Outcomes of novel coronavirus disease 2019 (COVID-19) infection in 107 patients with cancer from Wuhan, China.

BACKGROUND: Patients with cancer have a higher risk of coronavirus disease 2019 (COVID-19) than noncancer patients. The authors conducted a multicenter retrospective study to investigate the clinical manifestations and outcomes of patients with cancer who are diagnosed with COVID-19. METHODS: The authors reviewed the medical records of hospitalized patients who were treated at 5 hospitals in Wuhan City, China, between January 5 and March 18, 2020. Clinical parameters relating to cancer history (type and treatment) and COVID-19 were collected. The primary outcome was overall survival (OS). Secondary analyses were the association between clinical factors and severe COVID-19 and OS. RESULTS: A total of 107 patients with cancer were diagnosed with COVID-19, with a median age of 66 years (range, 37-98 years). Lung (21 patients; 19.6%), gastrointestinal (20 patients; 18.7%), and genitourinary (20 patients; 18.7%) cancers were the most common cancer diagnoses. A total of 37 patients (34.6%) were receiving active anticancer treatment when diagnosed with COVID-19, whereas 70 patients (65.4%) were on follow-up. Overall, 52.3% of patients (56 patients) developed severe COVID-19; this rate was found to be higher among patients receiving anticancer treatment than those on follow-up (64.9% vs 45.7%), which corresponded to an inferior OS in the former subgroup of patients (hazard ratio, 3.365; 95% CI, 1.455-7.782 [P = .005]). The detrimental effect of anticancer treatment on OS was found to be independent of exposure to systemic therapy (case fatality rate of 33.3% [systemic therapy] vs 43.8% [nonsystemic therapy]). CONCLUSIONS: The results of the current study demonstrated that >50.0% of infected patients with cancer are susceptible to severe COVID-19. This risk is aggravated by simultaneous anticancer treatment and portends for a worse survival, despite treatment for COVID-19.

Expression of toll-like receptors and their regulatory roles in murine cardiac telocytes.

Telocytes, newly discovered in the last decade, are interstitial cells found in numerous organs, with multiple proposed potential biological functions. Toll-like receptors (TLRs) play an important role in innate and adaptive immunity by recognizing pathogen-associated molecular patterns (PAMPs). However, it is still unknown whether telocytes express these innate receptors. We sought to determine the expression and role of TLRs in telocytes. In our study, we primarily detected TLR1-9 expression in telocytes. The proliferation, apoptosis and immunoregulatory activity of telocytes activated with or without TLR ligands were determined. Our results showed that purified telocytes expressed TLR2, TLR3 and TLR5. In particular, telocytes expressed high levels of TLR2 as observed using flow cytometry. When we stimulated telocytes with TLR2 or TLR3 agonists (Pam3CSK4, PolyI:C), iNOS expression was greatly increased after Pam3CSK4 treatment. Additionally, telocyte proliferation was reduced and cell apoptosis was increased after TLR agonist stimulation. A co-culture experiment showed that supernatant from telocytes pretreated with Pam3CSK4 inhibited T cell activation much more than that from untreated telocytes and this effect was mediated by iNOS. Overall, our results demonstrated TLR expression on telocytes for the first time and provided evidence of an immunoregulatory role of telocytes, indicating their clinical potential.

A systematic analysis of the resistance and sensitivity of HER2YVMA receptor tyrosine kinase mutant to tyrosine kinase inhibitors in HER2-positive lung cancer.

