Engineered Leukocyte Biomimetic Colorimetric Sensor Enables High-Efficient Detection of Tumor Cells Based on Bioorthogonal Chemistry.

Accurate detection of heterogeneous circulating tumor cells (CTCs) is critical as they can make tumor cells more aggressive, drug-resistant, and metastasizing. Although the leukocyte membrane coating strategy is promising in meeting the challenge of detecting heterogeneous CTCs due to its inherent antiadhesive properties, it is still limited by the reduction or loss of expression of known markers. Bioorthogonal glycol-metabolic engineering is expected to break down this barrier by feeding the cells with sugar derivatives with a unique functional group to establish artificial targets on the surface of tumor cells. Herein, an engineered leukocyte biomimetic colorimetric sensor was accordingly fabricated for high-efficient detection of heterogeneous CTCs. Compared with conventional leukocyte membrane coating, the sensor could covalently bound to the heterogeneous CTCs models fed with Ac4ManNAz in vitro through the synergy of bioorthogonal chemistry and metabolic glycoengineering, ignoring the phenotypic changes of heterogeneous CTCs. Meanwhile, a sandwich structure composed of leukocyte biomimetic layer/CTCs/MoS2 nanosheet was formed for visual detection of HeLa cells as low as 10 cells mL-1. Overall, this approach can overcome the dependence of conventional cell membrane biomimetic technology on specific cell phenotypes and provide a new viewpoint to highly efficiently detect heterogeneous CTCs.

Acute kidney injury prediction model utility in premature myocardial infarction.

The incidence of premature myocardial infarction (PMI) has been rising and acute kidney injury (AKI) occurring in PMI patients severely impacts prognosis. This study aimed to develop and validate a prediction model for AKI specific to PMI patients. The MIMIC-Ⅲ-CV and MIMIC-Ⅳ databases were utilized for model derivation of PMI patients. Single-center data served for external validation. There were 571 and 182 AKI patients in the training set (n = 937) and external validation set (n = 292) cohorts, respectively. Finally, a 7-variable model consisting of: Sequential Organ Failure Assessment (SOFA) score, coronary artery bypass grafting (CABG), ICU stay time, loop diuretics, estimated glomerular filtration rate (eGFR) HCO3- and Albumin was developed, achieving an AUC of 0.85 (95% CI: 0.83-0.88) in the training set. External validation also confirmed model robustness. This model may assist clinicians in the early identification of patients at elevated risk for PMI. Further validation is warranted before clinical application.

A new dyslipidemia-based scoring model to predict transplant-free survival in patients with hepatitis E-triggered acute-on-chronic liver failure.

BACKGROUND/AIMS: Hepatitis E virus (HEV)-triggered acute-on-chronic liver failure (ACLF) has unacceptably high short-term mortality. However, it is unclear whether the existing predictive scoring models are applicable to evaluate the prognosis of HEV-triggered ACLF. METHODS: We screened datasets of patients with HEV-triggered ACLF from a regional tertiary hospital for infectious diseases in Shanghai, China, between January 2011 and January 2021. Clinical and laboratory parameters were recorded and compared to determine a variety of short-term mortality risk factors, which were used to develop and validate a new prognostic scoring model. RESULTS: Out of 4952 HEV-infected patients, 817 patients with underlying chronic liver disease were enrolled in this study. Among these, 371 patients with HEV-triggered ACLF were identified and allocated to the training set (n = 254) and test set (n = 117). The analysis revealed that hepatic encephalopathy (HE), ascites, triacylglycerol and apolipoprotein A (apoA) were associated with 90-day mortality (P < 0.05). Based on these significant indicators, we designed and calculated a new prognostic score = 0.632 × (ascites: no, 1 point; mild to moderate, 2 points; severe, 3 points) + 0.865 × (HE: no, 1 point; grade 1-2, 2 points; grade 3-4, 3 points) - 0.413 × triacylglycerol (mmol/L) - 2.171 × apoA (g/L). Compared to four well-known prognostic models (MELD score, CTP score, CLIF-C OFs and CLIF-C ACLFs), the new scoring model is more accurate, with the highest auROCs of 0.878 and 0.896, respectively, to predict 28- and 90-day transplantation-free survival from HEV-triggered ACLF. When our model was compared to COSSH ACLF IIs, there was no significant difference. The test data also demonstrated good concordance. CONCLUSIONS: This study is one of the first to address the correlation between hepatitis E and serum lipids and provides a new simple and efficient prognostic scoring model for HEV-triggered ACLF.

