Biosynthetic Polymalic Acid as a Delivery Nanoplatform for Translational Cancer Medicine.

Poly(ß-L-malic acid) (PMLA) is a natural polyester produced by numerous microorganisms. Regarding its biosynthetic machinery, a nonribosomal peptide synthetase (NRPS) is proposed to direct polymerization of L-malic acid in vivo. Chemically versatile and biologically compatible, PMLA can be used as an ideal carrier for several molecules, including nucleotides, proteins, chemotherapeutic drugs, and imaging agents, and can deliver multimodal theranostics through biological barriers such as the blood-brain barrier. We focus on PMLA biosynthesis in microorganisms, summarize the physicochemical and physiochemical characteristics of PMLA as a naturally derived polymeric delivery platform at nanoscale, and highlight the attachment of functional groups to enhance cancer detection and treatment.

Translational medicine for acute lung injury.

Acute lung injury (ALI) is a complex disease with numerous causes. This review begins with a discussion of disease development from direct or indirect pulmonary insults, as well as varied pathogenesis. The heterogeneous nature of ALI is then elaborated upon, including its epidemiology, clinical manifestations, potential biomarkers, and genetic contributions. Although no medication is currently approved for this devastating illness, supportive care and pharmacological intervention for ALI treatment are summarized, followed by an assessment of the pathophysiological gap between human ALI and animal models. Lastly, current research progress on advanced nanomedicines for ALI therapeutics in preclinical and clinical settings is reviewed, demonstrating new opportunities towards developing an effective treatment for ALI.

CD8+ T cell-based cancer immunotherapy.

The immune system in humans is a defense department against both exogenous and endogenous hazards, where CD8+ T cells play a crucial role in opposing pathological threats. Various immunotherapies based on CD8+ T cells have emerged in recent decades, showing their promising results in treating intractable diseases. However, in the fight against the constantly changing and evolving cancers, the formation and function of CD8+ T cells can be challenged by tumors that might train a group of accomplices to resist the T cell killing. As cancer therapy stepped into the era of immunotherapy, understanding the physiological role of CD8+ T cells, studying the machinery of tumor immune escape, and thereby formulating different therapeutic strategies become the imperative missions for clinical and translational researchers to fulfill. After brief basics of CD8+ T cell-based biology is covered, this review delineates the mechanisms of tumor immune escape and discusses different cancer immunotherapy regimens with their own advantages and setbacks, embracing challenges and perspectives in near future.

Visualization of microRNA therapy in cancers delivered by small extracellular vesicles.

MicroRNA (miRNA) delivery by extracellular vesicles (EVs) has recently inspired tremendous developments in cancer treatments. However, hybridization between miRNA and its target mRNA is still difficult to be imaged in vivo to assess the therapeutic effects in time. Herein we design a nano-scale fluorescent "off-on" complex encapsulated by small extracellular vesicles (sEVs) for real-time visualization and evaluation of gene therapy efficiency in human gastric cancer cells and murine xenograft tumor models. The complex is formed by π-π stacking between graphene quantum dots (GQDs) and tumor suppressor miR-193a-3p conjugated fluorescent tag whose signals remain off when binding to GQDs. Loaded into sEVs using tunable sonication techniques, the GQDs/Cy5-miR particles enter the tumor cells and promote miR-193a-3p escape from endosomes. The miR-193a-3p in GQDs/Cy5-miR is unleashed to pair the specific target oncogene cyclin D1 (CCND1), therefore turning on the fluorescence of miRNA tags. We find out that GQDs/Cy5-miR@sEVs can activate the "turn-on" fluorescent signal and exhibit the longest retention time in vivo, which suggests a minimized degradation of miR-193a-3p in dynamic processes of miRNA-mRNA binding. More importantly, GQDs/Cy5-miR@sEVs significantly promote cancer apoptosis in vitro and in vivo via the enhanced cellular uptake. Our study demonstrates that GQDs/Cy5-miR@sEVs represent an efficient and refined theranostic platform for gene therapy in cancers.

The early warning research on nursing care of stroke patients with intelligent wearable devices under COVID-19.

