Engineering an Organic Nanoplatform for Augmented Pyroeletroimmunotherapy.

Photothermal immunotherapy has shown great promise in the treatment of tumor metastasis. However, the thermal resistance of tumor cells substantially compromises the treatment effect of photothermal immunotherapy. Herein, a high-performance organic pyroelectric nanoplatform, tBu-TPAD-BF2 nanoparticles (NPs), is rationally engineered for the effective pyroelectroimmunotherapy of tumor metastasis. Biocompatible tBu-TPAD-BF2 NPs with excellent pyroelectric and photothermal conversion properties are constructed by assembling organic, low-bandgap pyroelectric molecules with amphiphilic polymers. After internalization by tumor cells, treatment with tBu-TPAD-BF2 NPs causes an apparent temperature elevation upon near-infrared (NIR) laser irradiation, inducing potent immunogenic cell death (ICD). Additionally, the temperature variations under alternating NIR laser irradiation facilitate reactive oxygen species production for pyroelectric therapy, thus promoting ICD activation and lowering thermal resistance. Importantly, in vivo assessments illustrate that tBu-TPAD-BF2 NPs in combination with NIR laser exposure notably inhibit primary and distant tumor proliferation and prominently retarded lung metastasis. RNA profiling reveals that treatment with tBu-TPAD-BF2 NPs markedly suppresses metastasis under NIR laser illumination by downregulating metastasis-related genes and upregulating immune response-associated pathways. Therefore, this study provides a strategy for designing high-performance pyroelectric nanoplatforms to effectively cure tumor metastasis, thereby overcoming the inherent shortcomings of photothermal immunotherapy.

Identifying Risk Factors for Secondary Infection Post-SARS-CoV-2 Infection in Patients With Severe and Critical COVID-19.

Emerging evidence has unveiled the secondary infection as one of the mortal causes of post-SARS-CoV-2 infection, but the factors related to secondary bacterial or fungi infection remains largely unexplored. We here systematically investigated the factors that might contribute to secondary infection. By clinical examination index analysis of patients, combined with the integrative analysis with RNA-seq analysis in the peripheral blood mononuclear cell isolated shortly from initial infection, this study showed that the antibiotic catabolic process and myeloid cell homeostasis were activated while the T-cell response were relatively repressed in those with the risk of secondary infection. Further monitoring analysis of immune cell and liver injury analysis showed that the risk of secondary infection was accompanied by severe lymphocytopenia at the intermediate and late stages and liver injury at the early stages of SARS-CoV-2. Moreover, the metagenomics analysis of bronchoalveolar lavage fluid and the microbial culture analysis, to some extent, showed that the severe pneumonia-related bacteria have already existed in the initial infection.

Vitamin C supplementation is necessary for patients with coronavirus disease: An ultra-high-performance liquid chromatography-tandem mass spectrometry finding.

To administer vitamin C (VC) with precision to patients with the coronavirus disease (COVID-19), we developed an ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method to assess plasma VC concentrations. 31 patients with COVID-19 and 51 healthy volunteers were enrolled. VC stability was evaluated in blood, plasma, and precipitant-containing stabilizers. A proportion of 7.7 % of VC was degraded in blood at room temperature (RT) (approximately 20-25 °C) at 1.5 h post administration with respect to the proportion degraded at 0.5 h, but without statistical difference. VC was stable in plasma for 0.75 h at RT, 2 h at 4 °C, 5 days at -40 °C, and 4 h in precipitant-containing stabilizer (2 % oxalic acid) at RT. The mean plasma concentration of VC in patients with COVID-19 was 2.00 mg/L (0.5-4.90) (n = 8), which was almost 5-fold lower than that in healthy volunteers (9.23 mg/L (3.09. 35.30)) (n = 51). After high-dose VC treatment, the mean VC concentration increased to 13.46 mg/L (3.93. 34.70) (n = 36), higher than that in healthy volunteers, and was within the normal range (6-20 mg/L). In summary, we developed a simple UPLC-MS/MS method to quantify VC in plasma, and determined the duration for which the sample remained stable. VC levels in patients with COVID-19 were considerably low, and supplementation at 100 mg/kg/day is considered highly essential.

Regulatory CD4+ and CD8+ T cells are negatively correlated with CD4+ /CD8+ T cell ratios in patients acutely infected with SARS-CoV-2.

