Multiomics integration reveals NETosis heterogeneity and TLR2 as a prognostic biomarker in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant neoplasm characterized by a poor prognosis and limited therapeutic strategy. The PDAC tumor microenvironment presents a complex heterogeneity, where neutrophils emerge as the predominant constituents of the innate immune cell population. Leveraging the power of single-cell RNA-seq, spatial RNA-seq, and multi-omics approaches, we included both published datasets and our in-house patient cohorts, elucidating the inherent heterogeneity in the formation of neutrophil extracellular traps (NETs) and revealed the correlation between NETs and immune suppression. Meanwhile, we constructed a multi-omics prognostic model that suggested the patients exhibiting downregulated expression of NETs may have an unfavorable outcome. We also confirmed TLR2 as a potent prognosis factor and patients with low TLR2 expression had more effective T cells and an overall survival extension for 6 months. Targeting TLR2 might be a promising strategy to reverse immunosuppression and control tumor progression for an improved prognosis.

Fabrication of a novel polyvinylpyrrolidone/chitosan-Schiff base/Fe2O3 nanocomposite for efficient adsorption of Pb(II) and Hg(II) ions from aqueous solution.

A novel magnetic polyvinylpyrrolidone/chitosan-Schiff base/Fe2O3 (PVP/CS-SB/Fe2O3) adsorbent was prepared by one-pot facile co-precipitation route for adsorption of Pb(II) and Hg(II) ions from aqueous solution. Fourier transform infrared-spectroscopy (FT-IR), X-ray diffraction (XRD), scanning electron microscope (SEM), vibrating sample magnetometer (VSM) and Brunauer-Emmett-Teller (BET) were used to characterize the synthesized PVP/CS-SB/Fe2O3. The results predicted that the successfully synthesis of magnetic CSSB-PVP@Fe2O3. The effects of important factors such as pH solution, contact time, concentration of metal ions, adsorbent dose and co-existing ions on Pb(II) and Hg(II) adsorption were investigated. The maximum adsorption capacities of Pb(II) and Hg(II) ions at optimal conditions were 120 mg/g and 102.5 mg/g, respectively. The kinetic studies predicted that the adsorption followed the pseudo-second-order (PSO) model as chemisorption using the coordination of active sites of PVP/CS-SB/Fe2O3 with the metal ions and also n-π interactions. Reproducibility results predicted that the excellent regeneration ability after 6 adsorption cycles. According to the results of this work, the PVP/CS-SB/Fe2O3 nanocomposite is promising for Pb(II) and Hg(II) ions adsorption and can be potential as a simple, low-cost, high-efficient adsorbent for decontamination of other heavy metal ions from aqueous solution.

Effects of selenoprotein extracts from Cardamine hupingshanensis on growth, selenium metabolism, antioxidant capacity, immunity and intestinal health in largemouth bass Micropterus salmoides.