Human epidermal growth factor receptor 2 (HER2) has become a well-established target for the treatment of HER2-positive lung cancer. However, a frequently observed in-frame mutation that inserts amino acid quadruplex Tyr776-Val777-Met778-Ala779 at G776 (G776(YVMA)) in HER2 kinase domain can cause drug resistance and sensitivity, largely limiting the application of reversible tyrosine kinase inhibitors in lung cancer therapy. A systematic investigation of the intermolecular interactions between the HER2(YVMA) mutant and clinical small-molecule inhibitors would help to establish a complete picture of drug response to HER2 G776(YVMA) insertion in lung cancer, and to design new tyrosine kinase inhibitors with high potency and selectivity to target the lung cancer-related HER2(YVMA) mutant. Here, we combined homology modeling, ligand grafting, structure minimization, molecular simulation and binding affinity analysis to profile a number of tyrosine kinase inhibitors against the G776(YVMA) insertion in HER2. It is found that the insertion is far away from HER2 active pocket and thus cannot contact inhibitor ligand directly. However, the insertion is expected to induce marked allosteric effect on some regions around the pocket, including A-loop and hinges connecting between the N- and C-lobes of HER2 kinase domain, which may exert indirect influence to inhibitor binding. Most investigated inhibitors exhibit weak binding strength to both wild-type and mutant HER2, which can be attributed to steric hindrance that impairs ligand compatibility with HER2 active pocket. However, the cognate inhibitor lapatinib and the non-cognate inhibitor bosutinib were predicted to have low affinity for wild-type HER2 but high affinity for HER2(YVMA) mutant, which was confirmed by subsequent kinase assay experiments; the inhibitory potencies of bosutinib against wild-type and mutant HER2 were determined to be IC(50) > 1000 and =27 nM, respectively, suggesting that the bosutinib might be exploited as a selective inhibitor for mutant over wild-type HER2. Structural examination revealed that formation of additional non-bonded interactions such as hydrogen bonds and hydrophobic contacts with HER2 A-loop region due to G776(YVMA) insertion is the primary factor to improve bosutinib affinity upon the mutation.

Fragment-Fusion Transformer: Deep Learning-Based Discretization Method for Continuous Single-Cell Raman Spectral Analysis.

Raman spectroscopy has become an important single-cell analysis tool for monitoring biochemical changes at the cellular level. However, Raman spectral data, typically presented as continuous data with high-dimensional characteristics, is distinct from discrete sequences, which limits the application of deep learning-based algorithms in data analysis due to the lack of discretization. Herein, a model called fragment-fusion transformer is proposed, which integrates the discrete fragmentation of continuous spectra based on their intrinsic characteristics with the extraction of intrafragment features and the fusion of interfragment features. The model integrates the intrinsic feature-based fragmentation of spectra with transformer, constructing the fragment transformer block for feature extraction within fragments. Interfragment information is combined through the pyramid design structure to improve the model's receptive field and fully exploit the spectral properties. During the pyramidal fusion process, the information gain of the final extracted features in the spectrum has been enhanced by a factor of 9.24 compared to the feature extraction stage within the fragment, and the information entropy has been enhanced by a factor of 13. The fragment-fusion transformer achieved a spectral recognition accuracy of 94.5%, which is 4% higher compared to the method without fragmentation and fusion processes on the test set of cell Raman spectroscopy identification experiments. In comparison to common spectral classification models such as KNN, SVM, logistic regression, and CNN, fragment-fusion transformer has achieved 4.4% higher accuracy than the best-performing CNN model. Fragment-fusion transformer method has the potential to serve as a general framework for discretization in the field of continuous spectral data analysis and as a research tool for analyzing the intrinsic information within spectra.

WSS25 inhibits Dicer, downregulating microRNA-210, which targets Ephrin-A3, to suppress human microvascular endothelial cell (HMEC-1) tube formation.

WSS25 is a sulfated polysaccharide that inhibits angiogenesis. However, the mechanism underlying the regulation of angiogenesis by WSS25 is not well understood. Using microRNA (miRNA) microarray analysis, a total of 25 miRNAs were found to be upregulated and 12 (including miR-210) downregulated by WSS25 in human microvascular endothelial cells (HMEC-1). Interestingly, Dicer, a key enzyme for miRNA biosynthesis, was downregulated by WSS25 in HMEC-1 cells. Further studies indicated that HMEC-1 cell tube formation and miR-210 expression were suppressed while Ephrin-A3 expression was enhanced by the silencing of Dicer. In contrast, HMEC-1 cell tube formation and miR-210 expression were induced while Ephrin-A3 expression was suppressed by Dicer overexpression. Moreover, miR-210 was downregulated while Ephrin-A3 was upregulated by WSS25 in HMEC-1 cells. HMEC-1 cell migration and tube formation were arrested, while Ephrin-A3 expression was augmented by anti-miR-210. In addition, HMEC-1 cell tube formation was significantly attenuated or augmented when Ephrin-A3 was overexpressed or silenced, respectively. Nevertheless, the tube formation blocked by WSS25 could be partially rescued by manipulation of Dicer, miR-210 and Ephrin-A3. These results suggest a new pathway whereby WSS25 inhibits angiogenesis via suppression of Dicer, leading to downregulation of miR-210 and upregulation of Ephrin-A3.

