Phenotypic and functional exhaustion of circulating CD3+ CD56+ NKT-like cells in colorectal cancer patients.

CD3+ CD56+ NKT-like cells are crucial to antitumor immune surveillance and defense. However, research on circulating NKT-like cells in colorectal cancer (CRC) patients is limited. This investigation selected 113 patients diagnosed with primary CRC for preoperative peripheral blood collection. The blood from 106 healthy donors at the physical examination center was acquired as a healthy control (HC). The distribution of lymphocyte subsets, immunophenotype, and functional characteristics of NKT-like cells was comprehensively evaluated. Compared to HC, primary CRC patients had considerably fewer peripheral NKT-like cells in frequency and absolute quantity, and the fraction of NKT-like cells was further reduced in patients with vascular invasion compared to those without. The NKT-like cells in CRC patients had a reduced fraction of the activating receptor CD16, up-regulated expression of inhibitory receptors LAG-3 and NKG2A, impaired production of TNF-α and IFN-γ, as well as degranulation capacity. Moreover, the increased frequency of NKG2A+ NKT-like cells and the decreased expression of activation-related molecules were significantly correlated with tumor progression. In detail, NKG2A+ NKT-like cells indicated increased PD-1 and Tim-3 and reduced TNF-α than NKG2A- subgroup. Blocking NKG2A in vitro restored cytokine secretion capacity in NKT-like cells from CRC patients. Altogether, this research revealed that circulating NKT-like cells in CRC patients exhibited suppressive phenotype and functional impairment, which was more pronounced in NKG2A+ NKT-like cells. These findings suggest that NKG2A blockade may restore anti-tumor effector function in NKT-like cells, which provides a potential target for immunotherapy in CRC patients.

A Single Vaccine Protects against SARS-CoV-2 and Influenza Virus in Mice.

The ongoing SARS-CoV-2 pandemic poses a severe global threat to public health, as do influenza viruses and other coronaviruses. Here, we present chimpanzee adenovirus 68 (AdC68)-based vaccines designed to universally target coronaviruses and influenza. Our design is centered on an immunogen generated by fusing the SARS-CoV-2 receptor-binding domain (RBD) to the conserved stalk of H7N9 hemagglutinin (HA). Remarkably, the constructed vaccine effectively induced both SARS-CoV-2-targeting antibodies and anti-influenza antibodies in mice, consequently affording protection from lethal SARS-CoV-2 and H7N9 challenges as well as effective H3N2 control. We propose our AdC68-vectored coronavirus-influenza vaccine as a universal approach toward curbing respiratory virus-causing pandemics. IMPORTANCE The COVID-19 pandemic exemplifies the severe public health threats of respiratory virus infection and influenza A viruses. The currently envisioned strategy for the prevention of respiratory virus-causing diseases requires the comprehensive administration of vaccines tailored for individual viruses. Here, we present an alternative strategy by designing chimpanzee adenovirus 68-based vaccines which target both the SARS-CoV-2 receptor-binding-domain and the conserved stalk of influenza hemagglutinin. When tested in mice, this strategy attained potent neutralizing antibodies against wild-type SARS-CoV-2 and its emerging variants, enabling an effective protection against lethal SARS-CoV-2 challenge. Notably, it also provided complete protection from lethal H7N9 challenge and efficient control of H3N2-induced morbidity. Our study opens a new avenue to universally curb respiratory virus infection by vaccination.

Colourful phase change material-incorporated flexible film for efficient passive radiative cooling.

Passive radiative cooling involves the emission of thermal radiation into cold space and the reflection of solar radiation, which aims to cool and lower the temperature of objects. However, currently most radiative coolers have a white appearance which restricts their potential applications. We develop a coloured bilayer radiative cooling membrane using polyvinylidene fluoride/tetraethoxysilane (PVDF/TEOS) fibres, with incorporation of phase change materials (PCMs) and active dyes through a simple and large-area electrospinning process. In comparison to traditional emitters, PCM-incorporated colourful coolers provide energy storage capacity and colourful appearances. Our phase-transition-based colourful flexible film (PCFF) achieves a total solar reflectance of 0.81 and a mid-infrared (8-13µm) emissivity of 0.85 with superior mechanical strength and good hydrophobicity. We experimentally demonstrate that our PCFF can significantly reduce the temperature of objects exposed to direct sunlight, with a cooling effect of up to 9 °C compared to commercial fabrics of similar materials and colours. Our work provides a promising starting point for the design and manufacture of colourful and flexible thermal control films.