This study aimed to assess the impact of dietary selenoprotein extracts from Cardamine hupingshanensis (SePCH) on the growth, hematological parameters, selenium metabolism, immune responses, antioxidant capacities, inflammatory reactions and intestinal barrier functions in juvenile largemouth bass (Micropterus salmoides). The base diet was supplemented with four different concentrations of SePCH: 0.00, 0.30, 0.60 and 1.20 g/Kg (actual selenium contents: 0.37, 0.59, 0.84 and 1.30 mg/kg). These concentrations were used to formulate four isonitrogenous and isoenergetic diets for juvenile largemouth bass during a 60-day culture period. Adequate dietary SePCH (0.60 and 1.20 g/Kg) significantly increased weight gain and daily growth rate compared to the control groups (0.00 g/Kg). Furthermore, 0.60 and 1.20 g/Kg SePCH significantly enhanced amounts of white blood cells, red blood cells, platelets, lymphocytes and monocytes, and levels of hemoglobin, mean corpuscular volume and mean corpuscular hemoglobin in the hemocytes. In addition, 0.60 and 1.20 g/Kg SePCH increased the mRNA expression levels of selenocysteine lyase, selenophosphate synthase 1, 15 kDa selenoprotein, selenoprotein T2, selenoprotein H, selenoprotein P and selenoprotein K in the fish liver and intestine compared to the controls. Adequate SePCH not only significantly elevated the activities of antioxidant enzymes (Total superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase), the levels of total antioxidant capacity and glutathione, while increased mRNA transcription levels of NF-E2-related factor 2, Cu/Zn-superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase. However, adequate SePCH significantly decreased levels of malondialdehyde and H2O2 and the mRNA expression levels of kelch-like ECH-associated protein 1a and kelch-like ECH-associated protein 1b in the fish liver and intestine compared to the controls. Meanwhile, adequate SePCH markedly enhanced the levels of immune factors (alkaline phosphatase, acid phosphatase, lysozyme, complement component 3, complement component 4 and immunoglobulin M) and innate immune-related genes (lysozyme, hepcidin, liver-expressed antimicrobial peptide 2, complement component 3 and complement component 4) in the fish liver and intestine compared to the controls. Adequate SePCH reduced the levels of pro-inflammatory cytokines (tumour necrosis factor-α, interleukin 8, interleukin 1ß and interferon γ), while increasing transforming growth factor ß1 levels at both transcriptional and protein levels in the liver and intestine. The mRNA expression levels of mitogen-activated protein kinase 13 (MAPK 13), MAPK14 and nuclear factor kappa B p65 were significantly reduced in the liver and intestine of fish fed with 0.60 and 1.20 g/Kg SePCH compared to the controls. Histological sections also demonstrated that 0.60 and 1.20 g/Kg SePCH significantly increased intestinal villus height and villus width compared to the controls. Furthermore, the mRNA expression levels of tight junction proteins (zonula occludens-1, zonula occludens-3, Claudin-1, Claudin-3, Claudin-5, Claudin-11, Claudin-23 and Claudin-34) and Mucin-17 were significantly upregulated in the intestinal epithelial cells of 0.60 and 1.20 g/Kg SePCH groups compared to the controls. In conclusion, these results found that 0.60 and 1.20 g/Kg dietary SePCH can not only improve growth, hematological parameters, selenium metabolism, antioxidant capacities, enhance immune responses and intestinal functions, but also alleviate inflammatory responses. This information can serve as a useful reference for formulating feeds for largemouth bass.

Combined effect of simulated microgravity and low-dose ionizing radiation on structure and antibiotic resistance of a synthetic community model of bacteria isolated from spacecraft assembly room.

Understanding the structural and antibiotic resistance changes of microbial communities in space environments is critical for identifying potential pathogens that may pose health risks to astronauts and for preventing and controlling microbial contamination. The research to date on microbes under simulated space factors has primarily been carried out on single bacterial species under the individual effects of microgravity or low-dose radiation. However, microgravity (MG) and low-dose ionizing radiation (LDIR) coexist in the actual spacecraft environment, and microorganisms coexist as communities in the spacecraft environment. Thus, the microbial response to the real changes present during space habitation has not been adequately explored. To address this knowledge gap, we compared the dynamics of community composition and antibiotic resistance of synthetic bacterial communities under simulated microgravit, low-dose ionizing radiation, and the conditions combined, as it occurs in spacecraft. To ensure representative bacteria were selected, we co-cultured of 12 bacterial strains isolated from spacecraft cleanrooms. We found that the weakened competition between communities increased the possibility of species coexistence, community diversity, and homogeneity. The number of Bacilli increased significantly, while different species under the combined conditions showed various changes in abundance compared to those under the individual conditions. The resistance of the synthetic community to penicillins increased significantly under low doses of ionizing radiation but did not change significantly under simulated microgravity or the combined conditions. The results of functional predictions revealed that antibiotic biosynthesis and resistance increased dramatically in the community under space environmental stress, which confirmed the results of the drug sensitivity assays. Our results show that combined space environmental factors exert different effects on the microbial community structure and antibiotic resistance, which provides new insights into our understanding of the mechanisms of evolution of microorganisms in spacecraft, and is relevant to effective microbial pollution prevention and control strategies.

Evaluation of postoperative recovery: past, present and future.

