A number of multiresistant pathogens including Acinetobacter baumannii (A. baumannii) place a heavy burden on ventilator-associated pneumonia (VAP) patients in intensive care units (ICU). It is critically important to differentiate between bacterial infection and colonization to avoid prescribing unnecessary antibiotics. Quantitative culture of lower respiratory tract (LRT) specimens, however, requires invasive procedures. Nowadays, volatile organic compounds (VOCs) have been studied in vitro and in vivo to identify pathogen-derived biomarkers. Therefore, an exploratory pilot study was conceived for a proof of concept that the appearance and level of A. baumannii-derived metabolites might be correlated with the presence of the pathogen and its ecological niche (i.e. the infection and colonization states) in ICU ventilated patients. Twenty patients with A. baumannii VAP (infection group), 20 ventilated patients with LRT A. baumannii colonization (colonization group) and 20 ventilated patients with neurological disorders, but without pneumonia or A. baumannii colonization (control group) were enrolled in the in vivo pilot study. A clinical isolate of A. baumannii strains was used for the in vitro culture experiment. The adsorptive preconcentration (solid-phase microextraction fiber and Tenax(®) TA) and analysis technique of gas chromatography-mass spectrometry were applied in the studies. Breath profiles could be visually differentiated between A. baumannii cultivation in vitro and culture medium, and among in vivo groups. In the in vitro experiment, nine compounds of interest (2,5-dimethyl-pyrazine, 1-undecene, isopentyl 3-methylbutanoate, decanal, 1,3-naphthalenediol, longifolene, tetradecane, iminodibenzyl and 3-methyl-indene) in the headspace were found to be possible A. baumannii derivations. While there were eight target VOCs (1-undecene, nonanal, decanal, 2,6,10-trimethyl-dodecane, 5-methyl-5-propyl-nonane, longifolene, tetradecane and 2-butyl-1-octanol) exhibiting characteristics of A. baumannii VAP derivations. The selected VOC profile in vivo could be adopted to efficiently differentiate the presence of LRT A. baumannii from its absence, and LRT A. baumannii infection from its colonization (AUC  =  0.89 and 0.88, respectively). It is not feasible to simply transfer the metabolic biomarkers from the in vitro condition to in vivo. The direct detection of exhaled A. baumannii-derived VOCs may be adopted for an early alert of the LRT bacterial presence in ventilated ICU patients, and even in different parasitic states of A. baumannii (i.e. infection and colonization). However, further refinement and validation are required before its clinical use.

The success of programmed cell death protein 1 (PD-1)/PD-L1-based immunotherapy highlights the critical role played by PD-L1 in cancer progression and reveals an urgent need to develop new approaches to attenuate PD-L1 function by gaining insight into how its expression is controlled. Anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALK+ ALCL) expresses a high level of PD-L1 as a result of the constitutive activation of multiple oncogenic signaling pathways downstream of ALK activity, making it an excellent model in which to define the signaling processes responsible for PD-L1 upregulation in tumor cells. Here, using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 library screening, we sought a comprehensive understanding of the molecular effectors required for PD-L1 regulation in ALK+ ALCL. Indeed, we determined that PD-L1 induction is dependent on the nucleophosmin-ALK oncoprotein activation of STAT3, as well as a signalosome containing GRB2/SOS1, which activates the MEK-ERK and PI3K-AKT signaling pathways. These signaling networks, through STAT3 and the GRB2/SOS1, ultimately induce PD-L1 expression through the action of transcription factors IRF4 and BATF3 on the enhancer region of the PD-L1 gene. IRF4 and BATF3 are essential for PD-L1 upregulation, and IRF4 expression is correlated with PD-L1 levels in primary ALK+ ALCL tissues. Targeting this oncogenic signaling pathway in ALK+ ALCL largely inhibited the ability of PD-L1-mediated tumor immune escape when cocultured with PD-1-positive T cells and natural killer cells. Thus, our identification of this previously unrecognized regulatory hub not only accelerates our understanding of the molecular circuitry that drives tumor immune escape but also provides novel opportunities to improve immunotherapeutic intervention strategies.

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In this study, an experiment was designed to optimize the synthesis of seleno-Capparis spionosa L. polysaccharide (Se-CSPS) by response surface methodology. Three independent variables (reaction time, reaction temperature and ratio of Na2SeO3 to CSPS) were tested. Furthermore, the thermal stability, particle size, shape and cytotoxic activity of Se-CSPS in vitro were investigated. The optimum reaction conditions were obtained shown as follows: reaction time 7.5 h, reaction temperature 71 °C, and ratio of Na2SeO3 to CSPS 0.9 g/g. Under these conditions, the Se content in Se-CSPS reached 5.547 mg/g, which was close to the predicted value (5.518 mg/g) by the model. The thermal stability, particle size and shape of Se-CSPS were significantly different from those of CSPS. Additionally, a MTT assay indicated that the Se-CSPS could inhibit the proliferation of human gastric cancer SGC-7901 cells in a dose-dependent manner.

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There is evidence that cadmium can initiate carcinogenesis. However, the underlying mechanisms remain unknown. There is also evidence that moderate centrosome amplification can initiate tumorigenesis. The present study investigated whether cadmium could trigger cell centrosome amplification, and examined the underlying molecular mechanisms. We found that cadmium was able to cause cell centrosome amplification at the subtoxic concentrations, in a dose‐dependent manner. It could cause centrosome amplification via the signaling of reactive oxygen species (ROS). Proteomic analysis revealed that cadmium caused differential expressions of three proteins, which included HSPA1A which is associated with endoplasmic reticulum (ER) stress. Western blot analysis confirmed that cadmium upregulated HSPA1A. Further analyses showed that cadmium upregulated Bip and decreased the phosphorylation of ASK1 as well as increased the phosphorylation of MKK7 and c‐Jun N‐terminal kinases (JNK). Knockdown of JNK2 using small interfering RNA inhibited the cadmium‐induced centrosome amplification but not the level of ROS. N‐acetylcysteine did not inhibit the cadmium‐activated ER stress pathway. In conclusion, our results suggest that cadmium can induce cell centrosome amplification via ROS as well as ER stress through the Bip–TRAF2–ASK1–MKK7–JNK signaling route, in parallel. More studies are required to clarify whether centrosome amplification underlies cadmium‐induced carcinogenesis.

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Comprehensive Summary The environmental contamination of uranium will occur in scenarios such as nuclear accidents and leakage from nuclear waste storage sites, which eventually leads to the internal uranium exposure of people, causing consequential injuries of renal failure, osteosarcoma, etc. The development of uranyl specific chelating agents that could sequester uranium in vivo is in urgent need and is important for the safe and efficient development of nuclear industry. Metal organic frameworks (MOFs) already serve as efficient uranium depletion materials in solutions of a wide range of pH and ionic strength for nuclear fuel recycling, uranium extraction from seawater, as well as environmental decontamination. Herein, a chromium‐based nano‐metal organic framework (nano‐MOF) functionalized interiorly with 3,2‐HOPO ligands, MIL‐101‐HOPO, is rationally synthesized. In vitro adsorption experiments show that MIL‐101‐HOPO exhibits high adsorption selectivity and fast adsorption kinetics for uranyl. The results of in vivo uranyl decorporation assays reveal that MIL‐101‐HOPO with the decoration of HOPO ligands on the interior wall exhibits significantly increased uranyl removal ratio in kidneys comparing to the pristine nMOFs, and is more effective than the clinically used ZnNa3‐DTPA. All those results corroborate the interior functionalization of MOFs as an efficient strategy to develop promising uranyl decorporation agents.