Endogenous stimulus-controlled estradiol@AIEgen-based covalent organic framework for reduction of myocardial ischemia/reperfusion injury.

ATP stimulus-responsive tetrahedral DNA-gated fluorescent covalent organic frameworks (COFs) were developed for estradiol (E2) delivery and controllable release. The fluorescent COFs with an efficient E2 loading showed great potential against myocardial ischemia and reperfusion injury.

[Expression and effect of TIGIT in peripheral blood CD56+ T cells of patients with rheumatoid arthritis].

Objective To investigate the proportional change of CD56+ T cells in peripheral blood of patients with rheumatoid arthritis (RA) and the expression of T cell immunoglobulin and immune receptor tyrosine inhibitory motif domain (TIGIT) on the surface of CD56+ T cells, and to explore the effect of TIGIT on CD56+ T cell function in RA. Methods Fifty patients with RA and twenty healthy controls were selected. Flow cytometry was used to determine the proportion of CD56+ T cells in peripheral blood, and the correlation between the resulting cell ratio and clinical indicators of the disease was analyzed. Flow cytometry was used to measure the expression level of TIGIT in peripheral blood CD56+ T cells in RA patients. Density gradient centrifugation was used to isolate peripheral blood mononuclear cells which were subsequently cultured in vitro. The proportion of CD56+ T cells expressing Interferon-γ (IFN-γ) and Interleukin-17A (IL-17A) in peripheral blood of RA patients were measured. The differential expression of IFN-γ and IL-17A in TIGIT- CD56+ T cells and TIGIT+ CD56+ T cells was investigated. The serum IL-17A levels in RA patients were assayed by ELISA. Results Compared with the healthy controls, the proportion of CD56+ T cells in peripheral blood was reduced in RA patients, and the proportion of CD56+ T cells expressing IL-17A was significantly reduced; Serum IL-17A concentration was elevated in RA patients. CD56+ T cells in RA patients were with higher expression of TIGIT molecules, and IFN-γ was mainly derived from TIGIT- CD56+ T cells. There was no significant difference between the proportion of TIGIT- CD56+ T cells and TIGIT+ CD56+ T cells expressing IL-17A. Conclusion Abnormal expression of TIGIT affects cytokine secretion function of CD56+ T cells, which in turn participates in the RA disease progression. And IFN-γ is mainly derived from TIGIT- CD56+ T cells. However, TIGIT may not affect the IL-17A secretion level of CD56+ T cells.

Unveiling the Influence of a High-Fat Meal on the Pharmacokinetics of Oral Globalagliatin, A Glucokinase Activator, in Healthy Chinese Volunteers.