Postoperative recovery, as a window to observe perioperative treatment effect and patient prognosis, is a common outcome indicator in clinical research and has attracted more and more attention of surgeons and anaesthesiologists. Postoperative recovery is a subjective, multidimensional, long-term, complex process, so it is unreasonable to only use objective indicators to explain it. Currently, with the widespread use of patient-reported outcomes, various scales become the primary tools for assessing postoperative recovery. Through systematic search, we found 14 universal recovery scales, which have different structures, contents and measurement properties, as well as their own strengths and weaknesses. We also found that it is urgently necessary to perform further researches and develop a scale that can serve as the gold universal standard to evaluate postoperative recovery. In addition, with the rapid development of intelligent equipment, the establishment and validation of electronic scales is also an interesting direction.

Comparative analysis of the efficacy and safety of electromagnetic navigation bronchoscopy combined with x-ray or radial endobronchial ultrasound biopsy in the diagnosis of small peripheral pulmonary nodules.

OBJECTIVE: To compare the clinical value and safety of electromagnetic navigation bronchoscopy (ENB) combined with radial endobronchial ultrasound (R-EBUS) or x-ray in the diagnosis of small peripheral pulmonary nodules that cannot be diagnosed by conventional bronchoscopy. METHODS: Fifty-six patients with peripheral pulmonary nodules of <3 cm in diameter who underwent bronchoscopy at the First Affiliated Hospital of Soochow University and Dushu Lake Hospital of Soochow University from February 2019 to January 2022 were selected as the study subjects, including 24 patients who underwent ENB combined with x-ray and 32 patients who underwent ENB combined with R-EBUS. ENB was used as the guiding method in both groups, and x-ray group and R-EBUS group were combined with x-ray and R-EBUS, respectively, to determine whether the lesion was reached. In x-ray group, biopsy and brushing were performed under fluoroscopic guidance. Using the results of surgery, puncture pathology, or clinical follow-up 1 year as the gold standard, the diagnostic sensitivity, specificity, negative predictive value (NPV), diagnostic yield, negative likelihood ratio (LR-), Youden index, missed diagnosis rate, success rate, and κ value were compared between the two groups, and the occurrence of postoperative complications was also compared between the two groups. RESULTS: The negative predictive value of the R-EBUS group was significantly better than that of the x-ray group (p = 0.006). CONCLUSION: Even with smaller nodule diameters, the negative predictive value of ENB combined with R-EBUS were still higher than that of the x-ray group.

Salvage therapy of osimertinib plus anlotinib in advanced lung adenocarcinoma with leptomeningeal metastasis: A case report.

Leptomeningeal metastasis (LM) is one of the most serious complications of advanced non-small cell lung cancer (NSCLC) and lacks standard treatment. Patients with LM often have a poor prognosis. Here, we report a 51-year-old man diagnosed as advanced lung adenocarcinoma and gene sequencing indicated no sensitive driver gene mutation. Pemetrexed and cisplatin plus bevacizumab was administered as first-line therapy. He received pembrolizumab plus nab-paclitaxel as second-line therapy and developed neurological symptoms soon. Later, he was diagnosed LM by cerebrospinal fluid (CSF) cytology and gene sequencing of lung tissue rebiopsy demonstrated epidermal growth factor receptor (EGFR) sensitive mutation. The patient received high-dose (160mg) osimertinib therapy but still could not tolerate severe neurological symptoms and developed cardiac adverse event. After that, standard-dose (80mg) osimertinib plus anlotinib was administered and this treatment regimen resulted in the alleviation of neurological symptoms. As the recent follow up, the curative effect was evaluated stable disease (SD) and the patient gained a progression-free survival (PFS) of more than 15 months. We report this successful salvage therapy of osimertinib plus anlotinib in an advanced lung adenocarcinoma patient who developed LM after failure on previous treatment until EGFR mutation was confirmed through rebiopsy.

Single-Cell Sequencing Analysis and Multiple Machine Learning Methods Identified G0S2 and HPSE as Novel Biomarkers for Abdominal Aortic Aneurysm.