Regulatory T cell can protect against severe forms of coronaviral infections attributable to host inflammatory responses. But its role in the pathogenesis of COVID-19 is still unclear. In this study, frequencies of total and multiple subsets of lymphocytes in peripheral blood of COVID-19 patients and discharged individuals were analyzed using a multicolor flow cytometry assay. Plasma concentration of IL-10 was measured using a microsphere-based immunoassay kit. Comparing to healthy controls, the frequencies of total lymphocytes and T cells decreased significantly in both acutely infected COVID-19 patients and discharged individuals. The frequencies of total lymphocytes correlated negatively with the frequencies of CD3- CD56+ NK cells. The frequencies of regulatory CD8+ CD25+ T cells correlated with CD4+ /CD8+ T cell ratios positively, while the frequencies of regulatory CD4+ CD25+ CD127- T cells correlated negatively with CD4+ /CD8+ T cell ratios. Ratios of CD4+ /CD8+ T cells increased significantly in patients beyond age of 45 years. And accordingly, the frequencies of regulatory CD8+ CD25+ T cells were also found significantly increased in these patients. Collectively, the results suggest that regulatory CD4+ and CD8+ T cells may play distinct roles in the pathogenesis of COVID-19. Moreover, the data indicate that NK cells might contribute to the COVID-19 associated lymphopenia.

An inter-correlated cytokine network identified at the center of cytokine storm predicted COVID-19 prognosis.

The hyper-inflammatory response is thought to be a major cause of acute respiratory distress syndrome (ARDS) in patients with COVID-19. Although multiple cytokines are reportedly associated with disease severity, the key mediators of SARS-CoV-2 induced cytokine storm and their predictive values have not been fully elucidated. The present study analyzed maximal and early (within 10 days after disease onset) concentrations of 12-plex cytokines in plasma. We found consistently elevated plasma levels of IL-6, IL-8 and IL-5 in patients who were deceased compared with those who had mild/moderate or severe disease. The early plasma concentrations of IFN-a and IL-2 positively correlated with the length of the disease course. Moreover, correlation network analysis showed that IL-6, IL-8, and IL-5 located at the center of an inter-correlated cytokine network. These findings suggested that IL-8, IL-6, IL-5 might play central roles in cytokine storms associated with COVID-19 and that the early detection of multiple plasma cytokines might help to predict the prognosis of this disease.

Severe Coronavirus disease 2019 pneumonia patients showed signs of aggravated renal impairment.

BACKGROUND: This objective of this study was to identify a sensitive indicator of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: Samples were collected from 136 patients with Coronavirus disease 2019 (COVID-19) pneumonia admitted to the Shanghai public health clinical center (116 mild, 20 severe). The concentrations of serum urea, Uric Acid (UA), Creatinine (CREA), Erythrocyte sedimentation rate (ESR), high-sensitivity C-reactive protein (hs-CRP), procalcitonin (PCT), and urine protein (Pro) have been tested in this study. RESULTS: Higher levels of urea (female 7.00 ± 3.31, male 8.87 ± 5.18) Pro (female7/7, male 12/13), hs-CRP (female 2/7, male 5/13) ESR (female 94.43 ± 33.26, male 67.85 ± 22.77) were found in severe patients compared with the mild (urea: female 3.71 ± 1.00, male 4.42 ± 1.14; Pro: female 3/46, male 12/70; hs-CRP: female 1/46, male 3/70; ESR: female 43.32 ± 33.24, male 21.64 ± 21.82). UA is lower in the severe group (female 146.90 ± 54.01, male 139.34 ± 66.95) than in mild group (female 251.99 ± 64.35, male 339.81 ± 71.32). CREA and PCT did not show a significant difference between mild and severe patients, but the difference among the five biological markers (urea, Pro, hs-CRP, ESR, and UA) between mild and severe patients we tested was small (P < .05). CONCLUSION: Severe COVID-19 patients had higher levels of urea and Pro, while their UA levels were lower, reflecting poor kidney function in severe patients. However, higher levels of hs-CRP, ESR indicated that inflammatory responses were more active in severe patients.

"Founding Its Empire on Spells of Pleasure": Brunonian Excitability, the Invigorated English Opium-Eater, and De Quincey's "China Question".