INTRODUCTION: Glucokinase (GK) plays a pivotal role in maintaining glucose homeostasis; globalagliatin, a newly developed drug, is a GK activator (GKA). This study constitutes a randomized, open-label, two-cycle, two-crossover, single-dose, phase I clinical trial conducted at a single center with healthy Chinese volunteers, aiming to examine the influence of a high-fat meal on the pharmacokinetics (PK) of orally administered globalagliatin. METHODS: Twenty-four healthy volunteers were randomly divided into two groups, with a washout period of 16 days between the two cycles. The first cycle involved Group 1 volunteers who were orally administered globalagliatin 80 mg with 240 mL of water while fasting on Day 1. In contrast, Group 2 volunteers began oral administration of globalagliatin 80 mg with 240 mL of water, 30 min after consuming a high-fat meal (where high-fat content contributed to 54% of the total calories; the high-calorie meal amounted to 988.4 kcal). After the washout period, both groups of volunteers entered the second cycle of drug administration, with meals and medication being swapped on Day 17. Each volunteer collected blood samples at the following time points: 0 h (within 1 h before administration), and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, and 168 h after administration on both trial Day 1 and Day 17. The primary and secondary PK parameters were collected. The validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was used to determine the concentration of globalagliatin in collected plasma samples, and the results were analyzed using Phoenix WinNonlin software. Safety evaluation was conducted by detecting or observing various adverse events (AEs) and serious AEs (SAEs). RESULTS: All 24 healthy Chinese volunteers enrolled completed the study and underwent PK analysis. The maximum concentration (Cmax; ng/mL), area under the plasma concentration-time curve (AUC) from time zero to time of the last quantifiable concentration (AUCt; h·ng/mL), and AUC from time zero extrapolated to infinity (AUC∞; h·ng/mL) of fasting administration were 22.35 ± 7.02, 725.74 ± 303.04, and 774.07 ± 343.89, respectively, while the Cmax, AUCt, and AUC∞ administered after a high-fat meal were 28.95 ± 12.60, 964.84 ± 333.99, and 1031.28 ± 392.80, respectively. The geometric mean ratios of Cmax, AUCt, and AUC∞ for high-fat meal/fasting administration of globalagliatin were 124.81%, 135.24%, and 135.42%, respectively, with 90% confidence intervals of 109.97-141.65, 124.24-147.20, and 124.42-147.39, respectively. Compared with the fasting state, healthy volunteers who consumed a high-fat meal showed a 24.8% increase in Cmax, a 35.2% increase in AUCt, and a 35.4% increase in AUC∞. The geometric mean of Tmax was 4.69 h under fasting conditions and 5.93 h in a high-fat state, with a median of 4.98 h. Among the 24 enrolled volunteers, 9 cases (37.5%) had 11 AEs, and 6 cases (25.0%) had 7 adverse drug reactions (ADRs) after medication, all of which were cured or improved without taking any treatment measures. There were no SAEs in this study, no volunteers withdrew from the study due to AEs or ADRs, and no hypoglycemic events occurred during the trial. CONCLUSION: A high-fat meal increased the Cmax, AUCt, and AUC∞ of globalagliatin compared with fasting conditions in healthy Chinese adult volunteers. Meanwhile, globalagliatin showed favorable safety and tolerability under fasting or high-fat meal conditions.

Heparin impairs angiogenesis through inhibition of microRNA-10b.

Heparin, which has been used as an anticoagulant drug for decades, inhibits angiogenesis, whereas thrombin promotes tumor-associated angiogenesis. However, the mechanisms underlying the regulation of angiogenesis by heparin and thrombin are not well understood. Here, we show that microRNA-10b (miR-10b) is down-regulated by heparin and up-regulated by thrombin in human microvascular endothelial cells (HMEC-1). Overexpression of miR-10b induces HMEC-1 cell migration, tube formation, and angiogenesis, and down-regulates homeobox D10 (HoxD10) expression via direct binding of miR-10b to the putative 3' UTR of HoxD10. In addition, HMEC-1 cell migration and tube formation are induced by HoxD10 knockdown, whereas angiogenesis is arrested when HoxD10 expression is increased after anti-miR-10b or heparin treatments. Furthermore, expression of miR-10b and its transcription factor Twist are up-regulated by thrombin, whereas HoxD10 expression is impaired by thrombin. Using quartz crystal microbalance analysis, we show that heparin binds to thrombin, thereby inhibiting thrombin-induced expression of Twist and miR-10b. However, the expression of miR-10b is not attenuated by heparin any more after thrombin expression is silenced by its siRNA. Interestingly, we find that heparin attenuates miR-10b expression and induces HoxD10 expression in vivo to inhibit angiogenesis and impair the growth of MDA-MB-231 tumor xenografts. These results provide insight into the molecular mechanism by which heparin and thrombin regulate angiogenesis.