Stroke patients under the background of the new crown epidemic need to be home-based care. However, traditional nursing methods cannot take care of the patients' lives in all aspects. Based on this, based on machine learning algorithms, our work combines regression models and SVM to build a smart wearable device system and builds a system prediction module to predict patient care needs. The node is used to collect human body motion and physiological parameter information and transmit data wirelessly. The software is used to quickly process and analyze the various motion and physiological parameters of the patient and save the analysis and processing structure in the database. By comparing the results of nursing intervention experiments, we can see that the smart wearable device designed in this paper has a certain effect in stroke care.

Correction to: The early warning research on nursing care of stroke patients with intelligent wearable devices under COVID-19.

[This corrects the article DOI: 10.1007/s00779-021-01520-9.].

Effect of Hypertension Comorbidity on Clinical Characteristics of COVID-19 Patients Infected by the Wild-Type, the Delta or Omicron Variant SARS-CoV-2.

Background: Hypertension was the most common comorbidity in patients with the coronavirus disease 2019 (COVID-19). We aim to study the effect of comorbid hypertension on the clinical characteristics of COVID-19 patients with the underlying mechanism. Methods: We retrospectively analyzed 459, 336 and 659 COVID-19 patients who were infected by the wild-type, the delta and omicron variant, respectively, including their demographic information, medical history, immunization record (if available), and laboratory parameters, to investigate the clinical differences between COVID-19 patients with and without hypertension. Results: In this study 26.1%, 26.8%, and 12.9% of COVID-19 patients had pre-existing hypertension in the cohort of wild-type, delta, and omicron variant, respectively. Compared to non-hypertensive peers, hypertension patients demonstrated older age, higher occurrence of other major comorbidities, and poorer blood or coagulation parameters, showing worse prognosis. In case of the delta or omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hypertension patients produced robust antibody responses, although indistinguishable whether it was due to vaccination or natural infection and resembled those of non-hypertensive peers in blood cell and coagulation profiles with still varying viremic damages to major organs. Conclusions: Resultantly, COVID-19 infection promoted pro-inflammatory and pro-thrombotic states in hypertension patients, whereas vaccinated individuals would exhibit favorable prognoses.

Polymalic acid for translational nanomedicine.

With rich carboxyl groups in the side chain, biodegradable polymalic acid (PMLA) is an ideal delivery platform for multifunctional purposes, including imaging diagnosis and targeting therapy. This polymeric material can be obtained via chemical synthesis, or biological production where L-malic acids are polymerized in the presence of PMLA synthetase inside a variety of microorganisms. Fermentative methods have been employed to produce PMLAs from biological sources, and analytical assessments have been established to characterize this natural biopolymer. Further functionalized, PMLA serves as a versatile carrier of pharmaceutically active molecules at nano scale. In this review, we first delineate biosynthesis of PMLA in different microorganisms and compare with its chemical synthesis. We then introduce the biodegradation mechanism PMLA, its upscaled bioproduction together with characterization. After discussing advantages and disadvantages of PMLA as a suitable delivery carrier, and strategies used to functionalize PMLA for disease diagnosis and therapy, we finally summarize the current challenges in the biomedical applications of PMLA and envisage the future role of PMLA in clinical nanomedicine.

Differentiation of COVID-19 from seasonal influenza: A multicenter comparative study.

As coronavirus disease 2019 (COVID-19) crashed into the influenza season, clinical characteristics of both infectious diseases were compared to make a difference. We reported 211 COVID-19 patients and 115 influenza patients as two separate cohorts at different locations. Demographic data, medical history, laboratory findings, and radiological characters were summarized and compared between two cohorts, as well as between patients at the intensive care unit (ICU) andnon-ICU within the COVID-19 cohort. For all 326 patients, the median age was 57.0 (interquartile range: 45.0-69.0) and 48.2% was male, while 43.9% had comorbidities that included hypertension, diabetes, bronchitis, and heart diseases. Patients had cough (75.5%), fever (69.3%), expectoration (41.1%), dyspnea (19.3%), chest pain (18.7%), and fatigue (16.0%), etc. Both viral infections caused substantial blood abnormality, whereas the COVID-19 cohort showed a lower frequency of leukocytosis, neutrophilia, or lymphocytopenia, but a higher chance of creatine kinase elevation. A total of 7.7% of all patients possessed no abnormal sign in chest computed tomography (CT) scans. For both infections, pulmonary lesions in radiological findings did not show any difference in their location or distribution. Nevertheless, compared to the influenza cohort, the COVID-19 cohort presented more diversity in CT features, where certain specific CT patterns showed significantly more frequency, including consolidation, crazy paving pattern, rounded opacities, air bronchogram, tree-in-bud sign, interlobular septal thickening, and bronchiolar wall thickening. Differentiable clinical manifestations and CT patterns may help diagnose COVID-19 from influenza and gain a better understanding of both contagious respiratory illnesses.