What light can De Quincey's Confessions of an English Opium-Eater (1821) shed on its author's later advocacy of the First Opium War? To what degree did De Quincey's and other contemporaneous accounts of opium use in Britain influence metaphorical connections between bodily energy and national power in the 1830s and 1840s? Placing Confessions alongside John Brown's 1780 treatise, Elements of Medicine, this essay argues that De Quincey "nationalized" opium-eating by transforming mental exceptionality in British Romanticism into a medical body's connection with internal energies and external stimuli from China and "the Orient." The essay concludes that opium serves in De Quincey's Confessions as a crucial bridge between Romantic sublimity, in which it purportedly acted as a mysterious technology for self-strengthening, and Victorian consumerism, when the drug became both a popular commodity among national and global users.

Association of pvl gene with incomplete hemolytic phenotype in clinical Staphylococcus aureus.

Purpose: This experiment aimed to evaluate the correlation between the hemolytic phenotype of Staphylococcus aureus and pvl gene in terms of characteristics of antibiotic resistance. Materials and methods: Two-hundred and eleven strains of hospital-acquired S. aureus and their bacterial susceptibility to 20 antibiotics were determined by MicroScan WalkAway96. All strains were cultured on Columbia sheep blood agar plates for 24 hours and then underwent ten passages for investigation of their hemolytic phenotypes. S. aureus produced incomplete ß-hemolytic phenotype, termed as S. aureus strains with incomplete hemolytic phenotype (SIHP). The pvl gene was identified by PCR amplification followed by DNA sequencing. Statistical analyses of the data were performed using SPSS version 16.0 software. Results: Fifty-two (24.64%) strains were confirmed to maintain the incomplete hemolytic phenotype of S. aureus (SIHP). Meanwhile, 15 (7.11%) of 211 strains were found to carry the pvl gene, and eight of the 15 strains were SIHP. Compared with S. aureus strains with complete hemolytic phenotype (SCHP), SIHP showed higher susceptibility to seven of the 20 antibiotics (oxacillin, ciprofloxacin, gentamicin, ceftriaxone, cefoxitin, levofloxacin, and moxifloxacin) (P<0.05). The pvl-positive bacteria had a higher rate of resistance to four antibiotics (rifampin, ciprofloxacin, levofloxacin, and moxifloxacin) in comparison with the pvl-negative strains (P<0.05). Conclusion: SIHP had a high frequency of pvl gene. The pvl-positive isolates showed less resistance to rifampin, ciprofloxacin, levofloxacin, and moxifloxacin. Additionally, the majority of SIHP isolates (61.54%) were methicillin-resistant S. aureus. SIHP strains had significantly higher antibiotic resistance to cefoxitin when compared with SCHP, while SCHP strains had a high rate of antibiotic resistance to ciprofloxacin, gentamicin, ceftriaxone, levofloxacin, and moxifloxacin. The results may help to provide medical advice for selection of antibiotics for patients with SIHP-associated infections.

Effects of Desolvating Agent Types, Ratios, and Temperature on Size and Nanostructure of Nanoparticles from α-Lactalbumin and Ovalbumin.

In this study, we compare the preparation of ovalbumin (OVA) and α-lactalbumin (α-LA) nanoparticles using different desolvating agents (ethanol, acetone, and methanol) and water: desolvating agent volume ratios (1:3, 1:4, 1:5, 1:10, and 1:20). Also the effects of protein solution temperature (25, 50, and 80 ℃) on the size of nanoparticles and the stability of crosslinked nanoparticles for 30 d were studied. OVA and α-LA were shown to be good candidates for nanoparticulation and nanoparticles in the range of 60 to 230 nm were obtained. The comparison between the 2 proteins offers guidance to optimize OVA and α-LA nanoparticle fabrication and to efficiently obtain nanoparticles with desired characteristics. The particle sizes of OVA nanoparticles were found to be in the range of 60 to 160 nm, and the particle sizes of α-LA were between 150 and 230 nm. The sizes varied with different desolvating agents: for OVA, ethanol, and methanol both produced nanoparticles smaller than 100 nm; for α-LA, methanol produced the smallest nanoparticles. Water: desolvating agent ratios, in the studied range, did not show a significant effect on the particle sizes for both OVA and α-LA nanoparticles. The size and morphology of the nanoparticles were found to change when the protein solutions were heated up to 50 and 80 ℃ and cooled down before nanoparticulation and most nanoparticles had a smaller diameter.