Characteristics, Prognosis, and Prediction Model of Heart Failure Patients in Intensive Care Units Based on Preserved, Mildly Reduced, and Reduced Ejection Fraction.

Background: Heart failure (HF) patients in intensive care units (ICUs) are rather poorly studied based on varying left ventricular ejection fraction (LVEF) classification. Characteristics and prognosis of patients in ICUs with HF with mildly reduced ejection fraction (HFmrEF), HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF) require further clarification. Methods: Data involving clinical information and 4-year follow-up records of HF patients were extracted and integrated from the Medical Information Mart for Intensive Care III (MIMIC-III) database. Tests were carried out to identity differences among these three HF subtypes. Prognostic analyses were performed using Kaplan-Meier survival analysis and Cox proportional-hazards regression modeling. To develop a novel prediction nomogram, forward selection was used as the best-fit model. Prognostic heterogeneity of the subgroups prespecified by stratification factors in pairwise comparisons was presented using forest plots. Results: A total of 4150 patients were enrolled in this study. HFmrEF had the lowest all-cause mortality rate during the 4-year follow-up, which was significantly different from HFrEF and HFpEF (Log-Rank p < 0.001). The Cox proportional-hazards regression model also showed that a comparison of HFrEF versus HFmrEF indicated a hazard ratio (HR) of 0.76 (95% CI 0.61-0.94, p = 0.011) and HFrEF versus HFpEF indicated a HR 0.93 (95% CI 0.82-1.07, p = 0.307). Following a multivariable analysis, 13 factors were confirmed as independent. A new nomogram was established and quantified with a concordance index (C-index) of 0.70 (95% CI 0.67-0.73), and the internal validation indicated the accuracy of the model. Stratification factors such as a history of coronary artery bypass grafting (CABG) and comorbidity of chronic obstructive pulmonary disease (COPD) induced prognostic heterogeneity among the three subtypes. Conclusions: Clinical characteristics and prognosis significantly varied among the three subtypes of HF patients in ICUs, with HFmrEF patients achieving the best prognosis. The novel prediction model, tailored for this population, showed a satisfying prediction ability.

Effect of PCI Standardized Telephone Follow-Up Service Mode on Out-of-Hospital Complications, Rehospitalization Rate, and Quality of Life of Discharged Patients with Acute Coronary Syndrome after PCI.

Objective: To explore the effect of percutaneous coronary intervention (PCI) standardized telephone follow-up service mode on out-of-hospital complications, rehospitalization rate, and life quality of discharged acute coronary syndrome (ACS) patients after PCI. Methods: From August 2020 to March 2022, 218 ACS patients who were discharged after PCI were included. The controls accepted routine nursing care, and the researches accepted PCI standardized telephone follow-up service mode. The nursing satisfaction, rehospitalization rate, out-of-hospital complication rate, blood lipid level, and life quality score were taken as the comparisons. Results: The nursing satisfaction of study group (100.00%) was significantly higher than that of control group (88.07%). The rehospitalization rate was dramatically lower in the study group (3/109; 2.75%) than in the control group (25/109; 22.94%) (P < 0.05). In addition, compared with the control group, the incidence of complications (acute myocardial infarction and angina pectoris) was significantly reduced in the study group outside the hospital (P < 0.05). The blood lipid levels of TCHO, TG, LDL-C, and HDL-C were lower in the study group than in the controls. Further, after nursing, the quality of life score of the two groups was both decreased with a higher quality of life score in the study group (P < 0.05). Conclusion: The application of PCI standardized telephone follow-up service mode in discharged patients with acute coronary syndrome after PCI can reduce out-of-hospital complications and rehospitalization rate and improve blood lipid level and life quality.