Dysfunction of circulating CD3+CD56+ NKT-like cells in type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is associated with increased incidence and mortality of many cancers and infectious diseases. CD3+CD56+ NKT-like cells play pivotal roles in tumor surveillance and infection control. However, little is known about potential alterations in circulating NKT-like cells in T2DM patients. In this study, we found that the frequency and absolute counts of circulating NKT-like cells were significantly lower in patients with T2DM compared to healthy volunteers. Moreover, in T2DM patients, NKT-like cells were impaired in their production of IFN-γ and TNF-α as well as degranulation capacity. The expression of activating receptor NKG2D was markedly decreased on NKT-like cells in T2DM patients, while the expression of inhibitory receptors Tim-3 and LAG-3 was upregulated. In detail, Tim-3+NKT-like cells expressed higher LAG-3 and less IFN-γ and TNF-α compared to Tim-3-NKT-like cells. Importantly, we further found that the expression of Tim-3 in NKT-like cells from T2DM patients correlated positively with glycated hemoglobin (HbA1c) and fasting blood glucose (FBG) levels, as well as with diabetes duration. In conclusion, these results indicate that NKT-like cells from T2DM patients display an exhausted phenotype and reduced functionality. Moreover, Tim-3 expression on NKT-like cells likely serves a novel biomarker for duration of T2DM.

Blood Urea Nitrogen-to-Serum Albumin Ratio Predicts Fatal Outcomes in Severe Fever with Thrombocytopenia Syndrome Patients.

There are no effective therapies for severe fever with thrombocytopenia syndrome (SFTS), and existing predictors of mortality are still controversial. This retrospective study aimed to identify reliable early-stage indicators for predicting fatal outcomes in 217 patients hospitalized with an SFTS diagnosis between March 2021 and November 2023; 157 of the patients survived, and 60 died. Demographics, clinical characteristics, and laboratory parameters were reassessed in both groups. The mean age of participants was 64.0 (interquartile range: 54.5-71.0) years, and 42.4% (92/217) were males. Based on a multivariate Cox regression analysis, the blood urea nitrogen-to-serum albumin ratio (BAR) (hazard ratio [HR]:4.751; 95% CI: 2.208-10.226; P <0.001), procalcitonin level (HR: 1.946; 95% CI: 1.080-3.507; P = 0.027), and central nervous system symptoms (HR: 3.257; 95% CI, 1.628-6.513; P = 0.001) were independent risk factors for mortality in SFTS patients. According to a receiver operating characteristic curve analysis, a BAR with an area under the curve of 0.913 (95% CI: 0.873-0.953; P <0.001), a sensitivity of 76.7%, and a specificity of 90.4% showed better predictive performance for fatal outcomes than other classical indicators reported. The Kaplan-Meier survival curve confirmed that an increased BAR was linked with an unfavorable prognosis in SFTS patients (P <0.001 by log-rank test). In conclusion, the results indicate that high BAR levels are markedly related to substandard outcomes and are a reliable and readily accessible predictor of fatal outcomes in SFTS patients.

S100A9-/- alleviates LPS-induced acute lung injury by regulating M1 macrophage polarization and inhibiting pyroptosis via the TLR4/MyD88/NFκB signaling axis.

Acute lung injury (ALI) is characterized by pulmonary diffusion abnormalities that may progress to multiple-organ failure in severe cases. There are limited effective treatments for ALI, which makes the search for new therapeutic avenues critically important. Macrophages play a pivotal role in the pathogenesis of ALI. The degree of macrophage polarization is closely related to the severity and prognosis of ALI, and S100A9 promotes M1 polarization of macrophages. The present study assessed the effects of S100A9-gene deficiency on macrophage polarization and acute lung injury. Our cohort study showed that plasma S100A8/A9 levels had significant diagnostic value for pediatric pneumonia and primarily correlated with monocyte-macrophages and neutrophils. We established a lipopolysaccharide (LPS)-induced mouse model of acute lung injury and demonstrated that knockout of the S100A9 gene mitigated inflammation by suppressing the secretion of pro-inflammatory cytokines, reducing the number of inflammatory cells in the bronchoalveolar lavage fluid, and inhibiting cell apoptosis, which ameliorated acute lung injury in mice. The in vitro and in vivo mechanistic studies demonstrated that S100A9-gene deficiency inhibited macrophage M1 polarization and reduced the levels of pulmonary macrophage chemotactic factors and inflammatory cytokines by suppressing the TLR4/MyD88/NF-κB signaling pathway and reversing the expression of the NLRP3 pyroptosis pathway, which reduced cell death. In conclusion, S100A9-gene deficiency alleviated LPS-induced acute lung injury by inhibiting macrophage M1 polarization and pyroptosis via the TLR4/MyD88/NFκB pathway, which suggests a potential therapeutic strategy for the treatment of ALI.