Structure of a ß-glucan from Grifola frondosa and its antitumor effect by activating Dectin-1/Syk/NF-κB signaling.

A soluble homogeneous ß-glucan, GFPBW1, with a molecular mass of 300 kDa was purified from the fraction of the fruit bodies of Grifola frondosa extracted with 5% NaOH. Using various methods, such as infrared spectroscopy, NMR, methylation and monosaccharide composition analysis, its structure was determined to be a ß-D-(1-3)-linked glucan backbone with a single ß-D-(1-6)-linked glucopyranosyl residue branched at C-6 on every third residue. It induced TNF-α and IL-6 production and the activation of Syk and NF-κB signaling in resident peritoneal macrophages from ICR mice, which could be significantly inhibited by the blocking reagent laminarin. A competitive phagocytosis assay with FITC-zymosan indicated that GFPBW1 could bind to DC-associated C-type lectin 1 (Dectin-1). The TNF-α secretion and activation of Syk/NF-κB signaling triggered by GFPBW1 were enhanced in RAW264.7 cells overexpressing wild but not mutant (Δ38 and Y15S) Dectin-1. Furthermore, GFPBW1 potentiated the Concanavalin A-induced proliferative response of splenocytes and inhibited Sarcoma-180 growth allografted in ICR mice but not in immunodeficient BALB/c nu/nu mice. These results suggested that the antitumor activity of GFPBW1 was partially associated with the activation of macrophages via the Dectin-1/Syk/NF-κB signaling pathway. This molecule could be a promising biological response modifier with clear application for antitumor therapies.

TLR2 agonist promotes myeloid-derived suppressor cell polarization via Runx1 in hepatocellular carcinoma.

Myeloid-derived suppressor cells (MDSCs) play a critical role in maintaining the tumor immune microenvironment; thus, the promotion of MDSC polarization will improve immunotherapies for cancers. However, the mechanisms involved in controlling MDSC polarization in hepatocellular carcinoma remain largely unclear. In this study, we found that injection of Pam3CSK4 attenuated the process of tumor growth, along with reduction of MDSC and recovery of T cell function. Moreover, Pam3CSK4 promoted MDSC polarization by targeting Runx1. Runx1 inhibitor reversed the therapeutic effect of Pam3CSK4 by increasing tumor size and weight and decreasing the survival rate of tumor mice. In addition, targeting Runx1 reduced the expression of CD11c, F4/80, CD80/CD86 and MHC-II in MDSC after Pam3CSK4 stimulation in vivo and in vitro. MDSC also exhibited consistent changes with increasing reactive oxygen species (ROS) production after Pam3CSK4 and Ro5-3335 treatment. RNA sequence data revealed that tfrc, steap3, and gclm were up-regulated in the Pam3CSK4/Ro5-3335 group compared with Pam3CSK4 treatment alone, suggesting that the regulatory effect of TLR2 and Runx1 on MDSC might act through the ferroptosis pathway. Overall, our study has identified a critical role for TLR2 and Runx1 in regulating the differentiation and function of MDSCs and has provided a new mechanism of controlling MDSC polarization during HCC immunotherapy.

Absorption, distribution, metabolism, and excretion of [14C]Mefuparib (CVL218), a novel PARP1/2 inhibitor, in rats.

INTRODUCTION: Mefuparib (CVL218) is a novel second-generation poly-ADP-ribose polymerase (PARP) inhibitor for cancer treatment. CVL218 can easily enter the brain. However, the transport mechanism by which CVL218 crosses the blood-brain barrier (BBB) is unknown. METHODS: (1) [14C] CVL218 metabolism in rats was traced by a liquid scintillation counter and oxidative combustion. (2) Metabolic profiles and metabolites were identified by UHPLC-ß-RAM/UHPLC-Fraction Collector and UHPLC-Q Exactive Plus MS. (3) The partition coefficient Kp,uu,brain value was simulated by two strategies. One strategy was using ACD and GastroPlus Software based on the results of intravenous administration pharmacokinetics and plasma protein-binding studies. The reliability was confirmed by comparison with another strategy (brain/plasma distribution study). RESULTS: (1) Rapid drug elimination was observed 24 h after intragastric administration. The total cumulative excretion in urine and feces within 168 h accounted for 97.15% of the dose. The cumulative radioactive dose recovery in bile was 41.87% within 72 h. The drug-related substances were extensively distributed to the tissues within 48 h. (2) M8 was the major metabolite in plasma, urine, feces and bile. (3) CVL218 exhibited high brain protein-binding rate (88.16%). The Kp,uu,brain value (8.42) simulated by the simple software strategy was similar to that of the brain/plasma distribution study (7.01). CONCLUSIONS: CVL218 is a fast-metabolizing drug and is mainly excreted in feces. The B/P ratio prediction and observation data for CVL218 were consistent. Furthermore, the Kp,uu,brain value indicated that penetration through the BBB might be mediated by uptake transporters.