Accurate construction of cell membrane biomimetic graphene nanodecoys via purposeful surface engineering to improve screening efficiency of active components of traditional Chinese medicine.

Biomimetic nanoengineering presents great potential in biomedical research by integrating cell membrane (CM) with functional nanoparticles. However, preparation of CM biomimetic nanomaterials for custom applications that can avoid the aggregation of nanocarriers while maintaining the biological activity of CM remains a challenge. Herein, a high-performance CM biomimetic graphene nanodecoy was fabricated via purposeful surface engineering, where polyethylene glycol (PEG) was used to modifying magnetic graphene oxide (MGO) to improve its stability in physiological solution, so as to improve the screening efficiency to active components of traditional Chinese medicine (TCM). With this strategy, the constructed PEGylated MGO (PMGO) could keep stable at least 10 days, thus improving the CM coating efficiency. Meanwhile, by taking advantage of the inherent ability of HeLa cell membrane (HM) to interact with specific ligands, HM-camouflaged PMGO showed satisfied adsorption capacity (116.2 mg/g) and selectivity. Finally, three potential active components, byakangelicol, imperatorin, and isoimperatorin, were screened from Angelica dahurica, whose potential antiproliferative activity were further validated by pharmacological studies. These results demonstrated that the purposeful surface engineering is a promising strategy for the design of efficient CM biomimetic nanomaterials, which will promote the development of active components screening in TCM.

Improved detection and recognition of glycoproteins using fluorescent polymers with a molecular imprint based on glycopeptides.

Highly specific novel glycopeptide-based fluorescent molecularly imprinting polymers (g-FMIPs) were constructed to recognize and determine the target glycoprotein in complex biological samples. The glycopeptide of ovalbumin (OVA), with the unique structural characteristics of glycan and peptide, and potential application in improving the specificity recognition of g-FMIPs, was selected as the template molecule. The nitrogen-doped graphene quantum dots (N-GQDs) were introduced for fluorescence response. The obtained g-FMIPs possessed rapid binding kinetics and high adsorption capacity. Notably, the g-FMIPs exhibited remarkable selectivity and sensitivity with a high imprinting factor of 6.57, good linearity of 0.625 - 5.00 µM, and limit of detection of 0.208 µM. After treatment with g-FMIPs, the concentration of OVA in eluted solution was 1.07 µM. The obtained recoveries at 1.43 µM, 2.86 µM, and 4.29 µM spiked concentrations were 97.2%, 93.5%, and 101%, respectively, and the relative standard deviations were 2.6%, 4.2%, and 1.1%, respectively. In summary, the proposed strategy will expand the MIPs construction method and its application prospects in precision recognition and sensitive detection of trace glycoproteins from complex biosamples.

Inside-Out-Oriented Cell Membrane Biomimetic Magnetic Nanoparticles for High-Performance Drug Lead Discovery.

Biomimetic cell membrane-coated nanoparticles have been broadly applied because of their superior biochemical properties. The right-side-out cell membrane coating manner provides nanoparticles with an immune-evasive stealth function in vivo. However, this acts as a drag for drug discovery when the drug targets are the intracellular domain of transmembrane receptors. Herein, inside-out-oriented cell membrane-coated nanoparticles were prepared for screening tyrosine kinase inhibitors, which specifically interacted with the intracellular kinase domain of the epidermal growth factor receptor. Biotinylated human lung adenocarcinoma epithelial cell membranes specifically interacted with streptavidin-immobilized Fe3O4 magnetic nanoparticles and then formed inside-out-oriented cell membrane-coated magnetic nanoparticles (IOCMMNPs). The cell membrane orientation of the IOCMMNPs was successfully confirmed by immunogold electron microscopy, fluorescently labeled confocal microscopy, sialic acid quantification assay, and the adsorption capacity assay. Moreover, IOCMMNPs possessed satisfactory binding capacity, selectivity, and high sensitivity (limit of detection = 0.4 × 10-3 µg mL-1). Ultimately, IOCMMNPs successfully targeted two main compounds from Strychnos nux-vomica whose potential antitumor activities were further validated by pharmacological studies. The application of the inside-out cell membrane coating strategy further enhances the drug screening efficiency and broadens the insight and methodologies for drug lead discovery. This inside-out cell membrane coating concept also provides a method for the future development of engineered cell membrane-coated nanotechnology.