Epidemiological Features and Impact of High Glucose Level on Virulence Gene Expression and Serum Resistance of Klebsiella pneumoniae Causing Liver Abscess in Diabetic Patients.

Purpose: Klebsiella pneumoniae (K. pneumoniae) is a Gram-negative bacterium that is predominantly associated with liver abscesses in global diabetic patients. High levels of glucose in the surrounding of K. pneumonia increase its pathogenicity including capsular polysaccharide (CPS) and fimbriae. Other important virulent factors include outer membrane protein A (ompA) and regulator mucoid phenotype A (rmpA). The objective of this investigation was to elucidate the effects of high glucose on rmpA and ompA gene expression and serum resistance of K. pneumoniae causing liver abscess. Patients and Methods: The clinical history of 57 patients suffering from K. pneumoniae-caused liver abscesses (KLA) was acquired and their clinical and laboratory manifestations in the presence or absence of diabetes were analyzed. The antimicrobial susceptibility, serotypes, and virulence genes were tested. Clinical isolates of 3 serotype-K1 hypervirulent K. pneumoniae (hvKP) were used to detect the effect of exogenous high glucose on rmpA, ompA, and clbB genes expression, and bacterial serum resistance. Results: KLA patients with diabetes showed higher C-reactive protein (CRP) compared to non-diabetic KLA patients. Furthermore, the diabetic group showed increased incidences of sepsis and invasive infections, and their length of hospital stay was also prolonged. Pre-incubation of K. pneumoniae in high glucose (0.5%) concentration up-regulated rmpA, ompA, and clbB genes expression. However, cAMP supplementation, which was inhibited by environmental glucose, reversed the increase of rmpA and ompA in a cAMP-dependent manner. Moreover, hvKP strains incubated in high glucose also exhibited enhanced protection from serum killing. Conclusion: High glucose levels reflected by poor glycemic control has increased gene expression of rmpA and ompA in hvKP by the cAMP signaling pathway and enhanced its resistance to serum killing, thus providing a new and reasonable explanation for the high incidences of sepsis and invasive infections in KLA patients with diabetes.

A follow-up study on the recovery and reinfection of Omicron COVID-19 patients in Shanghai, China.

Limited follow-up data is available on the recovery of Omicron COVID-19 patients after acute illness. It is also critical to understand persistence of neutralizing antibody (NAb) and of T-cell mediated immunity and the role of hybrid immunity in preventing SARS-CoV-2 reinfection. This prospective cohort study included Omicron COVID-19 individuals from April to June 2022 in Shanghai, China, during a large epidemic caused by the Omicron BA.2 variant. A total of 8945 patients from three medical centres were included in the follow up programme from November 2022 to February 2023. Of 6412 individuals enrolled for the long COVID analysis, 605 (9.4%) individuals experienced at least one sequelae, mainly had fatigue and mental symptoms specific to Omicron BA.2 infection compared with other common respiratory tract infections. During the second-visit, 548 (12.1%) cases of Omicron reinfection were identified. Hybrid immunity with full and booster vaccination had reduced risk of SARS-CoV-2 reinfection by 0.29-fold (95% CI: 0.63-0.81) and 0.23-fold (95% CI: 0.68-0.87), respectively. For 469 participants willing to the hospital during the first visit, those who received full (72 [IQR, 36-156]) or booster (64 [IQR, 28-132]) vaccination had significantly higher neutralizing antibody titers than those with incomplete vaccination (36 [IQR, 16-79]). Moreover, non-reinfection cases had higher neutralizing antibody titers (64 [IQR, 28-152]) compared to reinfection cases (32 [IQR, 20-69]).

Tim-3 Expression Causes NK Cell Dysfunction in Type 2 Diabetes Patients.

