 3 gene knockout mice displayed decreased number of dendritic cells (DCs). However, whether caspase 3 participate in the function of DCs is unclear. Thus, the present study aims to investigate the role of caspase 3 in the maturation and antitumor function of DCs. METHODS: Caspase 3 gene was overexpressed in DC2.4 cell line through Lentivirus system. The impact of caspase 3 gene overexpression on the biological behavior of DC2.4 cells was determined by CCK-8, colony formation and apoptosis analysis. The impact of caspase 3 gene overexpression on the antigen uptake, maturation, migration, T cell activation of DC2.4 cells was analyzed with phagocytosis, transwell and mixed lymphocyte reaction assay. Tumor growth and tumor infiltrated T cells were also investigated through tumor bearing model. RESULTS: Caspase 3 gene overexpression could slightly increase the apoptosis of DC2.4 cells. Antigen uptake capability and maturation of DC2.4 cells were significantly promoted through caspases 3 gene overexpression. However, CXCR4 expression on DC2.4 cells and migration of DC2.4 cells were not influenced. Caspase 3 gene overexpression also enhanced the T cell activation and cytotoxicity of activated T cells. Finally, overexpression of caspase 3 gene significantly increased the tumor suppression of DC2.4 cells, accompanied by increased infiltration of CD4+ and CD8+ Cells in tumor tissue. CONCLUSION: Caspase 3 gene overexpression could promote maturation and enhance antitumor capability of DC2.4 cells.

The Expression of ILT4 in Myeloid Dendritic Cells in Patients with Hepatocellular Carcinoma.

Immunoglobulin-like transcript (ILT) 4 is an inhibitory immune receptor of the immunoglobulin superfamily, which could deliver inhibitory signals and induce immunosuppression. The significance of the expression of ILT4 in mDCs subsets in patients with hepatocellular carcinoma (HCC) remains unclear. In this study, the frequency of mDCs subsets in the peripheral blood of 121 patients with HCC and 103 normal controls, and in the tumor and tumor free liver tissues (TFL) of 43 HCC patients was analyzed by flow cytometry. Then, the expressions of ILT4 in mDCs subsets in the microenvironment of liver cancer were also analyzed. Results showed that the percentage of CD1c+ subset was dramatically decreased in peripheral blood mononuclear cells (PBMCs) of HCC patients compared with normal controls, and also significantly decreased in tumor tissue compared with the TFL. The decreased of CD1c+ subset in blood could be a diagnostic factor for HCC with the area under the receiver operating characteristic curve 0.975 (P < 0.01). The percentage of ILT4+CD1c+ subset was dramatically increased in tumor than that of TFL and blood. There were significant correlations between the percentage of ILT4+ in CD1c+ subset in tumor and that of in blood. The percentage of ILT4+CD1c+ subset in tumor tissue was strongly associated with the Edmondson-Steiner stage in HCC (P = 0.03). Furthermore, the capacity of ILT4+CD1c+ subset producing IFN-γ was lower than ILT4- CD1c subset in PBMC of HCC patients following Poly I:C stimulation. Taken together, the increased ILT4+CD1c+ subset in tumor tissue might play an important role in immune suppression for patients with HCC.