Clinical Immunophenotype at Disease Onset in Previously Healthy Patients With Cryptococcal Meningitis.

Cryptococcal meningitis (CM) is a global disease with significant morbidity and mortality. Although low peripheral blood cluster of differentiation 4 (CD4) cell counts are found to be related to a high burden of cryptococcus in HIV-infected patients, little is known about possible immune defects in previously healthy patients (PHPs). We performed a retrospective study of 41 CM patients treated from January 2005 to December 2014 who did not have HIV-infection. There were 33 PHPs and 8 not previously healthy patients (non-PHPs). We analyzed clinical test data pertaining to peripheral blood T cells, antibodies, inflammation markers, and cerebral spinal fluid (CSF) completed during the disease onset phase and 5 years following diagnosis. PHPs had significantly higher counts of cluster of differentiation 3 (CD3), cluster of differentiation 4 (CD4), and cluster of differentiation 45 (CD45) cells, and lower percentages of CD8 cells than non-PHPs (P < 0.05). Measurements of inflammatory markers and immunoglobulin in blood were comparable except for lower immunoglobulin A (IgA) levels in non-PHPs (P = 0.0410). Examination of CSF revealed lower white blood cell (WBC) counts in non-PHPs. Five-year mortality in PHPs was higher than in non-PHPs (22.0% vs 12.5%) but this was not statistically significant (P > 0.05). Multivariate analysis revealed that higher immunoglobulin G (IgG) levels in serum during disease onset may be an independent predictor of mortality (P = 0.015). In conclusion, PHPs demonstrate an immunophenotype that is distinct from that of non-PHPs, leading to an improved understanding of the immunology of cryptococcal meningitis.

[Establishment of animal model of chronic optic nerve injury and pathological changes thereof: experiment with cats].

OBJECTIVE: To establish an animal model of chronic optic nerve injury which is suitable for experimental research. METHODS: Dil, a tracer, was injected through the bone windows into the brain of 48 cats so as to mark the retinal ganglion cells (RGCs). Two weeks later the 48 cats were randomly divided into 6 equal groups. The normal group did not receive any other treatment. Other 8 cats underwent sham operation. Imitating the clinical pterional approach, a balloon was implanted into the place under the optic nerve and chiasm in the other 32 cats, then the volume of the balloons were increased by injecting contrast agent at different times to cause the optic nerve and chiasm compressed chronically for 1, 2, 4, or 6 weeks. Flash-visual evoked potential (F-VEP) was measured before operation and at the corresponding observation times in different groups. By the end of the experiment the cats were killed with the specimens of retina and optic nerve taken out to undergo light microscopy and electron microscopy to observe the pathological changes. Eight eyes were taken out from each group to calculate the number of RCGs 1, 2, 4, and 8 weeks after operation respectively. RESULTS: Microscopy showed retina showed profound morphological changes 8 weeks after compression; Demyelination of optic nerve began to occur 2 weeks after compression and progressed later. Axonal degeneration was found 4 week after compression and became more significant 8 weeks later. Under electron microscopy, pathological changes of retina was found 4 weeks and more prominent 8 weeks after compression; Slight demyelination and disorganized of cytoskeleton in the optic nerve were shown 2 weeks after compression, and became more profound later; Myelin regeneration was found 8 weeks after compression. The number of RGCs was reduced significantly by 37% (293/465) since 8 weeks after compression. F-VEP recording showed an extension of latency and depression of amplitude 4 weeks after compression, and the changes were more significant 8 weeks later. CONCLUSION: An animal model of chronic optic nerve injury by compression has been established which is stable and well repeatable. The pathological changes of compressed optic nerve are aggravated gradually as the compression lasts and the volume increases. Degeneration of RGCs occurs secondarily and obviously later than the axonal degeneration.