Type 2 diabetes mellitus (T2DM) is characterized by high blood glucose levels and chronic low-grade inflammation. It shows a strong association with obesity and immune dysfunction, which makes T2DM patients more susceptible to infectious diseases. NK cells play an important role in pathogen control and tumor surveillance. However, whether NK cell distribution and functional status are altered in T2DM is unclear. To address this issue, we compared surface receptor expression and cytokine production between peripheral blood NK cells from 90 T2DM patients and 62 age- and sex-matched healthy controls. We found a significantly lower frequency and absolute number of NK cells in patients than in controls. Interestingly, the expression of inhibitory receptor Tim-3 was significantly increased, while the expression of the activating receptor NKG2D was significantly decreased, in T2DM NK cells. Both TNF-α secretion and degranulation capacity (evidenced by CD107a expression) were dampened in NK cells from patients. The expression of Tim-3 on NK cells correlated positively with both HbA1c and fasting blood glucose levels and negatively with the percentage and absolute number of total NK cells and was associated with increased NK cell apoptosis. In addition, Tim-3 expression on NK cells negatively correlated with TNF-α production, which could be restored by blocking Galectin-9/Tim-3 pathway. Our results suggest that NK cell dysfunction secondary to augmented Tim-3 expression occurs in T2DM patients, which may partly explain their increased susceptibility to cancer and infectious disease.

Potential Biomarkers and Drugs for Nanoparticle-Induced Cytotoxicity in the Retina: Based on Regulation of Inflammatory and Apoptotic Genes.

The eye is a superficial organ directly exposed to the surrounding environment. Thus, the toxicity of nanoparticle (NP) pollutants to the eye may be potentially severer relative to inner organs and needs to be monitored. However, the cytotoxic mechanisms of NPs on the eyes remain rarely reported. This study was to screen crucial genes associated with NPs-induced retinal injuries. The gene expression profiles in the retina induced by NPs [GSE49371: Au20, Au100, Si20, Si100; GSE49048: presumptive therapeutic concentration (PTC) TiO2, 10PTC TiO2] and commonly used retinal cell injury models (optic nerve injury procedure: GSE55228, GSE120257 and GSE131486; hypoxia exposure: GSE173233, GSE151610, GSE135844; H2O2 exposure: GSE122270) were obtained from the Gene Expression Omnibus database. A total of 381 differentially expressed genes (including 372 mRNAs and 9 lncRNAs) were shared between NP exposure and the optic nerve injury model when they were compared with their corresponding controls. Function enrichment analysis of these overlapped genes showed that Tlr2, Crhbp, Ccl2, Cxcl10, Fas, Irf8, Socs3, Stat3, Gbp6, Casp1 and Syk were involved in inflammatory- and apoptotic-related processes. Protein-protein interaction network analysis revealed eight of them (Tlr2, Ccl2, Cxcl10, Irf8, Socs3, Stat3, Casp1 and Syk) were hub genes. Moreover, Socs3 could interact with upstream Stat3 and downstream Fas/Casp1/Ccl2/Cxcl10; Irf8 could interact with upstream Tlr2, Syk and downstream Cxcl10. Competing endogenous RNAs network analysis identified Socs3, Irf8, Gdf6 and Crhbp could be regulated by lncRNAs and miRNAs (9330175E14Rik-mmu-miR-762-Socs3, 6430562O15Rik-mmu-miR-207-Irf8, Gm9866-mmu-miR-669b-5p-Gdf6, 4933406C10Rik-mmu-miR-9-5p-Crhbp). CMap-CTD database analyses indicated the expression levels of Tlr2, Ccl2, Cxcl10, Fas, Irf8, Socs3, Stat3, Gbp6, Casp1 and Syk could be reversed by folic acid. Crhbp and Gdf6 were also verified to be downregulated, while Tlr2, Ccl2, Irf8, Socs3 and Stat3 were upregulated in hypoxia/H2O2-induced retinal injury models. Hereby, our findings suggest that Crhbp, Irf8, Socs3 and Gdf6 as well as their upstream mRNAs, lncRNAs and miRNAs may be potential monitoring biomarkers and therapeutic targets for NP-induced retinal injuries. Folic acid supplementation may be a preventive and therapeutic approach.

Vitamin Supplementation Protects against Nanomaterial-Induced Oxidative Stress and Inflammation Damages: A Meta-Analysis of In Vitro and In Vivo Studies.