Restoration of HBV-specific CD8+ T-cell responses by sequential low-dose IL-2 treatment in non-responder patients after IFN-α therapy.

Patients with chronic hepatitis B (CHB) undergoing interferon (IFN)-α-based therapies often exhibit a poor HBeAg serological response. Thus, there is an unmet need for new therapies aimed at CHB. This study comprised two clinical trials, including 130 CHB patients, who were treatment-naïve; in the first, 92 patients were systematically analyzed ex vivo for interleukin-2 receptor (IL-2R) expression and inhibitory molecules expression after receiving Peg-IFN-α-2b therapy. In our second clinical trial, 38 non-responder patients, in whom IFN-α therapy had failed, were treated with or without low-dose IL-2 for 24 weeks. We then examined the hepatitis B virus (HBV)-specific CD8+ T-cell response and the clinical outcome, in these patients. Although the majority of the participants undergoing Peg-IFN-α-2b therapy were non-responders, we observed a decrease in CD25 expression on their CD4+ T cells, suggesting that IFN-α therapy may provide a rationale for sequential IL-2 treatment without increasing regulatory T cells (Tregs). Following sequential therapy with IL-2, we demonstrated that the non-responders experienced a decrease in the numbers of Tregs and programmed cell death protein 1 (PD-1) expression. In addition, sequential IL-2 administration rescued effective immune function, involving signal transducer and activator of transcription 1 (STAT1) activation. Importantly, IL-2 therapy significantly increased the frequency and function of HBV-specific CD8+ T cells, which translated into improved clinical outcomes, including HBeAg seroconversion, among the non-responder CHB patients. Our findings suggest that sequential IL-2 therapy shows efficacy in rescuing immune function in non-responder patients with refractory CHB.

Reduced CCR6+IL-17A+Treg Cells in Blood and CCR6-Dependent Accumulation of IL-17A+Treg Cells in Lungs of Patients With Allergic Asthma.

Human regulatory T (Treg) cells play a central role in controlling allergic inflammation in the airways. A reduced number of peripheral Treg cells and decreased suppressive function have been previously reported in the pathogenesis of allergic asthma. However, the characteristic role of specific Treg cell subsets and their mechanisms in the pathogenesis of allergic asthma remain unclear. In this study, we examined the proportion of different Treg cell subsets in both healthy subjects and patients with allergic asthma using flow cytometry and single-cell RNA sequencing. The migration function of the cells was compared using cell sorting and Transwell experiments. Furthermore, two allergen-challenged mouse models and a cell transfer experiment were used to examine the role of these Treg subsets. We found that the proportion of CD25+Foxp3+CD127- Treg cells in the peripheral blood of patients with allergic asthma was lower than in those of healthy subjects. Furthermore, the circulating Treg cells expressed lower levels of CCR6 and IL-17 compared with healthy subjects. The chemokine from the airway mucosa, CCL20, was abundantly expressed, and Transwell experiments further proved that this chemokine promoted CCR6+ Treg cell migration in vitro. A mouse model induced by house dust mite (HDM) revealed that the number of CCR6+ Treg cells in the lung tissue increased remarkably. The incidence of allergic asthma may be related to an increase in Treg cells secreting IL-17 in the lung tissue. Recruited CCR6+ Treg cells are likely to differentiate into Th17-like cells under the Th17 environment present in the lungs. IL-17 derived from Th17-like cells could be associated with the pathology of allergic asthma by promoting Th17 responses, thereby favoring HDM-induced asthma exacerbations.