Identifying biomarkers for abdominal aortic aneurysms (AAA) is key to understanding their pathogenesis, developing novel targeted therapeutics, and possibly improving patients outcomes and risk of rupture. Here, we identified AAA biomarkers from public databases using single-cell RNA-sequencing, weighted co-expression network (WGCNA), and differential expression analyses. Additionally, we used the multiple machine learning methods to identify biomarkers that differentiated large AAA from small AAA. Biomarkers were validated using GEO datasets. CIBERSORT was used to assess immune cell infiltration into AAA tissues and investigate the relationship between biomarkers and infiltrating immune cells. Therefore, 288 differentially expressed genes (DEGs) were screened for AAA and normal samples. The identified DEGs were mostly related to inflammatory responses, lipids, and atherosclerosis. For the large and small AAA samples, 17 DEGs, mostly related to necroptosis, were screened. As biomarkers for AAA, G0/G1 switch 2 (G0S2) (Area under the curve [AUC] = 0.861, 0.875, and 0.911, in GSE57691, GSE47472, and GSE7284, respectively) and for large AAA, heparinase (HPSE) (AUC = 0.669 and 0.754, in GSE57691 and GSE98278, respectively) were identified and further verified by qRT-PCR. Immune cell infiltration analysis revealed that the AAA process may be mediated by T follicular helper (Tfh) cells and the large AAA process may also be mediated by Tfh cells, M1, and M2 macrophages. Additionally, G0S2 expression was associated with neutrophils, activated and resting mast cells, M0 and M1 macrophages, regulatory T cells (Tregs), resting dendritic cells, and resting CD4 memory T cells. Moreover, HPSE expression was associated with M0 and M1 macrophages, activated and resting mast cells, Tregs, and resting CD4 memory T cells. Additional, G0S2 may be an effective diagnostic biomarker for AAA, whereas HPSE may be used to confer risk of rupture in large AAAs. Immune cells play a role in the onset and progression of AAA, which may improve its diagnosis and treatment.

A retrospective cohort study of sintilimab and pembrolizumab as first-line treatments for advanced non-small cell lung cancer.

Background: Pembrolizumab and sintilimab have both been approved by the China National Medical Products Administration (NMPA) for the first-line treatment of advanced non-small cell lung cancer (NSCLC). These two drugs have several differences in biological characteristics and population in clinical trials. The current retrospective study was conducted to compare the efficacy and safety of sintilimab and pembrolizumab as first-line treatments in patients with advanced NSCLC. Methods: Consecutive patients with advanced NSCLC who received sintilimab or pembrolizumab as first-line therapy, with or without chemotherapy, from November 2018 to October 2021 in the First Affiliated Hospital of Soochow University and Dushu Lake Hospital Affiliated to Soochow University were retrospectively reviewed. Clinical data and treatment response were collected and survival was followed up. Kaplan-Meier method was used to estimate survival curves. The patients were divided into the sintilimab group and the pembrolizumab group according to the PD-1 inhibitors they received during treatment. The primary objective was to compare objective response rate (ORR) and progression-free survival (PFS) between the two groups. The secondary objectives were to compare disease control rate (DCR) and analyze adverse events (AEs) of the two groups. Results: A total of 124 patients were enrolled, including 68 patients (54.8%) in the sintilimab group and 56 patients (45.2%) in the pembrolizumab group. The baseline characteristics of the patients were comparable between the two groups. The ORR was 50% in the sintilimab group and 46.4% in the pembrolizumab group (P=0.69). The DCR was 89.7% and 89.3% in the sintilimab group and the pembrolizumab group, respectively (P=0.94). The median PFS time was 9.9 months in patients treated with sintilimab compared to 10.8 months in patients on pembrolizumab treatment [hazard ratio (HR) =0.960; 95% confidence interval (CI): 0.574-1.606; P=0.875]. The median OS time was not reached in either group of patients. The incidence of grade 3-4 treatment-related adverse events (TRAEs) was 25% (17/68) in the sintilimab group and 21.4% (12/56) in the pembrolizumab group. Conclusions: Sintilimab has similar efficacy to pembrolizumab as a first-line treatment option for patients with advanced NSCLC in clinical practice, with manageable AEs.

Diterpenoids from the Root Bark of Pinus massoniana and Evaluation of Their Phosphodiesterase Type 4D Inhibitory Activity.

Thirty-two diterpenoids were obtained from the root bark of Pinus massoniana, and, among them, five compounds (pinmassins A-E) were identified as undescribed analogues. Spectroscopic methods, X-ray single-crystal diffraction analysis, and ECD calculations were applied to establish the structure of the new isolates. Pinmassin D (4) and abieta-8,11,13,15-tetraen-18-oic acid (23) showed moderate phosphodiesterase type 4D (PDE4D) inhibitory effects with IC50 values of 2.8 ± 0.18 and 3.3 ± 0.50 µM, respectively, and their binding modes were investigated by a molecular docking study.