The extensive applications of nanomaterials have increased their toxicities to human health. As a commonly recommended health care product, vitamins have been reported to exert protective roles against nanomaterial-induced oxidative stress and inflammatory responses. However, there have been some controversial conclusions in regards to this field of research. This meta-analysis aimed to comprehensively evaluate the roles and mechanisms of vitamins for cells and animals exposed to nanomaterials. Nineteen studies (seven in vitro, eleven in vivo and one in both) were enrolled by searching PubMed, EMBASE, and Cochrane Library databases. STATA 15.0 software analysis showed vitamin E treatment could significantly decrease the levels of oxidants [reactive oxygen species (ROS), total oxidant status (TOS), malondialdehyde (MDA)], increase anti-oxidant glutathione peroxidase (GPx), suppress inflammatory mediators (tumor necrosis factor-α, interleukin-6, C-reactive protein, IgE), improve cytotoxicity (manifested by an increase in cell viability and a decrease in pro-apoptotic caspase-3 activity), and genotoxicity (represented by a reduction in the tail length). These results were less changed after subgroup analyses. Pooled analysis of in vitro studies indicated vitamin C increased cell viability and decreased ROS levels, but its anti-oxidant potential was not observed in the meta-analysis of in vivo studies. Vitamin A could decrease MDA, TOS and increase GPx, but its effects on these indicators were weaker than vitamin E. Also, the combination of vitamin A with vitamin E did not provide greater anti-oxidant effects than vitamin E alone. In summary, we suggest vitamin E alone supplementation may be a cost-effective option to prevent nanomaterial-induced injuries.

Identification of Candidate lncRNA and Pseudogene Biomarkers Associated with Carbon-Nanotube-Induced Malignant Transformation of Lung Cells and Prediction of Potential Preventive Drugs.

Mounting evidence has linked carbon nanotube (CNT) exposure with malignant transformation of lungs. Long non-coding RNAs (lncRNAs) and pseudogenes are important regulators to mediate the pathogenesis of diseases, representing potential biomarkers for surveillance of lung carcinogenesis in workers exposed to CNTs and possible targets to develop preventive strategies. The aim of this study was to screen crucial lncRNAs and pseudogenes and predict preventive drugs. GSE41178 (small airway epithelial cells exposed to single- or multi-walled CNTs or dispersant control) and GSE56104 (lung epithelial cells exposed to single-walled CNTs or dispersant control) datasets were downloaded from the Gene Expression Omnibus database. Weighted correlation network analysis was performed for these two datasets, and the turquoise module was preserved and associated with CNT-induced malignant phenotypes. In total, 24 lncRNAs and 112 pseudogenes in this module were identified as differentially expressed in CNT-exposed cells compared with controls. Four lncRNAs (MEG3, ARHGAP5-AS1, LINC00174 and PVT1) and five pseudogenes (MT1JP, MT1L, RPL23AP64, ZNF826P and TMEM198B) were predicted to function by competing endogenous RNA (MEG3/RPL23AP64-hsa-miR-942-5p-CPEB2/PHF21A/BAMBI; ZNF826P-hsa-miR-23a-3p-SYNGAP1, TMEM198B-hsa-miR-15b-5p-SYNGAP1/CLU; PVT1-hsa-miR-423-5p-PSME3) or co-expression (MEG3/MT1L/ZNF826P/MT1JP-ATM; ARHGAP5-AS1-TMED10, LINC00174-NEDD4L, ARHGAP5-AS1/PVT1-NIP7; MT1L/MT1JP-SYNGAP1; MT1L/MT1JP-CLU) mechanisms. The expression levels and prognosis of all genes in the above interaction pairs were validated using lung cancer patient samples. The receiver operating characteristic curve analysis showed the combination of four lncRNAs, five pseudogenes or lncRNAs + pseudogenes were all effective for predicting lung cancer (accuracy >0.8). The comparative toxicogenomics database suggested schizandrin A, folic acid, zinc or gamma-linolenic acid may be preventive drugs by reversing the expression levels of lncRNAs or pseudogenes. In conclusion, this study highlights lncRNAs and pseudogenes as candidate diagnostic biomarkers and drug targets for CNT-induced lung cancer.

Effects of Flavonoid Supplementation on Nanomaterial-Induced Toxicity: A Meta-Analysis of Preclinical Animal Studies.