Relationship between occupational noise exposure and hypertension: A cross-sectional study in steel factories.

BACKGROUND: Hazardous exposure to occupational noise may be associated with an increased risk of cardiovascular disease and hypertension. This study was performed to assess the relationship between noise exposure and hypertension prevalence in steelworkers. METHODS: A cross-sectional survey using self-reported noise exposure and audiometrically measured hearing loss was performed. One thousand eight hundred and seventy-four workers were interviewed. Multiple logistic regression was used to calculate odds ratios for hypertension by noise exposure. Linear regression analysis was used to test associations between noise exposure and systolic blood pressure (SBP) and diastolic blood pressure (DBP). RESULTS: Occupational noise-exposed subjects had significantly higher blood pressure levels than nonexposed subjects (SBP: 123.18 ± (standard deviation) 12.44 vs 119.80 ± 12.50 mm Hg; DBP: 77.86 ± 9.34 vs 75.49 ± 8.73 mmHg). The prevalence of hypertension was approximately 5% in the control group without noise exposure or hearing impairment and increased from 6% to 21% across the range of increasing degree of hearing loss and, separately, of cumulative exposure time. Noise exposure (any) was associated with an increase in the prevalence of hypertension (odds ratio, 2.03, 95% confidence interval [CI]: 1.15-3.58). Noise-induced hearing loss and cumulative noise exposure time were positively correlated with BP (hearing loss: SBP: ß = .09, 95% CI: 0.04-0.15 mm Hg, DBP: ß = .11, 95% CI: 0.06-0.17 mm Hg; cumulative exposure time: SBP: ß = .10, 95% CI: 0.04-0.15 mm Hg, DBP: ß = .09, 95% CI: 0.04-0.15 mm Hg). CONCLUSIONS: Noise exposure measured in two different ways was strongly associated with the prevalence of hypertension in steelworkers. Reducing noise in the steel factory could be a way of decreasing the risk of hypertension in this population.

Differences in Nanoparticle Uptake in Transplanted and Autochthonous Models of Pancreatic Cancer.

Human pancreatic ductal adenocarcinoma (PDAC) contains a distinctively dense stroma that limits the accessibility of anticancer drugs, contributing to its poor overall prognosis. Nanoparticles can enhance drug delivery and retention in pancreatic tumors and have been utilized clinically for their treatment. In preclinical studies, various mouse models differentially recapitulate the microenvironmental features of human PDAC. Here, we demonstrate that through utilization of different organic cosolvents and by doping of a homopolymer of poly(ε-caprolactone), a diblock copolymer composition of poly(ethylene oxide)- block-poly(ε-caprolactone) may be utilized to generate biodegradable and nanoscale micelles with different physical properties. Noninvasive optical imaging was employed to examine the pharmacology and biodistribution of these various nanoparticle formulations in both allografted and autochthonous mouse models of PDAC. In contrast to the results reported with transplanted tumors, spherical micelles as large as 300 nm in diameter were found to extravasate in the autochthonous model, reaching a distance of approximately 20 µm from the nearest tumor cell clusters. A lipophilic platinum(IV) prodrug of oxaliplatin was further able to achieve a ∼7-fold higher peak accumulation and a ∼50-fold increase in its retention half-life in pancreatic tumors when delivered with 100 nm long worm-like micelles as when compared to the free drug formulation of oxaliplatin. Through further engineering of nanoparticle properties, as well as by widespread adoption of the autochthonous tumor model for preclinical testing, future therapeutic formulations may further enhance the targeting and penetration of anticancer agents to improve survival outcomes in PDAC.

Progressive Saturation Improves the Encapsulation of Functional Proteins in Nanoscale Polymer Vesicles.