An integrative drug repositioning framework discovered a potential therapeutic agent targeting COVID-19.

The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires an urgent need to find effective therapeutics for the treatment of coronavirus disease 2019 (COVID-19). In this study, we developed an integrative drug repositioning framework, which fully takes advantage of machine learning and statistical analysis approaches to systematically integrate and mine large-scale knowledge graph, literature and transcriptome data to discover the potential drug candidates against SARS-CoV-2. Our in silico screening followed by wet-lab validation indicated that a poly-ADP-ribose polymerase 1 (PARP1) inhibitor, CVL218, currently in Phase I clinical trial, may be repurposed to treat COVID-19. Our in vitro assays revealed that CVL218 can exhibit effective inhibitory activity against SARS-CoV-2 replication without obvious cytopathic effect. In addition, we showed that CVL218 can interact with the nucleocapsid (N) protein of SARS-CoV-2 and is able to suppress the LPS-induced production of several inflammatory cytokines that are highly relevant to the prevention of immunopathology induced by SARS-CoV-2 infection.

Immunomodulation Induced During Interferon-α Therapy Impairs the Anti-HBV Immune Response Through CD24+CD38hi B Cells.

Type I interferon is widely used for antiviral therapy, yet has yielded disappointing results toward chronic HBV infection. Here we identify that PEG-IFNα-2b therapy toward persistent infection in humans is a double-edged sword of both immunostimulation and immunomodulation. Our studies of this randomised trial showed persistent PEG-IFNα-2b therapy induced large number of CD24+CD38hi B cells and launched a CD24+CD38hi B cells centered immunosuppressive response, including downregulating functions of T cells and NK cells. Patients with low induced CD24+CD38hi B cells have achieved an improved therapeutic effect. Specifically, using the anti-CD24 antibody to deplete CD24+CD38hi B cells without harming other B cell subsets suggest a promising strategy to improve the therapeutic effects. Our findings show that PEG-IFNα-2b therapy toward persistent infection constitutes an immunomodulation effect, and strategies to identifying the molecular basis for the antiviral versus immunomodulatory effects of PEG-IFNα-2b to selectively manipulate these opposing activities provide an opportunity to ameliorate anti-virus immunity and control viral infection.

The expression of high-mobility group protein box 1 correlates with the progression of non-small cell lung cancer.

High-mobility group protein box 1 (HMGB1) released from dying tumor cells promotes tumor progression, on the other hand HMGB1 activates dendritic cells and triggers anti-neoplastic response of T-cells in chemotherapy and radiotherapy. HMGB1 expression is up-regulated in many kinds of tumors. To investigate HMGB1 expression in non-small cell lung cancer, 63 patients were enrolled and tumor tissues were collected with matched normal lung tissues. HMGB1 mRNA and protein levels were quantified with real-time PCR, Western blots and immunohistochemistry. The HMGB1 expression in tumor tissue was lower than in matched normal lung tissue at mRNA levels (Paired t-test, t<0.001) and the down-regulation in stage III-IV patients was also significantly greater than one in stage I-II (one-way ANOVA, p=0.005). At protein level, HMGB1 expression was also down-regulated. Low HMGB1 expression in non-small cell lung cancer may explain the poor therapeutical outcome during chemotherapy and radiotherapy.

TLR4 is essential in acute lung injury induced by unresuscitated hemorrhagic shock.