Background: Nanomaterials, widely applied in various fields, are reported to have toxic effects on human beings; thus, preventive or therapeutic measures are urgently needed. Given the anti-inflammatory and antioxidant activities, supplementation with flavonoids that are abundant in the human diet has been suggested as a potential strategy to protect against nanomaterial-induced toxicities. However, the beneficial effects of flavonoids remain inconclusive. In the present study, we performed a meta-analysis to comprehensively explore the roles and mechanisms of flavonoids for animals intoxicated with nanomaterials. Methods: A systematic literature search in PubMed, EMBASE, and Cochrane Library databases was performed up to April 2022. STATA 15.0 software was used for meta-analyses. Results: A total of 26 studies were identified. The results showed that flavonoid supplementation could significantly increase the levels of antioxidative enzymes (superoxide dismutase, catalase, glutathione, glutathione peroxidase, and glutathione-S-transferase), reduce the production of oxidative agents (malonaldehyde) and pro-inflammatory mediators (tumor necrosis factor-α, interleukin-6, IL-1ß, C-reactive protein, immunoglobulin G, nitric oxide, vascular endothelial growth factor, and myeloperoxidase), and alleviate cell apoptosis (manifested by decreases in the mRNA expression levels of pro-apoptotic factors, such as caspase-3, Fas cell surface death receptor, and Bax, and increases in the mRNA expression levels of Bcl2), DNA damage (reductions in tail length and tail DNA%), and nanomaterial-induced injuries of the liver (reduced alanine aminotransferase and aspartate aminotransferase activities), kidney (reduced urea, blood urea nitrogen, creatinine, and uric acid concentration), testis (increased testosterone, sperm motility, 17ß-hydroxysteroid dehydrogenase type, and reduced sperm abnormalities), and brain (enhanced acetylcholinesterase activities). Most of the results were not changed by subgroup analyses. Conclusion: Our findings suggest that appropriate supplementation of flavonoids may be effective to prevent the occupational detriments resulting from nanomaterial exposure.

Evaluation of the protective roles of alpha-lipoic acid supplementation on nanomaterial-induced toxicity: A meta-analysis of in vitro and in vivo studies.

Extensive exposure to nanomaterials causes oxidative stress and inflammation in various organs and leads to an increased risk of adverse health outcomes; therefore, how to prevent the toxic effects are of great concern to human. Alpha-lipoic acid (ALA) has anti-oxidant and anti-inflammatory activities, suggesting it may be effective to prevent nanomaterial-induced toxicity. However, the results obtained in individual studies remained controversial. We aimed to comprehensively evaluate the effects of ALA supplementation on nanomaterial-induced toxicity by performing a meta-analysis. Databases of PubMed, EMBASE, and Cochrane Library were searched up to May 2022. STATA 15.0 software was used for statistical analysis. Twelve studies were included. Meta-analysis of eight in vivo studies showed ALA supplementation could exert significant effects on nanomaterial-induced oxidative stress (by reducing MDA, ROS and increasing GSH, CAT, GPx, and SOD), inflammation (by downregulating NO, IgG, TNF-α, IL-6, and CRP), apoptosis (by activation of pro-apoptotic caspase-3), DNA damage (by a reduction in the tail length) and organ damage (by a decrease in the liver biomarker ALT and increases in brain neuron biomarker AChE and heart biomarker CPK). Pooled analysis of four in vitro studies indicated ALA intervention increased cell viability, decreased ROS levels, inhibited cell apoptosis and chelated metal ions. Subgroup analyses revealed changing the levels of GSH, IL-6, and metal ions were the main protective mechanisms of ALA supplementation because they were not changed by any subgroup factors. In conclusion, ALA supplementation may represent a potential strategy for the prevention of the toxicity induced by nanomaterials.