On verification of splines based intraoperative reconstruction of cardiac anatomy: model research.

Three-dimensional (3D) endocardium visualization plays an extremely important role in localization and ablation of target areas and can improve the cure rate in computer-aided cardiac surgery. In this paper, we discuss how to reconstruct and update the corresponding endocardium surface model quickly and accurately based on the sparse point cloud that is collected dynamically on the left atrial intima. Firstly, we construct a specific mesh model, and then collect spatial points, and carried out the mesh grid approximation based on Thin Plate Splines (TPS) intra-operatively, finally, we obtained an approximate target shape after Taubin-based smooth. Experiments on four left atriums' (LA) CT Angiographies (CTA) demonstrated that the reconstructed surfaces can well fit to the target shape, the distance error of surface between the reconstructed and targets can meet clinical requirements, and the deformation time can also meet the need of real-time update. The results showed that our proposed method is robust, fast and flexible to implement.

Design, synthesis and biological evaluation of glucose-containing scutellarein derivatives as neuroprotective agents based on metabolic mechanism of scutellarin in vivo.

Based on metabolic mechanism of scutellarin in vivo that scutellarin could be hydrolyzed into scutellarein by ß-glucuronide enzyme, some glucose-containing scutellarein derivatives were designed and synthesized through the introduction of glucose moiety at C-7 position of scutellarein via a glucosidic bond. Biological activity evaluation showed that these glucose-containing scutellarein derivatives exhibited potent DPPH radical scavenging activities. Furthermore, the improvement of physicochemical properties such as anticoagulant and neuroprotective activities alongside with the water solubility was achieved by introducing glucose. These findings suggest that the introduction of the glucose moiety to scutellarein wattants further development of this kind of compounds as neuroprotective agents.

Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases.

Aggregated filamentous forms of hyperphosphorylated tau (a microtubule-associated protein) represent pathological hallmarks of Alzheimer's disease (AD) and other tauopathies. While axonal transport dysfunction is thought to represent a primary pathogenic factor in AD and other neurodegenerative diseases, the direct molecular link between pathogenic forms of tau and deficits in axonal transport remain unclear. Recently, we demonstrated that filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Here, we demonstrate that amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway in axoplasms isolated from squid giant axons. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Importantly, immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity, an early marker of pathological tau. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT. Results from these studies reveal a novel role for tau in modulating axonal phosphotransferases and provide a molecular basis for a toxic gain-of-function associated with pathogenic forms of tau.

Degradation of tau protein by puromycin-sensitive aminopeptidase in vitro.

Tau, a microtubule associated protein, aggregates into intracellular paired helical filaments (PHFs) by an unknown mechanism in Alzheimer's disease (AD) and other tauopathies. A contributing factor may be a failure to metabolize free cytosolic tau within the neuron. The buildup of tau may then drive the aggregation process through mass action. Therefore, proteases that normally degrade tau are of great interest. A recent genetic screen identified puromycin-sensitive aminopeptidase (PSA) as a potent modifier of tau-induced pathology and suggested PSA as a possible tau-degrading enzyme. Here we have extended these observations using human recombinant PSA purified from Escherichia coli. The enzymatic activity and characteristics of the purified PSA were verified using chromogenic substrates, metal ions, and several specific and nonspecific protease inhibitors, including puromycin. PSA was shown to digest recombinant human full-length tau in vitro, and this activity was hindered by puromycin. The mechanism of amino terminal degradation of tau was confirmed using a novel N-terminal cleavage-specific tau antibody (Tau-C6g, specific for cleavage between residues 13-14) and a C-terminal cleavage-specific tau antibody (Tau-C3). Additionally, PSA was able to digest soluble tau purified from normal human brain to a greater extent than either soluble or PHF tau purified from AD brain, indicating that post-translational modifications and/or polymerization of tau may affect its digestion by PSA. These results are consistent with observations that PSA modulates tau levels in vivo and suggest that this enzyme may be involved in tau degradation in human brain.