BACKGROUND: Acute lung injury (ALI) and acute respiratory distress syndrome in patients with hemorrhagic shock (HS) or resuscitation is associated with the expression of TLR4. However, the role of TLR4 in ALI induced by unresuscitated HS remains obscure. METHODS: The lung pathologic change was observed by hematoxylin and eosin staining. Interleukin-1beta and tumor necrosis factor-alpha were analyzed by enzyme-linked immunosorbent assay. Polymorphonuclear leukocyte sequestration and lung leak were analyzed by pulmonary myeloperoxidase activity and Evans blue dye. The expressions of TLR4 mRNA and protein were analyzed by reverse transcription-polymerase chain reaction and Western blot, respectively. TLR4 distribution was analyzed by immunohistochemistry. RESULTS: Lung neutrophil accumulation and microvascular permeability were significantly increased after unresuscitated HS, meanwhile, lung interleukin-1beta and tumor necrosis factor-alpha were gradually augmented. TLR4 mRNA, TLR4 distribution and TLR4 protein were also significantly increased in TLR4 wt mice, however, no above-mentioned changes appeared in TLR4 mutant mice. CONCLUSIONS: TLR4 is strongly associated with the pathogenesis of ALI induced by unresuscitated HS, which may serve as a useful therapeutic target.

[Effect of heparin upon inflammatory reaction of endotoxin-induced acute lung injury in rat].

OBJECTIVE: To investigate the effects of heparin upon inflammatory reaction and associated mechanism of endotoxin-induced acute lung injury (ALI) in rat. METHODS: Thirty-six male Sprague-Dawley rats were randomly divided into three equal groups namely: ALI group, heparin treatment group and normal control group. The ALI rats were induced by injecting endotoxin intravenously and sacrificed at 4 h after model establishment. The lung histology was scored by a modification of Smith technique. The albumin permeability of pulmonary microvascular (P(alb)) was measured by single nuclide tracer technique. Tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6) and von Willebrand factor (vWF) levels of serum were determined using commercial enzyme-linked immunosorbent assay kits. The expressions of lung tissue extacellular signal-regulated kinases (ERK)-1/2, P38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinases (JNK) were determined by Western blotting. RESULTS: The Smith lung injury score in heparin treatment group and ALI group were (5.00 +/- 1.26) and (8.00 +/- 1.09) respectively. The values were significantly higher than that of normal control group (0.67 +/- 0.52, both P < 0.01). However, the Smith lung injury score in heparin treatment group was significantly lower than that of ALI group (P < 0.01). The P(alb), TNF-alpha, IL-6 and vWF of heparin treatment group were (0.28 +/- 0.04), (1.92 +/- 0.35) microg/L, (1.22 +/- 0.13) ng/ml and (24.9 +/- 4.0) U/L respectively. The values were significantly higher than those of normal control group [0.20 +/- 0.02, (0.51 +/- 0.09) microg/L, (0.23 +/- 0.05) ng/ml and (14.0 +/- 3.0) U/L respectively, all P < 0.01] but significantly lower than those of ALI group [(0.38 +/- 0.04), (2.77 +/- 0.37) microg/L, (1.62 +/- 0.13) ng/ml and (31.8 +/- 7.5) U/L respectively, all P < 0.01]. The lung tissue levels of phospho-ERK1/2 and phospho-P38 MAPK expressions of heparin treatment group were markedly higher than those of normal control group, whereas markedly lower than those of ALI group. There was no marked difference of phospho-JNK expression in all three groups. CONCLUSION: Heparin markedly inhibits the expressions of phospho-ERK1/2 and phospho-P38 MAPK, down-regulates the inflammatory reaction, attenuates the endothelial permeability of pulmonary vasculature and significantly improves endotoxin-induced lung injury in rats.

Immunotherapy for gastric cancer: dilemmas and prospect.

Gastric cancer remains the second most common cause of cancer-related death worldwide. Because of the poor prognosis of late-stage gastric cancer patients, it is imperative to develop new strategies to improve the survival rate of this disease. Currently, immunotherapy is considered as an innovative approach for cancers such as lung cancer, gastric cancer and breast cancer. In fact, previous works have revealed promising results in this field. With further understanding of immunogenomics of gastric cancer, new immune checkpoint regulators could become more important. In addition, whole-genome sequencing and genome editing provide us with more information on the heterogeneity of gastric cancer, showing helpful tools to identify new predictive biomarkers and to achieve personalized treatment. Further research and better understanding of the functions of immune system will enhance immunotherapy treatment in the future.