Four Immune-Related Genes (FN1, UGCG, CHPF2 and THBS2) as Potential Diagnostic and Prognostic Biomarkers for Carbon Nanotube-Induced Mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM), a highly aggressive cancer, was mainly attributed to asbestos exposure. Carbon nanotubes (CNTs) share similar negative features to asbestos, provoking concerns about their contribution to MPM. This study was used to identify genes associated with CNT-induced MPM. METHODS: Microarray datasets were available in the Gene Expression Omnibus database. The limma method was used to identify differentially expressed genes (DEGs) in CNT-exposed MeT5A cells (GSE48855) or mice (GSE51636). Weighted correlation network analysis (WGCNA) and protein-protein interaction (PPI) network construction were conducted to screen hub DEGs. The mRNA expression levels of hub DEGs were validated on MPM samples of GSE51024, GSE2549 and GSE42977 datasets, and their diagnostic efficacy was determined by receiver operating characteristic curve analysis. The prognostic values of hub DEGs were assessed using online tools based on The Cancer Genome Atlas data. Their functions were annotated by Database for Annotation, Visualization and Integrated Discovery (DAVID) enrichment and correlation with immune cells and markers. RESULTS: WGCNA identified that two modules were associated with disease status. Thirty-one common DEGs in the GSE48855 and GSE51636 datasets were overlapped with the genes in these two modules. Twenty of them had a high degree centrality (≥4) in the PPI network. Four DEGs (FN1, fibronectin 1; UGCG, UDP-glucose ceramide glucosyltransferase; CHPF2, chondroitin polymerizing factor 2; and THBS2, thrombospondin 2) could predict the overall survival, and they were confirmed to be upregulated in MPM samples compared with controls. Also, they could effectively predict the MPM risk, with an overall accuracy of >0.9. DAVID analysis revealed FN1, CHPF2 and THBS2 functioned in cell-ECM interactions; UGCG influenced glycosphingolipid metabolism. All genes were positively associated with infiltrating levels of immune cells (macrophages or dendritic cells) and the expression of the dendritic cell marker (NRP1, neuropilin 1). CONCLUSION: These four immune-related genes represent potential biomarkers for monitoring CNT-induced MPM and predicting the prognosis.

Boosting Vaccine-Elicited Respiratory Mucosal and Systemic COVID-19 Immunity in Mice With the Oral Lactobacillus plantarum.

Boosting and prolonging SARS-CoV-2 vaccine-elicited immunity is paramount for containing the COVID-19 pandemic, which wanes substantially within months after vaccination. Here we demonstrate that the unique strain of probiotic Lactobacillus plantarum GUANKE (LPG) could promote SARS-CoV-2-specific immune responses in both effective and memory phases through enhancing interferon signaling and suppressing apoptotic and inflammatory pathways. Interestingly, oral LPG administration promoted SARS-CoV-2 neutralization antibodies even 6 months after immunization. Furthermore, when LPG was given immediately after SARS-CoV-2 vaccine inoculation, specific neutralization antibodies could be boosted >8-fold in bronchoalveolar lavage (BAL) and >2-fold in sera, T-cell responses were persistent and stable for a prolonged period both in BAL and the spleen. Transcriptional analyses showed that oral application of LPG mobilized immune responses in the mucosal and systemic compartments; in particular, gut-spleen and gut-lung immune axes were observed. These results suggest that LPG could be applied in combination with SARS-CoV-2 vaccines to boost and prolong both the effective and memory immune responses in mucosal and systemic compartments, thereby improving the efficacy of SARS-CoV-2 vaccination.

Exploration of a Sequential Gp140-Gp145 Immunization Regimen with Heterologous Envs to Induce a Protective Cross-Reactive HIV Neutralizing Antibody Response In Non-human Primates.

Raising a heterologous tier 2 neutralizing antibody (nAb) response remains a daunting task for HIV vaccine development. In this study, we explored the utility of diverse HIV-1 envelope (Env) immunogens in a sequential immunization scheme as a solution to this task. This exploration stemmed from the rationale that gp145, a membrane-bound truncation form of HIV Env, may facilitate the focusing of induced antibody response on neutralizing epitopes when sequentially combined with the soluble gp140 form as immunogens in a prime-boost mode. We first showed that gp140 DNA prime-gp145 Tiantan vaccinia (TV) boost likely represents a general format for inducing potent nAb response in mice. However, when examined in rhesus macaque, this modality showed little effectiveness. To improve the efficacy, we extended the original modality by adding a strong protein boost, namely native-like SOSIP.664 trimer displayed on ferritin-based nanoparticle (NP), which was generated by a newly developed click approach. The resulting three-immunization regimen succeeded in eliciting tier-2 nAb response with substantial breadth when implemented in rhesus macaque over a short 8-week schedule. Importantly, the elicited nAb response was able to effectively contain viremia upon a heterologous SHIV challenge. Collectively, our studies highlighted that diversification of Env immunogens, in both types and formulations, under the framework of a sequential immunization scheme might open new opportunity toward HIV vaccine development.

