A total of 26 bla_IMP-4-carrying strains of Pseudomonas aeruginosa and Klebsiella pneumoniae were isolated from 2009 to 2013 in a Chinese teaching hospital, and these strains can be assigned into multiple sequence types or allelic profiles as determined by multilocus sequence typing. Of these strains, P. aeruginosa P378 and K. pneumoniae 1220 harbor the IMP-4-encoding plasmids pP378-IMP and p1220-IMP, respectively, whose complete nucleotide sequences are determined to be genetically closely related to the IncN1-type plasmid pIMP-HZ1. pP378-IMP/p1220-IMP-like plasmids are hinted to be present in all the other bla_IMP-4-carrying strains, indicating the dissemination of pIMP-HZ1-related plasmids among K. pneumoniae or P. aeruginosa of different genotypes in this hospital. pP378-IMP carries two distinct accessory resistance regions, a bla_IMP-4-carrying class 1 integron In823b, and a truncated Tn3-family unit transposon ΔTn6292-3′ harboring the quinolone resistance gene qnrS1. Massive fragmentation and rearrangement of these accessory genetic contents occur among p1220-IMP and IMP-HZ1 relative to pP378-IMP. bla_IMP-4 is also present in the In823b remnants from p1220-IMP and IMP-HZ1, while qnrS1 is located in a Tn6292-derive fragment from pIMP-HZ1 but not found in p1220-IMP. pP378-IMP represents the first fully sequenced IncN-type plasmid from P. aeruginosa.

Luteolin (Lut) is a natural flavonoid polyphenolic compound with multiple pharmacological activities, such as anti-oxidant, anti-inflammatory, and anti-tumor effects. However, the poor aqueous solubility and low bioactivity of Lut restrict its clinical translation. Herein, we developed a reactive oxygen species (ROS)-responsive nanoplatforms to improve the bioactivity of Lut. Folic acid (FA) was employed to decorate the nanoparticles (NPs) to enhance its targeting ability. The size of Lut-loaded ROS-responsive nanoparticles (Lut/Oxi-αCD NPs) and FA-modified Lut/Oxi-αCD NPs (Lut/FA-Oxi-αCD NPs) is 210.5 ± 6.1 and 196.7 ± 1.8 nm, respectively. Both Lut/Oxi-αCD NPs and Lut/FA-Oxi-αCD NPs have high drug loading (14.83 ± 3.50 and 16.37 ± 1.47%, respectively). In vitro cellular assays verified that these NPs could be efficiently internalized by 4T1 cells and the released Lut from NPs could inhibit tumor cells proliferation significantly. Animal experiments demonstrated that Lut/Oxi-αCD NPs, especially Lut/FA-Oxi-αCD NPs obviously accumulated at tumor sites, and inhibited tumor growth ∼3 times compared to the Lut group. In conclusion, the antitumor efficacy of Lut was dramatically improved by targeting delivery with the ROS-responsive nanoplatforms.

Background: Although stimuli-responsive nanoplatforms were developed to deliver immunogenic cell death (ICD) inducers to enhance cancer immunotherapy, the complete release of ICD inducers into the tumor microenvironment (TME) was limited by the inadequate supplementation of endogenous stimulus (e.g., reactive oxygen species (ROS)). To address this issue, we synthesized a self-responsive nanomaterial with self-supplied ROS, which mainly consists of a ROS responsive moiety HPAP and cinnamaldehyde (CA) as the ROS-generating agent. The endogenous ROS can accelerate the degradation of HPAP in materials to release docetaxel (DTX, an ICD inducer). In intracellular acidic environment, the pH-sensitive acetal was cleaved to release CA. The released CA in turn induces the generation of more ROS through mitochondrial damage, resulting in amplified DTX release. Using this self-cycling and self-responsive nanomaterial as a carrier, DTX-loaded pH/ROS dual-responsive nanoparticles (DTX/FA-CA-Oxi-αCD NPs) were fabricated and evaluated in vitro and in vivo. Results: In vitro experiments validated that the NPs could be effectively internalized by FA-overexpressed cells and completely release DTX in acidic and ROS microenvironments to induce ICD effect. These NPs significantly blocked 4T1 cell migration and decreased cell invasion. In vivo experiments demonstrated that the tumor-targeted NPs significantly inhibited tumor growth and blocked tumor metastasis. More importantly, these NPs significantly improved immunotherapy through triggering effector T-cell activation and relieving the immunosuppressive state of the TME. Conclusions: Our results demonstrated that DTX/FA-CA-Oxi-αCD NPs displayed great potential in preventing tumor metastasis, inhibiting tumor growth, and improving the efficacy of anti-PD-1antibody. Graphical

We previously reported the complete sequence of the resistance plasmid pP10164-NDM, harboring bla_NDM (conferring carbapenem resistance) and ble_MBL (conferring bleomycin resistance), which is recovered from a clinical Leclercia adecarboxylata isolate P10164 from China. This follow-up work disclosed that there were still two multidrug-resistant (MDR) plasmids pP10164-2 and pP10164-3 coexisting in this strain. pP10164-2 and pP10164-3 were completely sequenced and shown to carry a wealth of resistance genes, which encoded the resistance to at least 10 classes of antibiotics (β-lactams. macrolides, quinolones, aminoglycosides, tetracyclines, amphenicols, quaternary ammonium compounds, sulphonamides, trimethoprim and rifampicin) and 7 kinds of heavy mental (mercury, silver, copper, nickel, chromate, arsenic and tellurium). All of these antibiotic resistance genes are associated with mobile elements such as transposons, integrons and insertion sequence-based transposable units, constituting a total of three novel MDR regions, two in pP10164-2 and the other one in pP10164-3. Coexistence of three resistance plasmids pP10164-NDM, pP10164-2 and pP10164-3 makes L. adecarboxylata P10164 tend to become extensively drug-resistant.