PURPOSE: To develop a technique that maximizes the encapsulation of functional proteins within neutrally charged, fully PEGylated and nanoscale polymer vesicles (i.e., polymersomes). METHODS: Three conventional vesicle formation methods were utilized for encapsulation of myoglobin (Mb) in polymersomes of varying size, PEG length, and membrane thickness. Mb concentrations were monitored by UV-Vis spectroscopy, inductively coupled plasma optical emission spectroscopy (ICP-OES) and by the bicinchoninic acid (BCA) assay. Suspensions were subject to protease treatment to differentiate the amounts of surface-associated vs. encapsulated Mb. Polymersome sizes and morphologies were monitored by dynamic light scattering (DLS) and by cryogenic transmission electron microscopy (cryo-TEM), respectively. Binding and release of oxygen were measured using a Hemeox analyzer. RESULTS: Using the established "thin-film rehydration" and "direct hydration" methods, Mb was found to be largely surface-associated with negligible aqueous encapsulation within polymersome suspensions. Through iterative optimization, a novel "progressive saturation" technique was developed that greatly increased the final concentrations of Mb (from < 0.5 to > 2.0 mg/mL in solution), the final weight ratio of Mb-to-polymer that could be reproducibly obtained (from < 1 to > 4 w/w% Mb/polymer), as well as the overall efficiency of Mb encapsulation (from < 5 to > 90%). Stable vesicle morphologies were verified by cryo-TEM; the suspensions also displayed no signs of aggregate formation for > 2 weeks as assessed by DLS. "Progressive saturation" was further utilized for the encapsulation of a variety of other proteins, ranging in size from 17 to 450 kDa. CONCLUSIONS: Compared to established vesicle formation methods, "progressive saturation" increases the quantities of functional proteins that may be encapsulated in nanoscale polymersomes.

Dendritic silica nanomaterials (KCC-1) with fibrous pore structure possess high DNA adsorption capacity and effectively deliver genes in vitro.

The pore size and pore structure of nanoporous materials can affect the materials' physical properties, as well as potential applications in different areas, including catalysis, drug delivery, and biomolecular therapeutics. KCC-1, one of the newest members of silica nanomaterials, possesses fibrous, large pore, dendritic pore networks with wide pore entrances, large pore size distribution, spacious pore volume and large surface area--structural features that are conducive for adsorption and release of large guest molecules and biomacromolecules (e.g., proteins and DNAs). Here, we report the results of our comparative studies of adsorption of salmon DNA in a series of KCC-1-based nanomaterials that are functionalized with different organoamine groups on different parts of their surfaces (channel walls, external surfaces or both). For comparison the results of our studies of adsorption of salmon DNA in similarly functionalized, MCM-41 mesoporous silica nanomaterials with cylindrical pores, some of the most studied silica nanomaterials for drug/gene delivery, are also included. Our results indicate that, despite their relatively lower specific surface area, the KCC-1-based nanomaterials show high adsorption capacity for DNA than the corresponding MCM-41-based nanomaterials, most likely because of KCC-1's large pores, wide pore mouths, fibrous pore network, and thereby more accessible and amenable structure for DNA molecules to diffuse through. Conversely, the MCM-41-based nanomaterials adsorb much less DNA, presumably because their outer surfaces/cylindrical channel pore entrances can get blocked by the DNA molecules, making the inner parts of the materials inaccessible. Moreover, experiments involving fluorescent dye-tagged DNAs suggest that the amine-grafted KCC-1 materials are better suited for delivering the DNAs adsorbed on their surfaces into cellular environments than their MCM-41 counterparts. Finally, cellular toxicity tests show that the KCC-1-based materials are biocompatible. On the basis of these results, the fibrous and porous KCC-1-based nanomaterials can be said to be more suitable to carry, transport, and deliver DNAs and genes than cylindrical porous nanomaterials such as MCM-41.

Protocol for isolating and identifying small extracellular vesicles derived from human umbilical cord mesenchymal stem cells.

Small extracellular vesicles (sEVs) are lipid bilayer-enclosed particles secreted by living cells. Here, we present a protocol for the collection and isolation of sEVs derived from human umbilical cord mesenchymal stem cells (hucMSCs). We describe steps for characterizing their morphology and integrity by transmission electron microscopy (TEM) and size distribution using nanoparticle tracking analysis (NTA) and an atomic force microscope (AFM). We then detail procedures for assessing nanoparticle size analysis and molecular markers by western blotting and Flow NanoAnalyzer.