A human cell-based SARS-CoV-2 vaccine elicits potent neutralizing antibody responses and protects mice from SARS-CoV-2 challenge.

To curb the pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), multiple platforms have been employed toward a safe and highly effective vaccine. Here, we develop a novel cell-based vaccine candidate, namely K562-S, by utilizing human cell K562 as a cellular carrier to display Spike (S) protein of SARS-CoV-2 on the membrane. Analogous to the traditional inactivated vaccine, K562-S cells can be propagated to a large scale by culturing and completely lose their viability after exposure to X-ray irradiation or formalin. We in turn demonstrated high immunogenicity of formalin-inactivated K562-S vaccine in both mouse and non-human primates and its protective efficacy in mice. In mice, immunization with inactivated K562-S vaccines can elicit potent neutralizing antibody (nAb) responses persisting longer than 5 months. We consequently showed in a hACE2 mouse model of SARS-CoV-2 infection that a two-shot vaccination with adjuvanted K562-S rendered greater than 3 log reduction in viral lung load and concomitant ameliorated lung pathology. Of importance, the administration of the same regimen in non-human primates was able to induce a neutralizing antibody titer averaging three-fold higher relative to human convalescent serum. These results together support the promise of K562-based, S-protein-expressing vaccines as a novel vaccination approach against SARS-CoV-2. Importantly, with a powerful capacity to carry external genes for cell-based vectors, this platform could rapidly generate two- and multiple-valent vaccines by incorporating SARS-CoV-2 mutants, SARS-CoV, or MERS-CoV.

A Systemic Prime-Intrarectal Pull Strategy Raises Rectum-Resident CD8+ T Cells for Effective Protection in a Murine Model of LM-OVA Infection.

As the entry sites of many pathogens such as human immunodeficiency virus (HIV), mucosal sites are defended by rapidly reacting resident memory T cells (TRM). TRMs represent a special subpopulation of memory T cells that persist long term in non-lymphoid sites without entering the circulation and provide the "sensing and alarming" role in the first-line defense against infection. The rectum and vagina are the two primary mucosal portals for HIV entry. However, compared to vaginal TRM, rectal TRM is poorly understood. Herein, we investigated the optimal vaccination strategy to induce rectal TRM. We identified an intranasal prime-intrarectal boost (pull) strategy that is effective in engaging rectal TRM alongside circulating memory T cells and demonstrated its protective efficacy in mice against infection of Listeria monocytogenes. On the contrary, the same vaccine delivered via either intranasal or intrarectal route failed to raise rectal TRM, setting it apart from vaginal TRM, which can be induced by both intranasal and intrarectal immunizations. Moreover, intramuscular prime was also effective in inducing rectal TRM in combination with intrarectal pull, highlighting the need of a primed systemic T cell response. A comparison of different pull modalities led to the identification that raising rectal TRM is mainly driven by local antigen presence. We further demonstrated the interval between prime and boost steps to be critical for the induction of rectal TRM, revealing circulating recently activated CD8+ T cells as the likely primary pullable precursor of rectal TRM. Altogether, our studies lay a new framework for harnessing rectal TRM in vaccine development.

IFN-κ suppresses the replication of influenza A viruses through the IFNAR-MAPK-Fos-CHD6 axis.

Type I interferons (IFNs) are the first line of defense against viral infection. Using a mouse model of influenza A virus infection, we found that IFN-κ was one of the earliest responding type I IFNs after infection with H9N2, a low-pathogenic avian influenza A virus, whereas this early induction did not occur upon infection with the epidemic-causing H7N9 virus. IFN-κ efficiently suppressed the replication of various influenza viruses in cultured human lung cells, and chromodomain helicase DNA binding protein 6 (CHD6) was the major effector for the antiviral activity of IFN-κ, but not for that of IFN-α or IFN-ß. The induction of CHD6 required both of the type I IFN receptor subunits IFNAR1 and IFNAR2, the mitogen-activated protein kinase (MAPK) p38, and the transcription factor c-Fos but was independent of signal transducer and activator of transcription 1 (STAT1) activity. In addition, we showed that pretreatment with IFN-κ protected mice from lethal influenza viral challenge. Together, our findings identify an IFN-κ-specific pathway that constrains influenza A virus and provide evidence that IFN-κ may have potential as a preventative and therapeutic agent against influenza A virus.