Biological imaging using nanoparticles of small organic molecules with fluorescence emission at wavelengths longer than 1000 nm.

Embedded in a polymer: A hydrophobic organic molecule that fluoresces in the near-infrared II (NIR-II) region was made water-soluble and biocompatible by its embedment in a polymer nanoparticle, which was then coated with hydrophilic poly(ethylene glycol) chains. The resulting nanoparticles exhibit bright fluorescence in the NIR-II window and high photostability in aqueous media and were used for in vivo imaging in mice.

Fluorescence Tracking of Small Extracellular Vesicles In Vivo.

In this study, we employed organic and inorganic dyes that have fluorescence under visible or near-infrared light region to stain human umbilical cord (Huc) mesenchymal stem cell (MSC)-, HEK293T cell- and HGC cell-derived small extracellular vesicles (sEVs), and then tracked their fluorescence signals in human gastric cancer xenografted murine models. Several biological characteristics were examined and compared when different dye-stained sEVs in the same tumor model or the same dye-stained sEVs between different tumor models were applied, including sEVs circulation in the blood, biodistribution of sEVs in major organs, and time-dependent tumor accumulation of sEVs. The results demonstrated that distinct tumor accumulation features were presented by sEVs if labeled by different fluorescent dyes, while sEVs derived from different cell lines showed homologous blood circulation and tumor accumulation. To conclude, although fluorescence imaging remains a reliable way to trace sEVs, single staining of sEVs membrane should be obviated in future work when examining the biological fate of sEVs.

Risk factors for hospitalization and pneumonia development of pediatric patients with seasonal influenza during February-April 2023.

Objectives: In China influenza remains a low activity for continuous 3 years due to COVID-19 controls. We here sought to study the clinical characteristics and risk factors of the influenza infection among children after the mandatory COVID-19 restrictions were lifted. Methods: We included 1,006 pediatric patients with influenza A virus (IAV) infection, enrolled in one tertiary hospital in Zhenjiang, Jiangsu Province, China, during February to April 2023. Patients were divided into the outpatient (n = 798) and inpatient (n = 208) groups, and their baseline characteristics were compared between two groups to conclude the risk factors for pediatric hospitalization. Separately, pediatric inpatients (n = 208) were further divided into the pneumonia and non-pneumonia groups with comparison of their clinical characteristics, including their laboratory test results and representative radiological features, to derive the key determinants for pneumonia development after hospitalization. Results: Compared to outpatients, IAV-infected pediatric inpatients exhibited younger age, higher female: male ratio, more co-infection of influenza B virus (IBV) and hematological abnormality. Multivariate regression analysis determined the independent risk factors of hospitalization to be the clinical symptom of abdominal pain (OR = 2.63, [95% CI, 1.05-6.57], p = 0.039), co-infection of IBV (OR = 44.33, [95% CI, 25.10-78.30], p = 0.001), elevated levels of lymphocytes (OR = 2.24, [95% CI,1.65-3.05], p = 0.001) and c-reactive proteins (CRPs) (OR = 1.06, [95% CI, 1.03-1.08], p = 0.001) upon hospital admission. Furthermore, the cough symptom (OR = 17.39, [95% CI, 3.51-86.13], p = 0.001) and hospitalization length (OR = 1.36, [95% CI, 1.12-1.67], p = 0.002) were determined to be risk factors of pneumonia acquirement for pediatric inpatients. Conclusion: While the abdominal pain, viral co-infection and some hematological abnormality mainly contribute to hospitalization of pediatric patients with IAV infection, the length of hospital stay and clinical sign of coughing upon hospital admission constitute the key determinants for nosocomial pneumonia development.

Construction of a novel nomogram based on competing endogenous RNAs and tumor-infiltrating immune cells for prognosis prediction in elderly patients with colorectal cancer.

Competitive endogenous RNAs (ceRNAs) and tumor-infiltrating immune cells play essential roles in colorectal cancer (CRC) tumorigenesis. However, their prognostic role in elderly patients with CRC is unclear. Gene expression profiles and clinical information for elderly patients with CRC were downloaded from The Cancer Genome Atlas. Univariate, LASSO, and multivariate Cox regression analyses were utilized for screening key ceRNAs and prevent overfitting. A total of 265 elderly patients with CRC were included. We constructed a novel ceRNA network consisting of 17 lncRNAs, 35 miRNAs, and 5 mRNAs. We established three prognosis predictive nomograms based on four key ceRNAs (ceRNA nomogram), five key immune cells (immune cell nomogram), and their combination (ceRNA-immune cell nomogram). Among them, the ceRNA-immune cell nomogram had the best accuracy. Furthermore, the areas under the curve of the ceRNA-immune cell nomogram were also significantly greater than the TNM stage at 1 (0.818 vs. 0.693), 3 (0.865 vs. 0.674), and 5 (0.832 vs. 0.627) years. Co-expression analysis revealed that CBX6 was positively correlated with activated dendritic cells (R = 0.45, p < 0.01), whereas negatively correlated with activated mast cells (R =- 0.43, p < 0.01). In conclusion, our study constructed three nomograms to predict prognosis in elderly patients with CRC, among which the ceRNA-immune cell nomogram had the best prediction accuracy. We inferred that the mechanism underlying the regulation of activated dendritic cells and mast cells by CBX6 might play a crucial role in tumor development and prognosis of elderly patients with CRC.

Stalk-derived carbon dots as nanosensors for Fe3+ ions detection and biological cell imaging.

Introduction: Iron is one of the most important needed elements for the growth and reproduction of living organisms. The detection of iron levels is important and developing fluorescent probes with excellent sensitivity for Fe3+ ions is of great significance. Carbon dot (CDs) is a new type of fluorescent nanomaterial based on abundant and low-cost carbon elements. The use of widely distributed renewable agricultural waste straw as a carbon precursor to prepare CDs sensor can not only reduce the pollution caused by burning straw to the atmospheric environment, but also achieve the transformation of resources from waste to treasure. Methods: In this study, CDs were obtained from corn stalk powder by pyrolysis and microwave process. The sensitivity and linear response range of CDs sensor was studied through analyzing the effect of different Fe3+ ions concentrations on the fluorescence quenching. The application of CDs in biological cell imaging was investigated using HGC-27 cells. Results: The fluorescence quenching showed a good linear relationship with the Fe3+ concentration in the range from 0 to 128 µM, and a low detection limit of 63 nM. In addition, the CDs have high recognition for Fe3+ ions. Meanwhile, the CDs have a low cytotoxicity and desirable biocompatibility, allowing the multicolor living cell imaging. Conclusion: The prepared CDs can be used as fluorescent sensors for the selective detection of Fe3+ ions and biological cell imaging. Our results supported that the conversion of agricultural waste into carbon nanomaterials has great potential to be developed.

A handheld contactless conductivity detector for monitoring the desalting of low-volume virus and cell samples.

Desalting of biosamples is crucial for analytical techniques intolerant to abundant salts. However, there is no simple tool to monitor the desalting of low-volume biosamples so far. Here we developed a handheld capacitively coupled contactless conductivity detector (hC4D) as a miniaturized device to measure the conductivity of 75 µL biosamples. Polyether-ether-ketone (PEEK) tubing was selected as the sample reservoir for sample loading via a pipette. Another pipetting of air pushed the sample solution out of the tubing to recollect the sample. Owing to the low sample consumption and easy sample recollection, hC4D is advantageous for testing expensive biosamples, such as viruses and cells. In addition, the whole process of sample injection, conductivity measurement, recollection, and calibration of conductivity can be completed within 1 min. To verify the feasibility of hC4D, we monitored the desalting progress of gel filtration (GF) of 200 µL blood samples, ultrafiltration (UF) of 300 µL virus samples, and dialysis of 7 mL cell samples. Three rounds of GF and UF completely removed the salts but led to poor sample recovery. In contrast, low concentrations of residual salts remained and better recovery was achieved after two rounds of GF and UF. We further utilized the hC4D to monitor the dialysis and tuned the salt concentration in the cell sample, such that we maintained the viability of cells in a low conductivity environment. These results indicated that hC4D is a promising tool for optimizing the desalting procedure of low-volume biosamples.